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Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease soon to become the second leading cause of cancer deaths in the US. Beside surgery, current therapies have narrow clinical benefits with systemic toxicities. FOLFIRINOX is the current standard of care, one component of which is 5- Fluorouracil (5-FU), which causes serious gastrointestinal and hematopoietic toxicities and is vulnerable to resistance mechanisms. Recently, we have developed polymeric fluoropyrimidines (F10, CF10) which unlike 5-FU, are, in principle, completely converted to the thymidylate synthase inhibitory metabolite FdUMP, without generating appreciable levels of ribonucleotides that cause systemic toxicities while displaying much stronger anti-cancer activity. Here, we confirm the potency of CF10 and investigate enhancement of its efficacy through combination with inhibitors in vitro targeting replication stress, a hallmark of PDAC cells. CF10 is 308-times more potent as a single agent than 5-FU and was effective in the nM range in primary patient derived models. Further, we find that activity of CF10, but not 5-FU, is enhanced through combination with inhibitors of ATR and Wee1 that regulate the S and G2 DNA damage checkpoints and can be reversed by addition of dNTPs indicative of CF10 acting, at least in part, through inducing replication stress. Our results indicate CF10 has the potential to supersede the established benefit of 5-FU in PDAC treatment and indicate novel combination approaches that should be validated in vivo and may be beneficial in established regimens that include 5-FU.

The development of effective therapeutic strategies for triple-negative breast cancer (TNBC), an aggressive subtype with limited treatment options, remains a critical challenge. This study aimed to design and evaluate a combination therapy using chitosan nanoparticles (Cs NPs) loaded with metformin (Met) and methotrexate (MTX) as a promising approach for TNBC management. The Cs NPs exhibited an average size of 78.8 ± 25.84 nm for blank Cs NPs, 84.50 ± 22.54 nm for Met-Cs NPs, and 86.70 ± 30.90 nm for MTX-Cs NPs, with positive surface charges of 26.40 ± 1.40 mV, 28.20 ± 1.60 mV, and 14.30 ± 2.40 mV, respectively. The drug encapsulation efficiency was 88.56 ± 2.26 % for Met-Cs NPs and 97.03 ± 0.52 % for MTX-Cs NPs. The cellular uptake studies demonstrated a time-dependent increase in the accumulation of Shikonin-labeled Cs NPs in 4T1 cells. The cytotoxicity assays revealed that Met-Cs NPs and MTX-Cs NPs exhibited significantly lower IC50 values (19.85 μg/mL and 103.2 ng/mL, respectively) compared to the plain drugs at 48 h. The combination of Met-/MTX-Cs NPs showed a synergistic cytotoxic effect, inducing 50 % cell death at 15.233 μg/mL of Met and 0.166 μg/mL of MTX. In vivo studies using a 4T1 xenograft mouse model demonstrated that the combination of Met-/MTX-Cs NPs resulted in a 100 % reduction in initial tumor volume, compared to a 40 % decrease with the free drug combination. The tumor growth inhibition was 70.45 % for the Met-/MTX-Cs NPs group, significantly higher than the 33.86 % observed in the free drug combination group. The findings of this study highlight the potential of the Met-/MTX-Cs NPs combination as a novel and effective therapeutic approach for TNBC management. The enhanced therapeutic efficacy, improved safety profile, and the ability to modulate key signaling pathways make this nanoparticle-based combination therapy a promising candidate for further clinical investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The BRCA1 dysfunction and HR deficiency in TNBC are responsible for high effectiveness of DNA-damaging agents in TNBC treatment. Preclinical and clinical studies confirmed the effectiveness of cisplatin in TNBC treatment. Nevertheless, the clinical utility of cisplatin is inadequate due to severe systemic side effects and resistance development. Dual-action cisplatin (IV) prodrugs provide an excellent opportunity to improve anticancer activity, reduce toxicities and minimize chance of resistance development. Therefore, in this investigation we have synthesized cisplatin-chlorambucil (CP-CBL) prodrug and loaded it with venetoclax (VTX) in phenylboronic acid conjugated TPGS-lactide nanoparticles (TNPs) to achieve tumor-targeted drug delivery thereby reducing the therapeutic dose as well as increasing the efficacy of free cisplatin, chlorambucil and venetoclax. The TNPs possessed particle size of 143 nm, PDI 0.186 and entrapment efficiency of 63.5 % and 56.4 % for VTX and CP-CBL. The TNPs followed Higuchi release kinetic model and represented biphasic release behaviour with early burst release of drug within 2 h succeeded by sustained drug release till 72 h. Further, the TNPs showed ∼ 42 folds and ∼ 19 folds reduction in the IC 50 values compared to free CP. Also, higher cellular uptake and therefore greater apoptotic index was observed for the TNPs in comparison to the untargeted nanoparticles. The TNPs further showed higher ROS generating potential, enhanced mitochondrial membrane depolarization, higher intensity of nuclear condensation and highest level of caspase-3 expression. Moreover, a noteworthy decrease in the tumor volume was noticed in the mice treated with TNPs along with lower serum toxicity biomarker levels compared to the free drugs. Overall, the developed TNPs proved to be a promising and safer strategy for inducing triple-hit action in TNBC management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Liver cancer stands as a leading cause of cancer-related deaths globally, challenging conventional treatments due to resistance to chemotherapy and targeted therapy. Although frontline medications show initial efficacy, prolonged use often leads to resistance and harm. Current clinical strategies rely on combination therapies, but evaluating their effectiveness remains challenging., Results: To address this, we developed a hydrogel-based diffusion microfluidic platform for assessing chemosensitivity. This platform features a hydrogel-filled diffusion layer linked to liquid wells, allowing the creation of drug gradients. Tumor spheroids, cultured on the non-adhesive hydrogel surface, were exposed to single or combination drug gradients. Analysis revealed that drug efficacy, quantified by IC 50 values, could be determined from responses to single drug gradients. A novel method was introduced to assess spheroid circularity as a time-invariant index of drug efficacy. Furthermore, exposing spheroids to 2D combination drug gradients allowed intuitive visualization of their responses via a color map. This analysis identified optimal drug combinations, exhibiting superior efficacy to monotherapy., Significance: The microfluidic platform enables assessment of synergistic effects and replicates in vivo conditions, enhancing the relevance of test results. By offering a streamlined, fast, and efficient drug screening approach, this platform aims to provide insight into tumor spheroid responses to varying drug combinations, facilitating more effective clinical applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Triple-negative breast cancer (TNBC) is prone to relapse due to the lack of effective therapeutic targets. Macrophages are the most abundant immune cells in the tumor microenvironment (TME) of breast cancer. Targeting the cross-talk between macrophages and cancer cells provides a more efficient strategy for anti-tumor therapy. Toll-like receptors (TLRs) are important players involved in macrophage activation, and TLR agonists are known to play roles in cancer therapy. However, the combination strategy of TLR agonists with chemotherapy drugs is still not well characterized., Methods: RT-PCR and Western blot were used to detect the expression of TLRs. The communication between breast cancer cells and macrophages were determined by co-culture in vitro. Tumor cells proliferation and migration were investigated by MTT assay and scratch wound assay. The effects of drug combinations and toxic side effects were assessed by immunohistochemistry and Hematoxylin & Eosin staining., Results: Expression of TLR3 and TLR4 were lower in breast tumor tissues compared with adjacent normal tissues. Patients with higher TLR3 or TLR4 expression levels had a better prognosis than those with lower expression levels. TLR3/4 expression was significantly inhibited when breast cancer cells MDA-MB-231 and E0771 were conditioned-cultured with macrophages in vitro and was also inhibited by pirarubicin (THP). However, the combination of TLR agonists and THP could reverse this response and inhibit the proliferation and migration of breast cancer cells. Additionally, this combination significantly reduced the tumor volume and weight in the murine model, increased the expression of TLR3/4 in mouse breast tumors., Conclusions: Our results provide new ideas for the combination strategy of THP with TLR agonists which improves prognosis of breast cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer, the most prevalent subtype, the pathological complete response (pCR) rate after neoadjuvant chemotherapy is less than 18 %, and the survival of patients with advanced-stage disease is approximately 34 %, highlighting the critical demand for more potent therapies. Recent research has underscored the substantial therapeutic benefits of the combination of CDK4/6 inhibitors and fulvestrant (Ful) in managing HR+/HER2- breast cancer. These therapeutics not only curtail tumor proliferation but also alter the tumor immune microenvironment, suggesting novel avenues for immunotherapy for this breast cancer subtype. Flow cytometry, PCR, WB, and RNA-seq experiments revealed that the combination of the CDK4/6 inhibitor palbociclib (Pal) with Ful upregulated CCL2 in tumor cells by inducing the SASP and activating the MAPK signaling pathway. CCL2 attracts Tregs to the tumor microenvironment, where it exerts an immunosuppressive effect. By administering the CCL2 inhibitor pirfenidone, we inhibited these effects and enhanced the antitumor efficacy of Pal + Ful. Our research revealed an immunosuppressive effect of CDK4/6 inhibitors and fulvestrant and suggested that CCL2 inhibitors may be a viable approach for treating patients with advanced HR+/HER2- breast cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Clinical trials in cancer are ideally built on a foundation of sound mechanistic rationale and well-validated drug activity in relevant disease models. The screening of approved and investigational drugs in cell-based phenotypic assays can provide evidence of drug activity, but alternative screening paradigms are needed to develop and optimize multidrug combination regimens. Here, we utilize in vitro screening outcomes across a panel of lymphoma cell lines to dissect the activity of four small-molecule drugs (Venetoclax, Ibrutinib, Prednisolone, and Lenalidomide) currently under investigation within ongoing clinical trials in lymphoma. Data from multiple concentration ranges and time points show that synergistic drug combinations promote apoptosis and cytotoxicity responses at concentrations and time points that are consistent with in vivo drug exposures. To fully map the interaction landscape of these agents in relevant cell models, we developed an in vitro assay format that facilitated time-course evaluations involving concurrent multidrug exposure which further highlighted rapid, synergistic apoptosis induction as a central engine for the activity of this multicomponent targeted therapy. In addition to several instances of exceptional drug+drug synergy, the genetically similar diffuse large B cell lymphoma models also displayed substantial heterogeneity in the degree of synergism between drug pairs. A parallel survey of chemotherapies exhibited limited combination benefit, supporting recent findings that multicomponent chemotherapy outcomes are driven by individual drug activity. Collectively, these data demonstrate how in vitro drug screening data can identify multidrug combinations that exploit drug synergy to overcome the functional diversity of human malignancies., Competing Interests: Competing interests statement:The authors declare no competing interest.

An important hallmark of glioblastoma aggressiveness is its altered metabolism of glucose. This metabolic shift wherein the tumor cells employ aerobic glycolysis regardless of oxygen availability via reprogramming of mitochondrial oxidative phosphorylation is known as the Warburg effect. Previous literatures have linked this metabolic reprograming to tumor progression and glioblastoma cell proliferation making it a key target for targeted drug therapy. Based on this lacuna, the current study aimed to explore the therapeutic efficacy of the triple-drug combination of temozolomide, metformin and epigallocatechin gallate in attenuating Warburg effect and glucose uptake in glioblastoma both in vitro and in vivo. Our results showed that the triple-drug combination had significantly reduced glucose uptake and reversed the Warburg effect in glioblastoma cells and in the glioma-induced xenograft rat model. Thus, the triple-drug combination would serve as an effective therapeutic regime to hamper glioblastoma progression via altering glucose metabolism and improving the overall prognosis in patient setting., Competing Interests: Declaration of competing interest Anitha T.S reports financial support was provided by ScirosBio, Al Khatem Tower, ADGM Square, Abu Dhabi, United Arab Emirates. Anitha T.S reports a relationship with ScirosBio, Al Khatem Tower, ADGM Square, Abu Dhabi, United Arab Emirates that includes: consulting or advisory and funding grants. Madhu Subramani, Anitha T. S, Shreyas S Kuduvalli, Daisy Precilla Senthilathiban has patent #PCT application No. PCT/IB2023/054358 pending to ScirosBio, Al Khatem Tower, ADGM Square, Abu Dhabi, United Arab Emirates. ScirosBio is a UAE based, Bio-Pharmaceutical startup, engaged in research, development and commercialization of biopharmaceutical drugs majorly related to various disease indications including oncology, neurological disorders, and diabetes. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Pyrimidine analogs are part of the first-line chemotherapy regimen for gastrointestinal cancers. Trifluridine combined with tipiracil, a specific thymidine phosphorylase inhibitor, in TAS-102 has recently emerged as a potential alternative in the face of primary or secondary chemoresistance to 5-fluorouracil. Despite its promise, we report that macrophage-specific overexpression of thymidine phosphorylase results in macrophage-induced chemoresistance to TAS-102 that is insensitive to tipiracil inhibition. Furthermore, we illustrate the human-specific nature of this mechanism, as mouse macrophages do not express substantial levels of thymidine phosphorylase, which constrains the applicability of mouse models. To study the importance of macrophages in chemoresistance to trifluridine, we developed a humanized mouse model with tumor-implanted human macrophages and demonstrated their important role in treatment resistance to pyrimidine analogs. Additionally, our findings revealed that macrophages represent a significant source of thymidine phosphorylase expression, comprising over 40 % of the expressing cells, in human colorectal cancer, thereby contributing to chemoresistance., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Arnaud MILLET reports financial support was provided by INSERM. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Treatment options for advanced intra-abdominal pediatric rhabdomyosarcoma (RMS) with peritoneal sarcomatosis (PS) include cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). However, optimal dosages and combination regimens of drugs used for HIPEC are underexplored. We aimed to evaluate the efficacy of HIPEC with cisplatin, doxorubicin, and their combination in vivo., Methods: We established PS/RMS mouse model by intraperitoneally injecting RH30 cells into NOD/LtSz-scid IL2Rγ-null mice. Two weeks post xenotransplantation, mice underwent a single HIPEC procedure at 42°C for 60 minutes. Treatment groups received cisplatin (50, 100, and 150 mg/m 2 ) and doxorubicin (30, 45, and 60 mg/m 2 ), administered alone or combined. The control group underwent an intraperitoneal lavage with isotonic saline. Peritoneal cancer index (PCI) was used to quantify the extent of peritoneal tumor spread. Tissue samples were evaluated regarding proliferation (Ki-67) and apoptosis (caspase 3)., Results: Mice treated with cisplatin at 100 mg/m 2 (PCI of 3.875, p = .007) and 150 mg/m 2 (PCI of 4.556, p = .026), and doxorubicin at 30 mg/m 2 (PCI of 2.875, p < .001) and 45 mg/m 2 (PCI of 4.143, p = .021) showed reduced PCI, with the combination of cisplatin 50 mg/m 2 and doxorubicin 30 mg/m 2 showing the most prominent effect (PCI of 3.333, p < .001) compared to the control group (PCI of 8.615). Histologically, there was no difference in Ki-67 or caspase 3 expression among the groups., Conclusions: The cisplatin- and doxorubicin-based HIPEC significantly reduces peritoneal tumor dissemination in vivo. Further investigations are needed to explore the underlying molecular responses to optimize therapeutic strategies., (© 2024 Wiley Periodicals LLC.)

Background: Fruquintinib has received approval for the management of patients with chemotherapy-resistant metastatic colorectal cancer (mCRC). However, combination of fruquintinib with immune checkpoint inhibitors (ICIs) is yet to be extensively studied. This study aims to assess the clinical efficacy, safety, and prognostic indicators of treatment regimen combining fruquintinib with ICIs in mCRC patients., Methods: We analyzed data from mCRC patients who were administered fruquintinib either as a monotherapy or in conjunction with ICIs following conventional chemotherapy. Parameters such as the objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and incidence of adverse events were meticulously evaluated. Furthermore, the relationship between blood markers and patient prognosis was examined., Results: A total of 72 mCRC patients were included in this study, with a median observation period of 48 months, 19 were treated with fruquintinib alone, while 53 received a combination therapy involving fruquintinib and ICIs. The combined therapy group exhibited superior ORR and DCR compared to the fruquintinib monotherapy group. Additionally, significant improvements in OS and PFS were observed in the combined treatment group. The occurrence of adverse events was generally manageable and well-tolerated across both groups, with no significant difference in incidence rates. Notably, albumin levels were identified as a prognostic marker for PFS and OS in the univariate Cox regression analysis., Conclusions: The combination of fruquintinib with ICIs demonstrated enhanced clinical efficacy and improved survival outcomes compared to fruquintinib monotherapy in mCRC patients. The safety of the combination regimen was deemed manageable and acceptable., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The overexpression of BCL-x L is closely associated with poor prognosis in hepatocellular carcinoma (HCC). While the strategy of combination of BCL-x L and MCL-1 for treating solid tumors has been reported, it presents significant hepatotoxicity. SIAIS361034, a novel proteolysis targeting chimera (PROTAC) agent, selectively induces the ubiquitination and subsequent proteasomal degradation of BCL-x L through the CRBN-E3 ubiquitin ligase. When combined with sorafenib, SIAIS361034 showed a potent synergistic effect in inhibiting hepatocellular carcinoma development both in vitro and in vivo. Since SIAIS361034 exhibits a high degree of selectivity for degrading BCL-x L in hepatocellular carcinoma, the hepatotoxicity typically associated with the combined inhibition of BCL-x L and MCL-1 is significantly reduced, thereby greatly enhancing safety. Mechanistically, BCL-x L and MCL-1 sequester the BH3-only protein BIM on mitochondria at baseline. Treatment with SIAIS361034 and sorafenib destabilizes BIM/BCL-x L and BIM/MCL1 association, resulting in the liberation of more BIM proteins to trigger apoptosis. Additionally, we discovered a novel compensatory regulation mechanism in hepatocellular carcinoma cells. BIM can rapidly respond to changes in the balance between BCL-x L and MCL-1 through their co-transcription factor MEF2C to maintain apoptosis resistance. In summary, the combination therapy of SIAIS361034 and sorafenib represents an effective and safe approach for inhibiting hepatocellular carcinoma progression. The novel balancing mechanism may also provide insights for combination and precision therapies in the treatment of hepatocellular carcinoma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The therapeutic potential of targeting PI3K/AKT/PTEN signalling in B-cell malignancies remains attractive. Whilst PI3K-α/δ inhibitors demonstrate clinical benefit in certain B-cell lymphomas, PI3K signalling inhibitors have been inadequate in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in part, due to treatment related toxicities. Clinically, AKT inhibitors exhibit a differentiated tolerability profile offering an alternative approach for treating patients with B-cell malignancies. To explore how AKT inhibition complements other potential therapeutics in the treatment of DLBCL patients, an in vitro combination screen was conducted across a panel of DLCBL cell lines. The AKT inhibitor, capivasertib, in combination with the BCL-2 inhibitor, venetoclax, produced notable therapeutic benefit in preclinical models of DLBCL. Capivasertib and venetoclax rapidly induced caspase and PARP cleavage in GCB-DLBCL PTEN wildtype cell lines and those harbouring PTEN mutations or reduced PTEN protein, driving prolonged tumour growth inhibition in DLBCL cell line and patient derived xenograft lymphoma models. The addition of the rituximab further deepened the durability of capivasertib and venetoclax responses in a RCHOP refractory DLBCL in vivo models. These findings provide preclinical evidence for the rational treatment combination of AKT and BCL-2 inhibitors using capivasertib and venetoclax respectively alongside anti-CD20 antibody supplementation for treatment of patients with DLBCL., Competing Interests: Competing interests: B.W., K.M., H.D., I.N., A.R., M.P., N.B., J.R.R., C.R., J.M., and S.B. are current or former AstraZeneca employees and shareholders., (© 2024. The Author(s).)

Purpose: In our previous study, we found that the Chk1 inhibitor prexasertib enhances the antitumour effect of the oral anticancer drug S-1 against pancreatic cancer cells. In this study, we investigated the effect of combining S-1 and ceralasertib, an oral inhibitor of ATR, which is located upstream of Chk1. Ceralasertib is currently being investigated in multiple clinical trials for various cancers., Methods: The cell-proliferation inhibitory effect was measured by MTT assay, using the pancreatic cancer cell lines BxPC-3, SUIT-2, PANC-1, and MIA PaCa-2, while apoptosis was measured by flow cytometry using PI/Annexin staining. The mechanism underlying the combined effect was analysed using western blotting, and the antitumor effect was analysed using a mouse xenograft model., Results: MTT assay revealed that the combination of S-1 and ceralasertib had a synergistic effect, leading to the suppression of cell proliferation. Measurement with PI/Annexin staining revealed that the combination of S-1 and ceralasertib induced apoptosis more efficiently than either drug alone. Western blotting results showed that ceralasertib inhibited S-1-induced activation of ATR and Chk1. The average estimated tumour volume after 3 weeks of administration was 601 mm 3 in the S-1 group, 580 mm 3 in the ceralasertib group, and 298 mm 3 in the combination group., Conclusion: The combination of S-1 and ceralasertib demonstrated a high antiproliferative effect in inhibiting tumour growth in vitro., Competing Interests: Declarations Conflict of interests The authors declare no competing interests. Ethical approval The protocol of the animal experiments was reviewed and approved by the Animal Experiment Committee of Showa Pharmaceutical University on November 21, 2022 (approval no. 2022–1-R1), and the experiments were performed in accordance with the animal experiment regulations and manual of Showa Pharmaceutical University. Consent to participate Not applicable. Consent to publish Not applicable., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Patients with relapsed or refractory multiple myeloma (RRMM) who have exhausted lenalidomide benefits require improved therapies. The 3-cohort phase 2 MM-014 trial (NCT01946477) explored pomalidomide in early lines of treatment for lenalidomide-exposed RRMM. In cohort B, pomalidomide plus daratumumab and dexamethasone (DPd) showed promising efficacy (median follow-up 28.4 months), as previously reported. Here, we report final overall survival (OS) in cohort B., Methods: Patients aged ≥ 18 years were treated in 28-day cycles: pomalidomide 4 mg orally daily from days 1 to 21; daratumumab 16 mg/kg intravenously on days 1, 8, 15, and 22 (cycles 1-2), days 1 and 15 (cycles 3-6), and day 1 (cycle ≥ 7); and dexamethasone 40 mg (age ≤ 75 years) or 20 mg (age > 75 years) orally on days 1, 8, 15, and 22. The primary endpoint was ORR. OS and safety were secondary endpoints., Results: Among 112 patients enrolled, 85 (75.9%) had lenalidomide-refractory disease and 27 (24.1%) had lenalidomide-relapsed disease. At a median follow-up of 41.9 months (range, 0.4-73.1), median OS was 56.7 months (95% confidence interval, 46.5-not reached). Treatment-emergent adverse events related to, and leading to discontinuation of, pomalidomide, dexamethasone, or daratumumab occurred in 7 (6.3%), 9 (8.0%), and 6 (5.4%) patients, respectively., Conclusion: With long-term follow-up, our results show favorable OS with DPd. The safety profile was consistent with previous reports, with no new safety signals identified. IMiD agent-based therapy can still be considered in patients with RRMM who experience progressive disease on or after lenalidomide., Competing Interests: Disclosure N.J.B. declares research funding from Bristol Myers Squibb (BMS); honoraria from AbbVie, Amgen, BMS/Celgene, Forus, Genentech, GlaxoSmithKline (GSK), Janssen, Karyopharm, Pfizer, Sanofi, and Takeda; and payment for expert testimony from BMS/Celgene, Karyopharm, and Pfizer. C.S. declares no competing financial interests. D.R. declares research funding from BMS; consulting fees from Amgen, BMS, and Janssen; honoraria from Amgen, BMS, GSK, Sanofi, and Takeda; payment for expert testimony from BMS and Janssen; and board membership with Canadian Myeloma Research Network (CMRG; Chief Medical Officer). M.S. declares payment for expert testimony from BMS, Gilead/Kite, Janssen, Novartis, Pfizer, and Sanofi; and participation on a data safety monitoring or advisory board with Janssen. J.M. declares consulting fees from BeiGene and Pharmacyclics; and participation on a data safety monitoring or advisory board with BeiGene. J.G.B. declares research funding from 2seventy bio, AbbVie, Acetylon, Amgen, BMS/Celgene, bluebird bio, C4 Therapeutics, CARsgen, Cartesian, Celularity, CRISPR, EMD Serono, Fate, Genentech, GSK, Ichnos, Incyte, Janssen, Karyopharm, Lilly, Novartis, Poseida, Sanofi, Takeda, and Teva; and consulting fees from bluebird bio, BMS/Celgene, CRISPR, Janssen, Kite, Legend, Roche, Secura, and Takeda. J.S. declares honoraria from BMS, Janssen, Pfizer, and Sanofi. G.J.S. declares research funding from AbbVie, Actinium, Actuate, Agios, AltruBio, Amgen, Aptevo, Arog, Astellas, AVM Bio, BioMea, Biopath, Biosight, BMS/Celgene, Celator, Cellectis, Celularity, Cogent, Constellation, Daiichi Sankyo, Deciphera, Delta-Fly, Fate, Forma, FujiFilm, Gamida, Genentech/Roche, Geron, Gilead/Kite, Glycomimetics, Immunogene, Incyte, Janssen, Jazz, Karyopharm, Kiadis, Kronos Bio, Kura, Loxo, Marker, Mateon, Novartis, Onconova, Ono-UK, Orca, Pfizer, PrECOG, Regimmune, Samus, Sangamo, Sellas, Stemline, Syros, Takeda, Tolero, and Trovagene; consulting fees from BMS/Celgene, Curios, and Daiichi Sankyo; honoraria from AbbVie, Agios, Amgen, Astellas, AstraZeneca, AVM Biotech, BMS, Celgene, Gamida, Gilead, GSK, Incyte, Karyopharm, Novartis, Ono, and Stemline; participation on a data safety monitoring or advisory board with Agios, Amgen, AstraZeneca, AVM Biotech, BMS, Gamida, Gilead, GSK, Incyte, Novartis, and Ono; and stock or stock options with Amgen, BMS, and Janssen/Johnson & Johnson. S.G. declares consulting fees from AstraZeneca, BMS, Kite, and Sanofi; and honoraria from Kite and Seagen. K.S. declares research funding from BMS; and honoraria from Amgen, BMS, and Sanofi. C.S.S. declares no competing financial interests. M.A-R. declares honoraria from BMS, Eisai, and Merck Sharp Dohme. M.B. declares no competing financial interests. D.Q. declares no competing financial interests. G.F. declares honoraria from Amgen, BMS, and Sanofi. H.L. declares employment and stock/stock options with BMS. C.G. declares employment and equity ownership with BMS. P.S. declares employment with BMS. D.S. declares research funding from BMS; consulting fees from BMS, Janssen, and Karyopharm; honoraria from BMS and Janssen; participation on a data safety monitoring or advisory board with BMS; and stock or stock options with COTA., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Clinical data demonstrate that metformin exhibits antiproliferative, proapoptotic and antimetastatic actions. Here, correlative molecular studies were undertaken to determine the roles of transmembrane tumour necrosis factor-related apoptosis-inducing ligand death receptors (DRs) and CD133, a glycoprotein biomarker of breast cancer (BC) stem cells, in the advantageous action of metformin on pathological and clinical outcomes in BC patients on neoadjuvant chemotherapy., Methods: We randomly assigned 70 nondiabetic BC patients in a 1:1 ratio to either neoadjuvant AC-T chemotherapy (4 cycles of adriamycin 60 mg/m 2 and cyclophosphamide 600 mg/m 2 , followed by 12 cycles of weekly paclitaxel 80 mg/m 2 ) or AC-T with adjunct metformin (850 mg twice/day). The expressions of DR4, DR5 and CD133 were quantified in excised tissue samples with residual tumour cells., Results: The overall clinical response (odds ratio: 22.67 [2.77-185.18], P = .004), breast-conserving surgery (odds ratio: 3.67 [1.303-10.321], P = .014) and pathological complete response (β = 2.49 ± 1.13 [0.274-4.712], P = .028) rates were significantly improved in the metformin arm. Tissues obtained from the metformin arm had upregulated mRNA expression of DR4 (Mean delta cycle thresholds ± standard error of the mean: 2.68 ± 0.25 vs. 4.87 ± 0.53, P = .0003) and DR5 (0.21 ± 0.25 vs. 4.29 ± 0.95, P = .0004) compared to control arm. The enhanced DR expression negatively correlated with that of CD133 + BC stem cells, which was significantly reduced by metformin at both cytoplasmic/membranous (43.48 vs. 100.00%, P < .0001) and nuclear sites (4.35 vs. 95.00%, P < .0001)., Conclusion: Metformin improves clinical and pathological responses to neoadjuvant AC-T chemotherapy in BC via prompting directionally opposite changes in DRs (increments) and CD133 + (decrements) expressions. This study was registered in ClinicalTrials.gov (registration number: NCT04170465, https://clinicaltrials.gov/ct2/show/NCT04170465)., (© 2024 British Pharmacological Society.)

Rosuvastatin (RSV) is widely used to treat hyperlipidemia and hypercholesterolemia and is recommended for the primary and secondary prevention of cardiovascular diseases (CVD). In this study, we aimed to explore its action and mechanism in lung adenocarcinoma (LUAD) therapy. Lewis and CMT64 cell-based murine subcutaneous LUAD models were employed to explore the effects of RSV monotherapy combined with cisplatin and gemcitabine. Human lung fibroblasts and human LUAD cell lines were used to assess the effects of RSV on normal and LUAD cells. Bioinformatics and RNA interference were used to observe the contribution of cyclin A2 (CCNA2) knockdown to RSV inhibition and to improve chemosensitivity in LUAD. RSV significantly suppressed grafted tumor growth in a murine subcutaneous LUAD model and exhibited synergistic anti-tumor activity with cisplatin and gemcitabine. In vitro and in vivo experiments demonstrated that RSV impaired the proliferation and migration of cancer cells while showing little inhibition of normal lung cells. RNA interference and CCK8 detection preliminarily indicated that RSV inhibited tumor growth and enhanced the chemosensitivity to cisplatin and gemcitabine by downregulating CCNA2. RSV suppressed LUAD progression and enhanced chemosensitivity to cisplatin and gemcitabine by downregulating CCNA2, which should be prior consideration for the treatment of LUAD, especially for patients co-diagnosed with hyperlipidemia and hypercholesterolemia.

Glioblastoma is characterized by a pronounced resistance to therapy with dismal prognosis. Transcriptomics classify glioblastoma into proneural (PN), mesenchymal (MES) and classical (CL) subtypes that show differential resistance to targeted therapies. The aim of this study was to provide a viable approach for identifying combination therapies in glioblastoma subtypes. Proteomics and phosphoproteomics were performed on dasatinib inhibited glioblastoma stem cells (GSCs) and complemented by an shRNA loss-of-function screen to identify genes whose knockdown sensitizes GSCs to dasatinib. Proteomics and screen data were computationally integrated with transcriptomic data using the SamNet 2.0 algorithm for network flow learning to reveal potential combination therapies in PN GSCs. In vitro viability assays and tumor spheroid models were used to verify the synergy of identified therapy. Further in vitro and TCGA RNA-Seq data analyses were utilized to provide a mechanistic explanation of these effects. Integration of data revealed the cell cycle protein WEE1 as a potential combination therapy target for PN GSCs. Validation experiments showed a robust synergistic effect through combination of dasatinib and the WEE1 inhibitor, MK-1775, in PN GSCs. Combined inhibition using dasatinib and MK-1775 propagated DNA damage in PN GCSs, with GCSs showing a differential subtype-driven pattern of expression of cell cycle genes in TCGA RNA-Seq data. The integration of proteomics, loss-of-function screens and transcriptomics confirmed WEE1 as a target for combination with dasatinib against PN GSCs. Utilizing this integrative approach could be of interest for studying resistance mechanisms and revealing combination therapy targets in further tumor entities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

High-risk neuroblastoma has a poor prognosis despite intensive treatment, highlighting the need for new therapeutic strategies. Genetic alterations in activators and inactivators of Rho GTPase have been identified in neuroblastoma suggested to activate Rho/Rho-kinase (ROCK) signaling. ROCK has also been implicated in therapy resistance. Therefore, we have explored the efficacy of the dual ROCK inhibitor RKI-1447 in neuroblastoma, emphasizing combination strategies. Treatment with RKI-1447 resulted in decreased growth, increased cell death, and inhibition of N-MYC in vitro and in vivo. A combination screen revealed enhanced effects between RKI-1447 and BET inhibitors. Synergistic effects from RKI-1447 and the BET inhibitor, ABBV-075, were confirmed in various neuroblastoma models, including zebrafish. Interestingly, ABBV-075 increased phosphorylation of both myosin light chain 2 and cofilin, downstream effectors of ROCK, increases that were blocked by adding RKI-1447. The combination treatment also augmented an inhibitory effect on C-MYC and, less pronounced, N-MYC protein expression. BET inhibitors have shown preclinical efficacy against neuroblastoma, but acquired resistance has limited their therapeutic benefit. We reveal that the combination of ROCK and BET inhibitors offers a promising treatment approach that can potentially mitigate resistance to BET inhibitors and reduce toxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Despite all prevention programs, many cases of colorectal cancer (CRC) are diagnosed when they have already metastasized. Herein, chemotherapy is required, and combination of 5-fluorouracil, irinotecan, and leucovorin (FOLFIRI) is one of the first-line treatments chosen. However, it is so toxic that compromises patient outcomes. Thus, with the aim of improving FOLFIRI pharmacokinetics while reducing its side effects, the three compounds that make it up were simultaneously absorbed in this work into polydopamine nanoparticles (PDA NPs), also loaded with an antibody to target CRC cells overexpressing the epithermal growth factor receptor (EGFR). All adsorptions, which were successfully executed without toxic solvents, were electrostatic in nature according to the calorimetry results obtained. Otherwise, based on the experiments done, 5-flurouracil, irinotecan, and leucovorin release from PDA NPs followed a burst-like pattern, which was possibly mediated by Fickian diffusion mechanisms. Finally, the assays performed with two EGFR-overexpressing CRC cell lines showed that the uptake of the nanosystem was rapid, and that its therapeutic effect was very significant. It managed to greatly reduce the viability of these cells to 22-30% after 72 h of incubation. Furthermore, when tumor spheroids were developed and treated with PDA NPs loaded with FOLFIRI and the anti-EGFR antibody (FOLFIRI-CTX@PDA NPs), these demonstrated to continue to have very marked therapeutic activity. In addition, FOLFIRI-CTX@PDA NPs affected to a lesser extent the survival rate of stromal cells, with which viability experiments were also done. Therefore, the novel developed PDA nanocarrier could be a promising strategy to enhance metastatic CRC therapy hereafter., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: Not applicable., (© 2024. The Author(s).)

5-Fluorouracil (5-FU) is frequently used to treat colorectal cancer (CRC), but its clinical application is limited by its toxicity. Natural compounds have been combined with chemotherapeutic drugs to reduce chemotherapy-related toxicity. Diosmetin, a natural flavonoid, has demonstrated anticancer effects against CRC. This study investigated diosmetin's potential in combination with 5-FU using a murine model of HCT-116 colon cancer xenografts in nu/nu nude mice. HCT-116 cells were injected into the right flanks of mice, and once tumors reached a size of 50 mm 3 , the mice were treated with diosmetin (100 mg/kg), 5-FU (30 mg/kg), or a combination of both at two dose levels (100 + 30 mg/kg and 50 + 15 mg/kg) for 4 weeks. Blood and tumors were collected on the final day for further analysis. Mice treated with the higher combination dose exhibited the smallest tumor volume (330.91 ± 88.49 mm 3 ). Biochemistry and histology analysis showed no toxicity or abnormalities in the liver, kidney, and heart with the combination therapy. Immunohistochemistry results revealed a notable reduction in the proliferation marker (Ki67) and inflammation marker (TLR4) in tumors from high-dose combination-treated mice. Moreover, immunofluorescence data indicated increased levels of apoptotic markers (Bax, Caspase-3, p53, p21) and downregulation of anti-apoptotic protein (Bcl-2) in the high-dose combination group. The findings suggest that 100 mg/kg of diosmetin combined with 30 mg/kg 5-FU significantly reduced tumor volume and had a less toxic effect on the heart compared to 5-FU monotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The RVd therapy, combining lenalidomide, bortezomib, and dexamethasone, is a mainstay treatment for multiple myeloma. A multiple myeloma patient developed pure red cell aplasia (PRCA) following RVd treatment, despite the absence of common PRCA triggers. In vitro analyses reveal lenalidomide as a pivotal disruptor of erythropoiesis. Single-cell transcriptome analysis unveils hyperactive CD8 +  T cells and impaired erythropoiesis in the patient's bone marrow. Unexpectedly, the patient's erythroid cells display abnormally high expression of genes in the antigen presentation pathway, particularly those for major histocompatibility class I (MHC-I) molecules. Functional assays demonstrate that lenalidomide treatment further augmented MHC-I expression in the patient's erythroid cells. Blocking MHC-I or depleting T cells alleviates the defective erythropoiesis of PRCA, suggesting that the interaction between erythroid cells with elevated MHC-I and T cells in the bone marrow might contribute to PRCA. Taken together, our study implicates a mechanism underlying lenalidomide-induced PRCA in treating cancer patients., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Resistance to chemotherapy remains the main challenge for cancer treatment. One of the mechanisms of tumor escape from cytotoxic agents could be the formation of cell-in-cell (CIC) structures, in which the outer cell protects the inner cell from unfavorable environment. Such structures have been found in many tumor types, however, their link to chemosensitivity is elusive. Here, we tested whether the CIC structures can promote resistance of colorectal cancer cells to chemotherapy. To identify CIC structures in cell cultures and in tumor xenografts, both transmission electron microscopy and confocal fluorescence microscopy of live and fixed cells as well as tissue slices and histopathology were used. Cytogenetic analysis was performed to detect chromosome instability associated with the drug resistance. It was found that in the five colorectal cancer cell lines intrinsic chemoresistance positively correlated with the ability of cells to spontaneously form CIC structures. Cultured cells treated with oxaliplatin and Irinotecan and tumor xenografts treated with FOLFOX or FOLFIRI regimens displayed an increased number of CICs after the treatment. The release of the inner cell from CIC structure was observed after removal of the drug. The number of CICs in the cell lines and tumors with acquired resistance to oxaliplatin was higher than in the drug-naive counterparts. The development of chemoresistance was also accompanied by the changes in the cell's ploidy. These preliminary data clearly demonstrate the associations of CIC structures with chemoresistance of colorectal cancer in cultured cells and tumor xenografts and show the prospect of further clinical validation of CICs as a potential prognostic marker for treatment efficiency., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the Privolzhsky Research Medical University (Approval No. 09 from 30.06.2023)., (© 2024. The Author(s).)

Background: Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel, engineered cytokine that selectively binds to the intermediate-affinity interleukin-2 receptor, preferentially activating CD8 + T cells and natural killer cells, with minimal expansion of regulatory T cells, thereby mitigating the risk of toxicities associated with high-affinity interleukin-2 receptor activation. Clinical outcomes with nemvaleukin are unknown. ARTISTRY-1 investigated the safety, recommended phase 2 dose (RP2D), and antitumor activity of nemvaleukin in patients with advanced solid tumors., Methods: This was a three-part, open-label, phase 1/2 study: part A, dose-escalation monotherapy, part B, dose-expansion monotherapy, and part C, combination therapy with pembrolizumab. The study was conducted at 32 sites in 7 countries. Adult patients with advanced solid tumors were enrolled and received intravenous nemvaleukin once daily on days 1-5 (21-day cycle) at 0.1-10 µg/kg/day (part A), or at the RP2D (part B), or with pembrolizumab (part C). Primary endpoints were RP2D selection and dose-limiting toxicities (part A), and overall response rate (ORR) and safety (parts B and C)., Results: From July 2016 to March 2023, 243 patients were enrolled and treated (46, 74, and 166 in parts A, B, and C, respectively). The maximum tolerated dose was not reached. RP2D was determined as 6 µg/kg/day. ORR with nemvaleukin monotherapy was 10% (7/68; 95% CI 4 to 20), with seven partial responses (melanoma, n=4; renal cell carcinoma, n=3). Robust CD8 + T and natural killer cell expansion, and minimal regulatory T cell expansion were observed following nemvaleukin treatment. ORR with nemvaleukin plus pembrolizumab was 13% (19/144; 95% CI 8 to 20), with 5 complete and 14 partial responses; 6 responses were in PD-(L)1 inhibitor-approved and five in PD-(L)1 inhibitor-unapproved tumor types. Three responses were in patients with platinum-resistant ovarian cancer. The most common grade 3-4 treatment-related adverse events (TRAEs) in parts B and C, respectively, were neutropenia (49%, 21%) and anemia (10%, 11%); 4% of patients in each part discontinued due to TRAEs., Conclusions: Nemvaleukin was well tolerated and demonstrated promising antitumor activity across heavily pretreated advanced solid tumors. Phase 2/3 studies of nemvaleukin are ongoing., Trial Registration Number: NCT02799095., Competing Interests: Competing interests: UNV declares research support from Bristol Myers Squibb and Merck; consulting fees from Alkermes, Novartis, Bristol Myers Squibb, Exelixis, Bayer, Gilead, Seattle Genetics, Pfizer, and Aveo; speaker honoraria fees from Exelixis, Bayer, and Pfizer. JM declares advisory board attendance and honoraria from Exelixis. IW declares participation in advisory board for GOG Partners; Travel/Honoraria fees from Regeneron and IIT Collaborative funding from Chimerix for trial purposes only. SDR declares stock ownership at Pfizer, Amgen, and Johnson & Johnson. CJH declares grants from Merck; consulting fees from Merck, Eisai, and Seagen; honoraria fees from Eisai, Seagen, and Astellas; and advisory board attendance for CRISPR and Seagen. AChauhan declares grants from Bristol Myers Squibb, Clovis, Tersera, and ECS Progastrin; consulting fees from Tersera, Novartis, Lexicon, Ipsen, Curium, and Seneca Therapeutics; and honoraria from Tersera, Novartis, Lexicon, and Ipsen. AS declares funding to the institution from Alkermes. KDL declares funding to the institution from Alkermes and Merck; and employment with Regeneron. DSB declares independent research grant (payments made to institution) from AstraZeneca; consulting fees from or advisory board attendance for Bristol Myers Squibb, Mirati Therapeutics, Novartis, Eli Lilly, Amgen, Merck, Novocure, Regeneron, Syneos Health, Tempus and Daiichi-Sankyo; honoraria fees from AstraZeneca; advisory board attendance or travel fees from Bristol Myers Squibb, Novocure, AstraZeneca, Mirati Therapeutics and Regeneron; leadership as panel member for non-small cell lung cancer, thymic malignancies and pleural and peritoneal mesothelioma for National Comprehensive Cancer Network (NCCN). OD and MSE declare no conflicts of interest. DFM declares consulting fees from or advisory board attendance for Roche/Genentech BioOncology, Guidepoint, Bristol Myers Squibb, Merck, Exelixis, Pfizer, Lovance, Werewolf Therapeutics, and Svnthekine; leadership at Beth Israel, Dana-Farber Harvard Cancer Center; committee service at Beth Israel, Dana-Farber Harvard Cancer Center; grant review for FDA, Dana-Farber Harvard Cancer Center, National Cancer Institute; and funding from Prometheus Laboratories, X4 Pharmaceuticals, Alkermes, NIH, and Dept of Defense. JFS declares consulting fees from Synlogic (institution) and Binhui Biopharmaceuticals (institution); leadership at Dialectic Therapeutics; stock ownership at AbbVie, Abbot, Bristol Myers Squibb, Intuitive Surgical, Johnson & Johnson, Merck, and Regeneron. QSC declares grants from AstraZeneca; consulting fees from AbbVie, Amgen, AnHeart, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daichii Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Novartis, Ocellaris, Pfizer, Roche, and Takeda; honoraria from AbbVie, Amgen, AnHeart, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daichii Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Novartis, Ocellaris, Pfizer, Roche, and Takeda; serving on data and safety monitoring board for Merck KgaA; and unpaid and medical advocacy leadership for Lung Cancer Canada. LG declares consulting fees from or advisory board attendance for Merck and GlaxoSmithKline; honoraria fees from Merck, AstraZeneca, Eisai, GlaxoSmithKline, Eisai-Merck, Novocure, and GOG; institutional research funding from Merck Sharp & Dohme, IMV, AstraZeneca, ImmunoGen, Tesaro/GlaxoSmithKline, Karyopharm Therapeutics, Alkermes, OncoQuest, Novocure, Esperas Pharma, Mersana, Roche, and K-Group Beta Inc. AChaudhry declares receiving grants or clinical trial contracts from Arcus, Boehringer Ingelheim, AbbVie, Exelixis, Medilink, Gilead, Seagen, BeiGene, Roche, Tvardi, Amgen, Bristol Myers Squibb, Henlius, Merck, Mersana, Eli Lilly, Zia Pharmaceuticals, and AstraZeneca. EC declares employment at START, HM Hospitales Group; leadership at START, PharmaMar, EORTC, Sanofi, BeiGene, Novartis, and Merus NV; stock and other ownership interests at START and Oncoart Associated; honoraria fees from HM Hospitales Group; consulting or advisory role at Nanobiotix, Janssen-Cilag, Roche/Genentech, TargImmune Therapeutics, Servier, Bristol Myers Squibb, Amunix, Adcendo, Anaveon, AstraZeneca/MedImmune, Chugai Pharma, MonTa, MSD Oncology, Nouscom, Novartis, OncoDNA, T-Knife, Elevation Oncology, PharmaMar, Ellipses Pharma, Syneos Health, Genmab, and Diaccurate; research funding to the company from START; other relationships as president and founder of Foundation INTHEOS (Investigational Therapeutics in Oncological Sciences), not-for-profit foundation PharmaMar, and not-for-profit CRIS Cancer Foundation. RD declares previous employment at and stock ownership in Mural Oncology. VB declares institutional research funding from Sanofi, Seattle Genetics, Loxo, Novartis, CytomX Therapeutics, Puma Biotechnology, Kura, Tesaro, Roche/Genentech, Bristol Myers Squibb, Menarini, Synthon, Janssen Oncology, Merck, Lilly, Merus, Pfizer, Bayer, Incyte, AbbVie, Zenith Epigenetics, Genmab, AstraZeneca, Adaptimmune, Alkermes, Amgen, Array BioPharma, Boehringer Ingelheim, BioNTech AG, and Boston Biomedical; consulting fees from OncoArt, and Guidepoint Global; honoraria fees from Loxo, Ideaya Biosciences, Puma Biotechnology, Amunix, Guidepoint Global, and EMD Serono; speakers’ bureau fees from Solti, Lilly, and Tactics; advisory board attendance or travel fees from START and Bayer; leadership at Next Oncology (Institution); stock ownership at 1TRIALSP; and employment at Quironsalud, Next Oncology. VV declares serving as a consultant or in an advisory role for Bristol Myers Squibb, Merck, AstraZeneca, Regeneron, G1 Therapeutics, Amgen, GSK, and Novocure., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The 5-fluorouracil (5-FU)-based chemotherapy regimen is a primary strategy for treating pancreatic cancer (PC). However, challenges related to 5-FU resistance persist. Investigating the mechanisms of 5-FU resistance and identifying a clinically viable therapeutic strategy are crucial for improving the prognosis of PC. Here, through clinical samples analysis, we found that the expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the rate-limiting enzyme in mevalonate metabolism, is negatively correlated with the efficacy of 5-FU treatment. There is a significant correlation between HMGCR and the pyroptosis marker gasdermin D (GSDMD), and the HMGCR inhibitor simvastatin can significantly inhibit the activation of pyroptosis signaling. The exogenous addition of geranylgeranyl pyrophosphate (GGPP), a key metabolite of the mevalonate pathway, can significantly reduce sensitivity to 5-FU, and simvastatin combined with 5-FU demonstrates a strong synergistic effect. Furthermore, in organoid models and genetically engineered mice with spontaneous PC, the combination of simvastatin and 5-FU significantly inhibits tumor growth. In conclusion, our study reveals the critical role of the mevalonate pathway in 5-FU resistance and proposes a clinically feasible combination therapy strategy., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no competing interests. Ethical approval: This research was conducted in accordance with the ethical standards and approved by the Human Research Ethics Committee of Lanzhou University Second Hospital (Permit No. 2023A-173). The animal research was reviewed and approved by the Animal Experiment Ethics Committee of Lanzhou University Second Hospital (Permit No. D2023–M2). Consent for Publication: Not applicable., (© 2024. The Author(s).)

Glioblastoma multiforme (GBM) is a highly aggressive form of primary brain tumor in adults, which unfortunately has an abysmal prognosis and poor survival rates. The reason behind the poor success rate of several FDA-approved drug is mainly attributed to insufficient drug distribution to the tumor site across the blood-brain barrier (BBB) and induction of resistance. In this study, we have developed a novel nanotherapeutic approach to achieve our goal. PLGA-based nanoencapsulation of both Temozolomide (TMZ) and EGFR inhibitor 3,3'-diindoyl methane (DIM) in a combinatorial approach enhances the delivery of them together. Their synergistic mode of actions, significantly enhances the cytotoxic effect of TMZ in vitro and in vivo. Moreover, the dual-loaded nanoformulation works more efficiently on DNA damage and apoptosis, resulting in a several-fold reduction in tumor burden in vivo, systemic drug toxicity, and increased survival. These findings suggest the preclinical potential of this new treatment strategy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Colorectal cancer (CRC), as a fatal cancer, is one of the most common cancers worldwide. Although the standard treatment for colorectal cancer is well researched and established, long-term patient survival remains poor, and mortality remains high. Therefore, more and more effective treatment options are needed. To evaluate the efficacy of bevacizumab, the histone demethylase inhibitor IOX1, or their combination for the treatment of colorectal cancer, we examined the effects of IOX1, bevacizumab, and IOX1 combined with bevacizumab on cell activity, proliferation, and migration of colorectal cancer cell lines HCT116, RKO, and CT26 by CCK8, colony formation assay, wound healing assay, and transwell assay. The effects of the drugs alone as well as in combination on apoptosis in colorectal cancer cell lines were examined by flow cytometry and further validated by Western blotting for apoptosis-related proteins. The antitumor effects of treatment alone or in combination on colorectal cancer cells were examined in animal models. Mice were injected subcutaneously with CT26 cells and the growth and immune infiltration in tumor tissues were detected by IHC after drug treatment. We found that IOX1 could effectively inhibit the activity of CRC cells and had a significant inhibitory effect on the proliferation and migration of CRC cells. The apoptosis rate increased in a dose-dependent manner after IOX1 treatment on colorectal cancer cells, and the expression of apoptosis-related proteins changed accordingly. Further combination with bevacizumab revealed that the combination had a more significant effect on the proliferation, migration, and apoptosis of CRC cells than either IOX1 or bevacizumab alone. In vivo experiments have found that both alone and combination drugs can inhibit the growth of mouse tumors, but the effect of combination inhibition is the most obvious. Combination therapy significantly inhibited the expression of proliferative marker (Ki67) in tumor xenograft models, and increased content of antigen-specific CD4 + , CD8 + T cell growth, and granzymeB (GZMB), which is associated with T cell cytotoxicity, was detected in combination therapy. Immunoassays suppressed the expression of relevant PD-1 and decreased. The anticancer drug bevacizumab and the histone demethylase inhibitor IOX1 may inhibit colon cancer cell growth by regulating apoptosis. The inhibitory effect of combination therapy on tumor growth may be achieved, in part, through upregulation of infiltration-mediated tumor immunity by T lymphocytes. The combination of IOX1 and bevacizumab produced significant synergistic effects. This study aims to provide a new direction for CRC combination therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Neoadjuvant therapy with trastuzumab, pertuzumab and paclitaxel (THP) has significantly improved the prognosis of patients with human epidermal growth factor receptor 2 (HER2) + breast cancer (BC). However, there remains a subset of non-responsive patients. Thus, this study sought to identify key regulators of THP neoadjuvant therapy resistance and potential targets to sensitize sensitivity., Methods: The Cancer Genome Atlas database, Gene Expression Omnibus and membrane protein database were used to identify the key regulator of THP neoadjuvant resistance. The biological functions and mechanisms of delta-like 4 proteins (DLL4) in THP therapy resistance were investigated in vitro and in vivo using the bioinformatic analysis, multiplex immunofluorescence, flow cytometry, sphere formation assays and chromatin immunoprecipitation, etc. Furthermore, DLL4-targeted chimeric antigen receptor (CAR)-T cells were established to sensitize THP therapy., Results: DLL4 was identified as a key target in THP neoadjuvant therapy resistance for HER2 + BC. Mechanistically, DLL4 + tumor cells exhibited enhanced stemness and resistance to the THP neoadjuvant chemotherapy. Additionally, soluble DLL4 can split away from tumor cells and diffuse into the stroma, where it can activate the Notch signaling pathway in neutrophils, inducing the formation and release of neutrophil extracellular traps (NETs) by regulating the transcription of MPO, PDIA4 and ELANE. This led to the exclusion of lymphocyte infiltration, thereby enhancing therapy resistance. What is more, we designed a DLL4-targeted CAR-T to eliminate DLL4 + tumor cells and reverse the resistant status., Conclusions: Our study revealed novel functions of DLL4 in cell stemness and immune infiltration, including NET formation and T cell exclusion, which collectively contributed to THP neoadjuvant therapy resistance in HER2 + BC. Furthermore, we provided a CAR-T-based therapy to sensitize the THP neoadjuvant therapy., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Higher cytotoxic T lymphocyte (CTL) numbers in the tumor microenvironment (TME) predict pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) and positive long-term outcomes in triple-negative breast cancer (TNBC). pCR to NAC is achieved only in 30-40% of patients. The combination of NAC with pembrolizumab increases the pCR rate but at the cost of immune-related adverse events (irAEs). Based on these considerations, we tested if systemic infusion of the chemokine modulatory regimen (CKM; selective toll-like receptor 3 (TLR3) agonist rintatolimod, interferon (IFN)-α2b, and cyclooxygenase-2 (COX-2) inhibitor celecoxib) regimen can be safely combined with NAC to enhance intratumoral CTL numbers and NAC effectiveness., Methods: Phase I study NCT04081389 evaluated nine patients with early-stage TNBC who received 3 weeks of paclitaxel with CKM (dose-escalation of IFN-α2b), followed by 9 weeks of paclitaxel alone, dose-dense doxorubicin and cyclophosphamide, and surgery. Primary and secondary endpoints were safety and clinical efficacy, respectively., Results: The combination treatment was well-tolerated with no dose-limiting toxicities or irAEs. 5/9 patients achieved pCR and one patient had microinvasive disease (ypTmic). We observed elevated IFN signature and uniform decreases in CTL numbers (average 8.3-fold) in the blood of all treated patients. This was accompanied by reciprocal uniform increases in CD8β (overall 5.9-fold), CD8α/FoxP3 (2.11-fold), and CCL5 (4.73-fold) transcripts in TME, particularly pronounced in patients with pCR. Multiplex immunohistochemistry revealed selectively increased numbers of CTL (but not regulatory T cells) in both the epithelial and stromal tumor compartments and early decreases in the numbers of αSMA + vascular/stromal cells in the tumors of all pCR patients., Conclusions: Combined paclitaxel/CKM regimen was safe, with desirable TME changes and preliminary indications of promising pCR+ypTmic of 66%, comparable to the combination of NAC with pembrolizumab., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Breast cancer is the most common cancer affecting women worldwide. The associated morbidity and mortality have been on the increase while available therapies for its treatment have not been totally effective. The most common treatment, chemotherapy, sometimes has dangerous side effects because of non-specific targeting, in addition to poor therapeutic indices, and high dose requirements. Consequently, agents with anticancer effects are being sought that can reduce the side effects induced by chemotherapy while increasing its cytotoxicity to cancer cells. This is possible using natural compounds that are safe and biologically active. There are many reports on plant polysaccharides due to their bioactive and anticancer properties. The use of plant polysaccharide together with a conventional cytotoxic drug may offer wide benefits in cancer therapy, producing synergistic effects, thereby reducing drug dose and, so, its associated side effects. In this review, we highlight an overview of the use of plant polysaccharides and chemotherapeutic drugs in breast cancer preclinical studies, including their mechanisms of anticancer activities. The findings emphasize the potential of plant polysaccharides to improve chemotherapeutic outcomes in breast cancer, paving the way for more effective and safer treatment strategies.

Background: Patients with metastatic hepatoblastoma are treated with severely toxic first-line chemotherapies in combination with surgery. Yet, inadequate response of lung metastases to neo-adjuvant chemotherapy still compromises patient outcomes making new treatment strategies, tailored to more efficient lung clearance, mandatory., Methods: We harnessed a comprehensive patient-derived xenograft platform and a variety of in vitro and in vivo assays to establish the preclinical and biological rationale for a new drug for patients with metastatic hepatoblastoma., Results: The testing of a library of established drugs on patient-derived xenografts identified histone deacetylase inhibitors, most notably panobinostat, to be highly efficacious on hepatoblastoma cells, as compared to non-cancerous cells. Molecularly, the anti-tumor effect of panobinostat is mediated by posttranslational obstruction of the MYC oncoprotein as a result of dual specificity phosphatase 1 upregulation, thereby leading to growth inhibition and programmed cell death. Of clinical importance, upregulation of the MYC target gene nucleophosmin 1 is indicative of response to panobinostat and associated with metastatic disease in patients with hepatoblastoma. The combination of panobinostat with the current SIOPEL 4 induction protocol, consisting of cisplatin and doxorubicin, revealed high synergies already at low nanomolar levels. The simulation of a clinical trial, with this combination therapy, in patient-derived xenograft models, and ultimately heterotypic lung metastasis mimics clearly underscored the potency of this approach., Conclusion: Integrated studies define MYC inhibition by panobinostat as a novel treatment element to be introduced into the therapeutic strategy for patients with metastatic hepatoblastoma., Competing Interests: Declarations Ethics approval and consent to participate In vivo testing in mice was carried out according to the Italian Decree (08/2023-UT). Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests., (© 2024. The Author(s).)

Combinatorial immunotherapy may improve the efficacy of neoadjuvant checkpoint inhibitors in locoregionally advanced melanoma. In this issue of Cancer Cell, Davar and colleagues report a promising phase 2 neoadjuvant trial of the TLR9 agonist vidutolimod in combination with nivolumab. Analyses suggest a unique myeloid expression signature is associated with response., Competing Interests: Declaration of interests J.W.S. reports research funding from IO Biotech (Inst), Regeneron (Inst), and Daiichi Sankyo (Inst) and a consulting or advisory role from IO Biotech. M.A.P. reports a consulting or advisory role from Bristol-Myers Squibb; Cancer Expert Now; Chugai Pharma; Eisai; Erasca, Inc; Intellisphere; Merck; MJH Associates; Nektar; Novartis; Pfizer; and WebMD and research funding from Array BioPharma (Inst); Bristol-Myers Squibb (Inst); Infinity Pharmaceuticals (Inst); Merck (Inst); Novartis (Inst); and Rgenix (Inst)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Intratumoral TLR9 agonists and anti-PD-1 produce clinical responses and broad immune activation. We conducted a single-arm study of neoadjuvant TLR9 agonist vidutolimod combined with anti-PD-1 nivolumab in high-risk resectable melanoma. In 31 evaluable patients, 55% major pathologic response (MPR) was observed, meeting primary endpoint. MPR was associated with necrosis, and melanophagocytosis with increased CD8 + tumor-infiltrating lymphocytes and plasmacytoid dendritic cells (pDCs) in the tumor microenvironment, and increased frequencies of Ki67 + CD8 + T cells peripherally. MPRs had an enriched pre-treatment gene signature of myeloid cells, and response to therapy was associated with gene signatures of immune cells, pDCs, phagocytosis, and macrophage activation. MPRs gut microbiota were enriched for Gram-negative bacteria belonging to the Bacteroidaceae and Enterobacteriaceae families and the small subgroup of Gram-negative Firmicutes. Our findings support that combined vidutolimod and nivolumab stimulates a broad anti-tumor immune response and is associated with distinct baseline myeloid gene signature and gut microbiota. ClinicalTrials.gov identifier: NCT03618641., Competing Interests: Declaration of interests D.D. reports grants/research support (NIH/NCI and Checkmate Pharmaceuticals) and consulting (Checkmate Pharmaceuticals) during the conduct of the study. D.D. also reports grants/research support (Arcus, Immunocore, Merck, Regeneron Pharmaceuticals Inc., Tesaro/GSK.), consulting (ACM Bio, Ascendis, Castle, Clinical Care Options [CCO], Gerson Lehrman Group [GLG], Immunitas, Medical Learning Group [MLG], Replimmune, Trisalus, Xilio Therapeutics), speakers’ bureau (Castle Biosciences), steering committee membership (Immunocore, Replimmune) and patents related to gut microbial signatures of response and toxicity to immune checkpoint blockade (US Patent 63/124,231 and US Patent 63/208,719) outside the submitted work. P.D. is currently employed by Nanostring Technologies and reports stock options. Y.G.N. reports grants/research support (Bristol-Myers Squibb, Merck Sharp & Dohme and Pfizer) and consulting (Checkmate Pharmaceuticals) outside the submitted work. J.J.L. reports grants/research support (multiple), membership on data safety monitoring boards (multiple), membership on scientific advisory boards with no stock ownership or stock options (multiple), membership on scientific advisory boards with stock for (multiple), consulting (multiple) and a provisional patent for cancer immunotherapy (PCT/US18/36052: Microbiome Biomarkers for anti-PD-1/PD-L1 responsiveness: diagnostic, prognostic and therapeutic uses thereof) all outside the submitted work. D.M. is currently employed by Codiak Biosciences and reports stock options. D.B., J.W. and A.K. were formerly employed by CheckMate and report stock options. M.G.F. is currently employed by Regeneron Pharmaceuticals Inc. and reports stock options. J.M.K. reports grants/research support (Bristol-Myers Squibb, Amgen Inc.) and consulting (Bristol-Myers Squibb, Checkmate Pharmaceuticals, Novartis, Amgen Inc., Checkmate, Castle Biosciences, Inc., Immunocore LLC, Iovance, Novartis.) outside the submitted work. J.M.T. reports grants and consulting from Bristol-Myers Squibb, Merck Sharp & Dohme, Astra Zeneca, and Compugen outside the submitted work. H.M.Z. reports grants/research support (NIH/NCI and Checkmate Pharmaceuticals) and consulting (Checkmate Pharmaceuticals) during the conduct of the study. H.M.Z. also reports grants/research support (NIH/NCI, Bristol-Myers Squibb and GlaxoSmithKline), personal fees (GlaxoSmithKline, Bayer, and Vedanta) and pending provisional patents related to gut microbial signatures of response and toxicity to immune checkpoint blockade (US Patent 63/124,231 and US Patent 63/208,719) outside the submitted work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Bendamustine-rituximab (BR) therapy stands out as a promising alternative for elderly patients with diffuse large B-cell lymphoma (DLBCL), demonstrating notable efficacy when conventional regimens pose challenges. Despite its clinical success, the intricate mechanisms underlying BR therapy have remained elusive., Methods: DLBCL cell lines were used to investigate the mechanism of BR therapy in vitro. RNA-seq and Western blot were used to explore the target pathways of BR therapy. STING was knocked out using Crispr-cas9 and inhibited using H-151 to investigate its role in BR therapy. Bulk RNA-seq and single-cell RNA-seq data from patients were analyzed to investigate the association between STING and pyroptosis pathways, validated using STING downregulated cells. Flow cytometry, transwell experiments and co-culture experiments were performed to investigate the inflammatory phenotype of DLBCL cells after BR treatment and its effect on T-cell recruitment and activation., Results: This study elucidates that BR elicits direct tumoricidal effects by promoting apoptosis and inducing cell cycle arrest. The synergistic impact with rituximab is further potentiated by complement addition, demonstrating the pivotal role of in vivo antibody-dependent cellular cytotoxicity. Moreover, our investigation reveals that, through a cGAS-STING-dependent pathway, prolonged exposure to BR induces pyroptosis in DLBCL cells. Activation of the cGAS-STING pathway by BR therapy triggers the release of inflammatory factors and upregulates major histocompatibility complex molecules, shaping an immunologically hot tumor microenvironment., Conclusions: This unique dual influence not only directly targets DLBCL cells but also engages the patient's immune system, paving the way for innovative combination therapies. The study provides comprehensive insights into the multifaceted actions of BR in DLBCL, offering a foundation for refined and personalized treatment strategies in elderly patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

BACKGROUNDInhibition of Bruton's tyrosine kinase with ibrutinib blocks the function of myeloid-derived suppressor cells (MDSC). The combination of ibrutinib and nivolumab was tested in patients with metastatic solid tumors.METHODSSixteen patients received ibrutinib 420 mg p.o. daily with nivolumab 240 mg i.v. on days 1 and 15 of a 28-day cycle. The effect of ibrutinib and nivolumab on MDSC, the immune profile, and cytokine levels were measured. Single-cell RNA-Seq and T cell receptor sequencing of immune cells was performed.RESULTSCommon adverse events were fatigue and anorexia. Four patients had partial responses and 4 had stable disease at 3 months (average 6.5 months, range 3.5-14.6). Median overall survival (OS) was 10.8 months. Seven days of Bruton's tyrosine kinase (BTK) inhibition significantly increased the proportion of monocytic-MDSC (M-MDSC) and significantly decreased chemokines associated with MDSC recruitment and accumulation (CCL2, CCL3, CCL4, CCL13). Single-cell RNA-Seq revealed ibrutinib-induced downregulation of genes associated with MDSC-suppressive function (TIMP1, CXCL8, VEGFA, HIF1A), reduced MDSC interactions with exhausted CD8+ T cells, and decreased TCR repertoire diversity. The addition of nivolumab significantly increased circulating NK and CD8+ T cells and increased CD8+ T cell proliferation. Exploratory analyses suggest that MDSC and T cell gene expression and TCR repertoire diversity were differentially affected by BTK inhibition according to patient response.CONCLUSIONIbrutinib and nivolumab were well tolerated and affected MDSC and T cell function in patients with solid metastatic tumors.TRIAL REGISTRATIONClinicalTrials.gov NCT03525925.FUNDINGNIH; National Cancer Institute Cancer; National Center for Advancing Translational Sciences; Pelotonia.

Despite a great progress in identifying treatment options for patients with malignant melanoma, novel therapies tend to be costly and, in some cases, produce adverse effects forcing the melanoma patients to withdraw drugs. There is a strong need for less expensive drugs with a more favorable spectrum of anticancer actions. This study was designed to assess whether LY-2183240 (a potent inhibitor of both, anandamide cellular reuptake and fatty acid amide hydrolase (FAAH), an enzyme that degrades anandamide) has antiproliferative and cytotoxic effects on various human malignant melanoma cell lines (primary A375 and FM55P, metastatic SK-MEL28 and FM55M2) when administered alone or in combination with docetaxel, paclitaxel, mitoxantrone and cisplatin via the MTT assay. The MTT, LDH and BrdU assays were used to evaluate the potency and safety of LY-2183240, whereas isobolographic analysis of interactions was applied to characterize the interactions of LY-2183240 with the studied chemotherapeutics (docetaxel, paclitaxel, mitoxantrone and cisplatin). The isobolography confirmed that the combinations of LY-2183240 with docetaxel, paclitaxel and mitoxantrone produced additive interactions in all the tested melanoma cell lines. Only two antagonistic interactions for LY-2183240 combined with cisplatin in the A375 and FM55P cell lines were observed by the MTT assay. In conclusion, LY-2183240 can be considered an add-on drug for the treatment of melanoma, when combined with docetaxel, paclitaxel, or mitoxantrone, but not with cisplatin., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript or in the decision to publish the results., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Osteosarcoma is the most common form of primary bone cancer, which primarily afflicts children and adolescents. Chemotherapy, consisting of doxorubicin, cisplatin and methotrexate (MAP) increased the 5-year osteosarcoma survival rate from 20% to approximately 60% by the 1980s. However, osteosarcoma survival rates have remained stagnant for several decades. Patients whose disease fails to respond to MAP receive second-line treatments such as etoposide and, in more recent years, the kinase inhibitor regorafenib. BCL-2 and its close relatives enforce cellular survival and have been implicated in the development and progression of various cancer types. BH3-mimetics antagonize pro-survival members of the BCL-2 family to directly stimulate apoptosis. These drugs have been proven to be efficacious in other cancer types, but their use in osteosarcoma has been relatively unexplored to date. We investigated the potential efficacy of BH3-mimetics against osteosarcoma cells in vitro and examined their cooperation with regorafenib in vivo. We demonstrated that osteosarcoma cell lines could be killed through inhibition of MCL-1 combined with BCL-2 or BCL-x L antagonism. Inhibition of MCL-1 also sensitized osteosarcoma cells to killing by second-line osteosarcoma treatments, particularly regorafenib. Importantly, we found that inhibition of MCL-1 with the BH3-mimetic S63845 combined with regorafenib significantly prolonged the survival of mice bearing pulmonary osteosarcoma metastases. Together, our results highlight the importance of MCL-1 in osteosarcoma cell survival and present a potential therapeutic avenue that may improve metastatic osteosarcoma patient outcomes., (© 2024. The Author(s).)

Background: Alternating sequential administration of drugs may be a promising approach to overcome chemotherapy resistance in advanced pancreatic ductal adenocarcinoma (PDAC)., Methods: This study was an open-label, single-arm, and prospective trial included patients with untreated advanced PDAC. They received 2 cycles of NS regimen (nab-paclitaxel:125 mg/m2, intravenously injected on days 1 and 8, plus S-1:40-60 mg, orally twice per day for 1-14 days) followed by 2 cycles of GemOx regimen (gemcitabine, intravenously injected on days 1 and 8, and oxaliplatin: 130 mg/m2, intravenously injected on day 1). The primary efficacy endpoint was a progression-free survival rate at 6 months (PFSR-6m). The secondary efficacy endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Specific mRNA transcripts were used to explore survival associated genes., Results: Forty-two patients received a minimum of one treatment cycle, and of these, 30 patients completed one alternating treatment consisting of 4 cycles. The PFSR-6m was 71% (95% CI = 58%-87%). The median PFS and OS were 6.53 months (95% CI = 6.03-8.43) and 11.4 months (95% CI = 9.8-14.4), respectively. Common grades 3-4 hematological AEs included neutropenia 30.9%, leukopenia 26.2%, anemia 2.4%, and thrombocytopenia in 11.9%. Patients with OS > 10 months showed high expression of HLA-DQA2 while melanoma-associated antigen genes (MAGE) were notably upregulated in patients with OS < 10 months., Conclusion: The alternating sequential administration of the NS and GemOx regimens may be a novel approach for first-line chemotherapy in patients with advanced PDAC requiring further study (ClinicalTrials.gov Identifier: ChiCTR1900024867)., (© The Author(s) 2024. Published by Oxford University Press.)

MRTX1133 is currently being evaluated in patients with pancreatic ductal adenocarcinoma (PDAC) tumors harboring a KRASG12D mutation. Combination strategies have the potential to enhance the efficacy of MRTX1133 to further promote cell death and tumor regression. In this study, we demonstrated that MRTX1133 increased the levels of the proapoptotic protein BIM in PDAC cells and conferred sensitivity to the FDA-approved BCL2 inhibitor venetoclax. Combined treatment with MRTX1133 and venetoclax resulted in cell death and growth suppression in 3D cultures. BIM was required for apoptosis induced by the combination treatment. Consistently, BIM was induced in tumors treated with MRTX1133, and venetoclax enhanced the efficacy of MRTX1133 in vivo. Venetoclax could also resensitize MRTX1133-resistant PDAC cells to MRTX1133 in 3D cultures, and tumors established from resistant cells responded to the combination of MRTX1133 and venetoclax. These results provide a rationale for the clinical testing of MRTX1133 and venetoclax in patients with PDAC. Significance: The combination of MRTX1133 and the FDA-approved drug venetoclax promotes cancer cell death and tumor regression in pancreatic ductal adenocarcinoma, providing rationale for testing venetoclax with KRASG12D inhibitors in patients with pancreatic cancer., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Glioblastoma is a highly aggressive brain cancer that is resistant to conventional immunotherapy strategies. Botensilimab, an Fc-enhanced anti-CTLA-4 antibody (FcE-aCTLA-4), has shown durable activity in "cold" and immunotherapy-refractory cancers., Methods: We evaluated the efficacy and immune microenvironment phenotype of a mouse analogue of FcE-aCTLA-4 in treatment-refractory preclinical models of glioblastoma, both as a monotherapy and in combination with doxorubicin delivered via low-intensity pulsed ultrasound and microbubbles (LIPU/MB). Additionally, we studied 4 glioblastoma patients treated with doxorubicin, anti-PD-1 with concomitant LIPU/MB to investigate the novel effect of doxorubicin modulating FcγR expressions in tumor-associated macrophages/microglia (TAMs)., Results: FcE-aCTLA-4 demonstrated high-affinity binding to FcγRIV, the mouse ortholog of human FcγRIIIA, which was highly expressed in TAMs in human glioblastoma, most robustly at diagnosis. Notably, FcE-aCTLA-4-mediated selective depletion of intratumoral regulatory T cells (Tregs) via TAM-mediated phagocytosis, while sparing peripheral Tregs. Doxorubicin, a chemotherapeutic drug with immunomodulatory functions, was found to upregulate FcγRIIIA on TAMs in glioblastoma patients who received doxorubicin and anti-PD-1 with concomitant LIPU/MB. In murine models of immunotherapy-resistant gliomas, a combinatorial regimen of FcE-aCTLA-4, anti-PD-1, and doxorubicin with LIPU/MB, achieved a 90% cure rate, that was associated robust infiltration of activated CD8+ T cells and establishment of immunological memory as evidenced by rejection upon tumor rechallenge., Conclusions: Our findings demonstrate that FcE-aCTLA-4 promotes robust immunomodulatory and anti-tumor effects in murine gliomas and is significantly enhanced when combined with anti-PD-1, doxorubicin, and LIPU/MB. We are currently investigating this combinatory strategy in a clinical trial (clinicaltrials.gov NCT05864534)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Modulation of glucocorticoid receptor (GR) activity in tumor cells enhances chemotherapy efficacy. We evaluated the selective GR modulator relacorilant plus nab-paclitaxel in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who had received at least 2 prior therapy lines., Patients and Methods: In this open-label, single-arm, phase III study, patients received once-daily oral relacorilant (100 mg, titrated to 150 mg in 25 mg increments/cycle) and nab-paclitaxel (80 mg/m2) on days 1, 8, and 15 of 28-day cycles. The primary efficacy endpoint was objective response rate (ORR) by blinded independent central review. Progression-free survival (PFS), overall survival (OS), target gene modulation, and safety were also assessed., Results: Of 43 patients enrolled, 31 were evaluable for ORR (12 did not reach first postbaseline radiographic assessment). An interim analysis to assess whether ORR was ≥10% showed no confirmed responses and the study was discontinued. Two (6.5%) patients attained unconfirmed partial responses and 15 (48.4%) had stable disease. Fourteen of 31 (45.2%) patients had reductions in target lesion size, despite prior nab-paclitaxel exposure in 12 of the 14. Median PFS and OS were 2.4 months (95% CI, 1.4-4.2) and 3.9 months (95% CI, 2.8-4.9), respectively. The most common adverse events were fatigue and nausea. RNA analysis confirmed that relacorilant plus nab-paclitaxel suppressed 8 cortisol target genes of interest., Conclusion: Relacorilant plus nab-paclitaxel showed modest antitumor activity in heavily pretreated patients with mPDAC, with no new safety signals. Studies of this combination in other indications with a high unmet medical need are ongoing., (© The Author(s) 2024. Published by Oxford University Press.)

Venetoclax is a BH3 mimetic that was recently approved for the treatment of acute myeloid leukemia (AML) treatment. However, the effect of venetoclax on AML remains limited, and a novel strategy is required. Here, we demonstrate for the first time that the cytotoxic effect of venetoclax drastically increased when by combined with the naturally occurring flavonoid quercetin. Combined treatment with venetoclax and quercetin caused most of AML KG-1 cells to exhibit a condensed morphology. Cell cycle analysis revealed that the combination strongly induced cell death. Caspase inhibitor blocked this cell death, and the combination induced poly (ADP-ribose) polymerase (PARP) cleavage, indicating that apoptosis was the primary mechanism. These effects were also observed in another AML cell line Kasumi-1 but not in chronic myeloid leukemia (CML) K562 cells. Public data analysis demonstrated that B-cell/CLL lymphoma 2 (Bcl-2) expression is increased in AML cells compared to other malignant tumors, and the survival and the growth of AML cell line depends on Bcl-2. We found that quercetin increased Bcl-2-associated X protein (Bax) expression in KG-1. Our study provides a novel function for quercetin and presents a promising strategy for AML treatment using venetoclax., (© 2024. The Author(s).)

Background: Hyperleukocytic acute myeloid leukemia (HL-AML) is associated with early complications and high mortality rates, highlighting the urgent need for more effective therapeutic strategies., Methods: This study conducted label-free proteomic analysis on serum from HL-AML and non-HL AML (NHL-AML) patients, integrating the data with the OHSU transcriptomic database. Flow cytometry was used to evaluate the in vitro impact of bortezomib. The in vivo effectiveness of bortezomib was assessed using the patient-derived xenograft (PDX) model of HL-AML., Results: Through integrated analysis of serum proteomics and transcriptomics, we observed an abnormal enrichment of the NF-kappa B pathway in HL-AML, suggesting its potential as a novel therapeutic target. Given that bortezomib is an inhibitor of the NF-kappa B pathway, HL-AML bone marrow cells were treated with varying concentrations of bortezomib (0, 5, 10, and 20 nM) in vitro. The results indicated a significant cytotoxic effect of bortezomib on HL-AML cells, accompanied by increased apoptosis rates and decreased proliferation. Co-administration of bortezomib with the frontline clinical chemotherapeutic regimen of daunorubicin and cytarabine (DA regimen) significantly extended mouse survival. Bone marrow immunophenotyping showed reductions in CD45 + and CD33 + cell populations, indicating disease amelioration. Immunohistochemical analysis further confirmed the inhibitory effect on the NF-kappa B pathway, as evidenced by reduced levels of P-IKBα and P-p65 proteins, validating the proposed therapeutic mechanism., Conclusions: These data suggest that combination therapy involving bortezomib and the DA regimen may represent a promising strategy for HL-AML., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Despite advances made in targeted biomarker-based therapy for acute myeloid leukemia (AML) treatment, remission is often short and followed by relapse and acquired resistance. Functional precision medicine (FPM) efforts have been shown to improve therapy selection guidance by incorporating comprehensive biological data to tailor individual treatment. However, effectively managing complex biological data, while also ensuring rapid conversion of actionable insights into clinical utility remains challenging., Methods: We have evaluated the clinical applicability of quadratic phenotypic optimization platform (QPOP), to predict clinical response to combination therapies in AML and reveal patient-centric insights into combination therapy sensitivities. In this prospective study, 51 primary samples from newly diagnosed (ND) or refractory/relapsed (R/R) AML patients were evaluated by QPOP following ex vivo drug testing., Results: Individualized drug sensitivity reports were generated in 55/63 (87.3%) patient samples with a median turnaround time of 5 (4-10) days from sample collection to report generation. To evaluate clinical feasibility, QPOP-predicted response was compared to clinical treatment outcomes and indicated concordant results with 83.3% sensitivity and 90.9% specificity and an overall 86.2% accuracy. Serial QPOP analysis in a FLT3-mutant patient sample indicated decreased FLT3 inhibitor (FLT3i) sensitivity, which is concordant with increasing FLT3 allelic burden and drug resistance development. Forkhead box M1 (FOXM1)-AKT signaling was subsequently identified to contribute to resistance to FLT3i., Conclusion: Overall, this study demonstrates the feasibility of applying QPOP as a functional combinatorial precision medicine platform to predict therapeutic sensitivities in AML and provides the basis for prospective clinical trials evaluating ex vivo-guided combination therapy., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background and Study Aims: This study aimed to ascertain the inhibitory effect of ginsenoside Rg3 (Rg3) combined with 5-fluorouracil (5-FU) on 5-FU-resistant cells HCT116/5-FU and its molecular mechanism., Material and Methods: The HCT116 cell line resistant to 5-FU (HCT116/5-FU) was established by repeated exposure to gradually increasing 5-FU concentrations. The effects of different concentrations of Rg3 and 5-FU on colorectal cancer (CRC) cell proliferation were evaluated, and suitable concentrations were screened for subsequent experiments. The treatment efficacy of Rg3 and 5-FU alone and in combination with CRC cell activity was observed, and the inhibitory effect of Rg3 and 5-FU on the Hedgehog pathway was verified. Finally, the effects of Rg3 and 5-Fu on in vivo tumor formation were evaluated in vivo., Results: Rg3 enhanced the therapeutic efficacy of 5-FU in HCT116 cells by inducing apoptosis and suppressing cell activities and epithelial-mesenchymal transition (EMT), showing strong anti-tumor effects. Rg3 enhances the chemosensitivity of drug-resistant HCT116/5-FU cells to 5-FU. Additionally, the expression of Hedgehog pathway-relevant proteins (PTCH1, PTCH2, GLI1, and SHH) was increased in drug-resistant HCT116/5-FU cells, and Rg3 and 5-FU co-treatment downregulated the expression of PTCH1, PTCH2, GLI1, and SHH proteins in HCT116/5-FU cells. Rg3 reversed 5-FU resistance via by modulating the Hedgehog pathway. Rg3, in combination with 5-FU, repressed human CRC xenograft growth in nude mice, suppressed the expression of the proliferative nuclear factor KI67 in tumors, and promoted apoptosis., Conclusion: Rg3 enhances the anticancer effects of 5-FU in CRC cells that are sensitive and resistant to 5-FU, and its mechanism of action may be related to the inhibition of Hedgehog pathway activation., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.)

Background: High dose chemotherapy is one of the therapeutic strategies for breast cancer and doxorubicin (DOX) as a chemotherapy agent is widely used. DOX indication is limited due to its dose-depended cardiotoxicity. Recently, cannabidiol (CBD) shows antitumoral and cardioprotective effects, so we hypothesized that CBD administration with high-dose DOX chemotherapy can improve anticancer activity and reduce cardiotoxic side effects., Method: Mice breast cancer model established by injecting 4T1 cell lines. One group was not injected by 4T1 cells as a not cancerous group and received normal saline (NS, 0.1 mL). In cancerous groups, first group was considered as cancerous control and received NS (0.1 mL); the second group received CBD (5 mg/kg, IP) on Days 1,7, and 14; in the third group DOX (5 mg/kg, IV) as CBD schedule was administrated; the fourth group treated with CBD 1 day before DOX injection as pretreatment, and the last group was treated with CBD and DOX at same time with previous doses and schedules. On Day 21, all mice were sacrificed, heart and lungs tissues were obtained and histological sections were isolated. SOD2, iNOS, MMP2, MMP9 were evaluated through western blot and TUNEL test preformed for breast tumor., Results: Tumor size and weight significantly decreased in DOX, pretreatment CBD + DOX and CBD + DOX groups. Administration of CBD with DOX could not prevent weight loss. TUNEL test demonstrated the highest tumor cell apoptosis in pretreatment CBD + DOX and CBD + DOX. In lungs belonged to CBD + DOX, there was not any sign of metastasis. Cardiac histopathological examination of pretreatment CBD + DOX and CBD + DOX did not show any sign of congestion or inflammation. In CBD + DOX SOD2 increased, also iNOS, MMP2, and MMP9 decreased compared to DOX., Conclusions: This study demonstrated that simultaneous administration of CBD and DOX can increase antitumoral effect and reduce DOX cardiotoxicity. Nevertheless, CBD can induce cardiotoxicity as administrated alone., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The child cancer, neuroblastoma (NB), is characterised by a low incidence of mutations and strong oncogenic embryonal driver signals. Many new targeted epigenetic modifier drugs have failed in human trials as monotherapy., Methods: We performed a high-throughput, combination chromatin-modifier drug screen against NB cells. We screened 13 drug candidates in 78 unique combinations., Results: We found that the combination of two histone methyltransferase (HMT) inhibitors: GSK343, targeting EZH2, and SGC0946, targeting DOT1L, demonstrated the strongest synergy across 8 NB cell lines, with low normal fibroblast toxicity. High mRNA expression of both EZH2 and DOT1L in NB tumour samples correlated with the poorest patient survival. Combination HMT inhibitor treatment caused activation of ATF4-mediated endoplasmic reticulum (ER) stress responses. In addition, glutathione and several amino acids were depleted by HMT inhibitor combination on mass spectrometry analysis. The combination of SGC0946 and GSK343 reduced tumour growth in comparison to single agents., Conclusion: Our results support further investigation of HMT inhibitor combinations as a therapeutic approach in NB., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Adavosertib is a first-in-class, selective small-molecule inhibitor of Wee1. Olaparib is an inhibitor of poly(ADP-ribose) polymerase (PARP). Preclinical data suggest that adavosertib enhances the antitumor effect of PARP inhibitors., Objective: The safety, tolerability, and efficacy of adavosertib plus olaparib were evaluated in patients with refractory solid tumors to define the maximum tolerated dose (MTD) and recommended phase II dose (RP2D)., Patients and Methods: Eligible patients in part A (dose finding) had a refractory solid tumor for which there is no established treatment and had received ≥ 1 prior course of systemic therapy; in part B (dose expansion), patients had platinum-sensitive extensive-stage or relapsed small-cell lung cancer (SCLC). Patients received adavosertib [once (qd) or twice daily (bid)] for 3 consecutive days with 4 days off treatment (3/4), or 5 consecutive days with 2 days off (5/2), plus olaparib (bid) for 14 or 21 days of a 21-day cycle., Results: A total of 130 patients were enrolled in the study, 120 in part A and 10 in part B. The MTD for adavosertib bid was 175 mg (days 1-3, 8-10/21-day cycle) plus continuous olaparib 200 mg bid; the once-daily MTD (and RP2D) was adavosertib 200 mg (days 1-3, 8-10/21-day cycle) plus continuous olaparib 200 mg bid. In the MTD/RP2D cohort, one patient (7%) experienced a dose-limiting toxicity (DLT) of thrombocytopenia. The most common treatment-related adverse events (TRAEs) in the cohorts in which MTD/RP2D for bid dosing and RP2D for qd dosing were determined were fatigue (64.3% and 15.4%, respectively), diarrhea (42.9% and 30.8%), decreased appetite (35.7% and 23.1%), nausea (35.7% and 15.4%), and anemia (35.7% and 38.5%). In the SCLC dose-expansion cohort, TRAEs occurred in eight patients (88.9%), including thrombocytopenia (66.7%) and anemia (55.6%). In part A, objective response rate (ORR) was 14.8% [95% confidence interval (CI) 8.7-22.9] overall; for the cohorts in which MTD/RP2D for bid dosing and RP2D for qd dosing were determined, ORR was 30.8% (9.1-61.4) and 9.1% (0.2-41.3), respectively. ORR was 11.1% [95% CI 0.3-48.2; one partial response (PR)], disease control rate was 22.2% (2.8-60.0; one PR, one stable disease), and median progression-free survival was 1.5 months (1.3-4.2) in the SCLC dose-expansion cohort., Conclusions: Adverse events and DLTs observed in the bid MTD and once-daily MTD/RP2D dosing schedules were manageable and consistent with known adavosertib and olaparib safety profiles. Limited antitumor activity was observed with adavosertib plus olaparib combination therapy., Trial Registration: ClinicalTrials.gov, NCT02511795 (registration: 28 July 2015)., Competing Interests: Declarations Funding This study was funded by AstraZeneca and is part of an alliance between AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA, who are codeveloping olaparib. Disclosure of Potential Conflicts of Interests Erika P. Hamilton: Institutional funding (AstraZeneca, Pfizer, Genentech/Roche, Lilly, Puma Biotechnology, Daiichi Sankyo, Mersana, Boehringer Ingelheim, Cascadian Therapeutics, Hutchinson MediPharma, OncoMed, MedImmune, Stem CentRx, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, Millennium, TapImmune, BerGenBio, Medivation, Tesaro, Eisai, H3 Biomedicine, Radius Health, Acerta Pharma, Takeda, Macrogenics, Abbvie, Immunomedics, Fujifilm, eFFECTOR Therapeutics, Merus, Nucana, Regeneron, Leap Therapeutics, Taiho Pharmaceutical, EMD Serono, Clovis, CytomX, InventisBio, Novartis, Silverback, Black Diamond, ArQule, Sermonix Pharmaceuticals, Sutro Biopharma, Zenith Epigenetics, Arvinas, Torque Therapeutics, Harpoon Therapeutics, Fochon Pharmaceuticals, Orinove, Molecular Templates, Unum Therapeutics, Aravive, Dana Farber Cancer Institute, G1 Therapeutics, Karyopharm Therapeutics, and Compugen) and non-financial support (Amgen, Bayer, Bristol-Myers Squibb, Genzyme, Helsinn Therapeutics, HERON, Lexicon, Medivation, Merck, Novartis, Roche, Sysmex, Guardant Health, Foundation Medicine, Deciphera, and NanoString). Gerald S. Falchook: Royalties, self (Wolters Kluwer); advisory role, institution (AbbVie, Fujifilm, Silicon, Navire, Turning Point, Predicine, Inspirna, Regeneron, Jubilant, BostonGene, Teon, Merck, Sanofi, and BridgeBio); advisory role, self (EMD Serono); speaker’s honorarium for CME (Total Health Conferencing and Rocky Mountain Oncology Society); travel, self, for work and/or research related to institution [Amgen, Bristol-Myers Squibb, EMD Serono, Fujifilm, Millennium, Sarah Cannon Research Institute (employer), and Synthorx/Sanofi]; research funding, to institution (3-V Biosciences, Abbisko, Abbvie, ABL Bio, ADC Therapeutics, Accutar, Agenus, Aileron, American Society of Clinical Oncology, Amgen, ARMO/Eli Lilly, Artios, AstraZeneca, Bayer, BeiGene, Bioatla, Bioinvent, Biothera, Bicycle, Black Diamond, Boehringer Ingelheim, Celgene, Celldex, Ciclomed, Curegenix, Curis, Cyteir, Daiichi, DelMar, eFFECTOR, Eli Lilly, EMD Serono, Epizyme, Erasca, Exelixis, Freenome, Fujifilm, Genmab, GlaxoSmithKline, Hutchison MediPharma, IGM Biosciences, Ignyta, Immunitas, ImmunoGen/MacroGenics, Incyte, Jacobio, Jazz, Jounce, Jubilant, Kolltan, Loxo/Bayer, MedImmune, Merck, Metabomed, Millennium, Mirati, miRNA Therapeutics, Molecular Templates, National Institutes of Health, Navire/BridgeBio, NGM Bio, NiKang, Novartis, OncoMed, Oncorus, Oncothyreon, Poseida, Precision Oncology, Prelude, PureTech, Pyramid, RasCal, Regeneron, Relay, Rgenix, Ribon, Samumed, Sapience, Seagen, Silicon, Simcha, Sirnaomics, Strategia, Syndax, Synthorx/Sanofi, Taiho, Takeda, Tallac, Tarveda, Teneobio, Tesaro, Tocagen, Turning Point, U.T. MD Anderson Cancer Center, Vegenics, Xencor, and Zhuhai Yufan). Judy S. Wang: Consulting fees (Janssen, Stemline/Menarini, BioNTech, and Kanaph Therapeutics); honoraria for speakers’ bureau (AstraZeneca and Eisai); research funding to institution only (Syndax, AstraZeneca, Phoenix, Accutar, Celgene, BMS, Tenebio, LOXO, Nurix, Step Pharma, BioNTech, Moderna, Merck, Compugen, Boehringer Ingelheim, Kymab, Sanofi, Bicycle, Cyteir, Daiichi Sankyo, Xencor, Ribon, Klus Pharma, Artios, Genentech, Treadwell, MabSpace, IGM, Immunogen, PureTech, Erasca, Bayer, 7.8 Pharma, NGMBio, Zymeworks, Immuno-Onc, Astellas, Immunitas, Prelude, Blueprint, Beigene, Pionyr, Agenus, Adagene, Macrogenics, Jazz, StingThera, Coherus, Takeda, Taiho, Jounce, Evelo, Vedanta, Stemline, GSK, Janssen, Black Diamond, Vigeo, Relay, and Jacobio). Siqing Fu: Clinical trial research support/grant funding, institution {National Institutes of Health [NIH]/National Cancer Institute [NCI] P30CA016672 – Core Grant [Cancer Center Support Grant (CCSG) Shared Resources]; Abbisko; BeiGene; BioAtla, LLC.; Boehringer Ingelheim; CUE Biopharma, Inc.; Eli Lilly & Co.; Exelisis; Greenfire Bio, Inc.; Hookipa Biotech; IMV, Inc.; Innovent Biologics, Co., Ltd.; K-Group Beta; Lyvgen Biopharm, Co., Ltd.; MacroGenics; MediLink Therapeutics, Co. Ltd.; Millennium Pharmaceuticals, Inc.; Nerviano Medical Sciences; NeuPharma, Inc.; NextCure, Inc.; Ningbo NewBay Technology Development Co., Ltd.; Novartis; NovoCure; Nykode Therapeutics AS.; Parexel International, LLC; Pionyr Immunotherapeutics, Inc.; PureTech Health, LLC; Sellas Life Sciences Group; Soricimed Biopharma, Inc.; SQZ Biotechnologies; Sumitomo Dainippon; Taiho Oncology and NCCN; Treadwell Therapeutics; Turnstone Biologics; Tyligand Bioscience, Ltd.; and Virogin Biotech, Ltd}. Amit M. Oza: principal investigator (PI) and steering committees (AstraZeneca, GSK, and Clovis); advisory boards (AstraZeneca, Morphosys); CEO [Ozmosis Research (uncompensated)], institutional support for clinical trials (AstraZeneca, GSK, Esperas Pharm, Clovis, Karyopharm, Ocellaris, Senhwa, Merck, ImmunoGen, Immunovaccine, Pfizer, Aravive, Mersana, Seagen, Alkermes, Verastem, Zentalis, Shuttck Labs, Sutro, NovoCure, Plexxikon, and Amgen). Esteban Rodrigo Imedio: Former employee (AstraZeneca). Sanjeev Kumar: Employee and stock ownership (AstraZeneca). Lone Ottesen: Former employee and stock ownership (AstraZeneca). Ganesh M. Mugundu: Former employee and stock ownership (AstraZeneca). Elza C. de Bruin: Employee and stock ownership (AstraZeneca). Mark J. O’Connor: Employee and stock ownership (AstraZeneca). Suzanne F. Jones: Consulting/advisory role (Amgen) – all payments to institution; stock ownership (HCA Healthcare). David R. Spigel: Institutional funding (AstraZeneca, Genentech/Roche, Novartis, Celgene, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, Abbvie, Foundation Medicine, GlaxoSmithKline, Lilly, Merck, Moderna Therapeutics, Nektar, Takeda, Amgen, University of Texas Southwestern Medical Center – Simmons Cancer Center, G1 Therapeutics, Neon Therapeutics, Celldex, Clovis Oncology, Daiichi Sankyo, EMD Serono, Acerta Pharma, Oncogenex, Astellas Pharma, GRAIL, Transgene, Aeglea Biotherapeutics, Tesaro, Ipsen, ARMO BioSciences, and Millennium); consultation (AstraZeneca, TRM Oncology, Precision Oncology, Evelo Therapeutics, Illumina, PharmaMar, Genentech/Roche, Novartis, Celgene, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, Abbvie, Foundation Medicine, GlaxoSmithKline, Lilly, and Merck); travel and expenses (AstraZeneca, Genzyme, Intuitive Surgical, Purdue Pharma, Spectrum Pharmaceuticals, Sysmex, EMD Serono, Genentech/Roche, Novartis, Celgene, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, Abbvie, Foundation Medicine, GlaxoSmithKline, Lilly, and Merck). Bob T. Li: Uncompensated advisor and consultant (Amgen, AstraZeneca, Boehringer Ingelheim, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, and Lilly); research grants, institution (Amgen, AstraZeneca, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Hengrui USA, and Lilly); academic travel support (Jiangsu Hengrui Medicine and MORE Health); inventor on two institutional patents at MSK (US62/685,057 and US62/514,661); intellectual property rights as a book author at Karger Publishers and Shanghai Jiao Tong University Press. Ethics Approval and Consent to Participate The institutional review boards of all participating sites approved the study, all patients provided written informed consent, and the study was conducted in accordance with the Declaration of Helsinki. Consent to Publish Not applicable. Availability of Data and Material Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Data for studies directly listed on Vivli can be requested through Vivli at www.vivli.org. Data for studies not listed on Vivli could be requested through Vivli at https://vivli.org/members/enquiries-about-studies-not-listed-on-the-vivli-platform/. AstraZeneca Vivli member page is also available outlining further details: https://vivli.org/ourmember/astrazeneca/. Code Availability Not applicable. Author Contributions Writing – original draft; writing – review and editing: E.P. Hamilton, G.S. Falchook, J.S. Wang, S. Fu, A.M. Oza, E.R. Imedio, S. Kumar, L. Ottesen, G.M. Mugundu, E. de Bruin, M. J. O’Connor, S.F. Jones, D.R. Spigel, and B.T. Li. Investigation: E.P. Hamilton, G.S. Falchook, J.S. Wang, S. Fu, A.M. Oza, and B.T. Li. Methodology: E.R. Imedio, S. Kumar, G.M. Mugundu, S.F. Jones, and D.R. Spigel. Conceptualization: E.R. Imedio, S. Kumar, G.M. Mugundu, M. J. O’Connor, S.F. Jones, and D.R. Spigel. Supervision: E.R. Imedio, S. Kumar, and G.M. Mugundu. Project administration: E.R. Imedio, S. Kumar, and G.M. Mugundu., (© 2024. The Author(s).)

The poor vascularization of solid tumors results in oxygen-deprived areas within the tumor mass. This phenomenon is defined as tumor hypoxia and is considered to be a major contributor to tumor progression in breast and ovarian cancers due to hypoxia-cascade-promoted increased metastasizing capacity. Hence, targeting hypoxia is a strategic cancer treatment approach, however, the hypoxia-modulating drugs face several limitations in monotherapies. Here, we investigated the impact of the potent hypoxia-inducible factor inhibitory compound acriflavine on tumor cell proliferation, migration, and metabolism under hypoxic conditions. We identified that acriflavine inhibited the proliferation of breast and ovarian tumor cells. To model the potential benefits of additional hypoxia response inhibition next to standard chemotherapy, we combined acriflavine with a frequently used chemotherapeutic agent, paclitaxel. In most breast and ovarian cancer cell lines used, we identified additive effects between the two drugs. The most significant findings were detected in triple-negative breast cancer cell lines, where we observed synergism. The drug combination effectively impeded tumor growth and metastasis formation in an in vivo orthotopic triple-negative breast cancer model as well. Additionally, we demonstrated that an epithelial-mesenchymal transition inhibitory drug, rolipram, combined with acriflavine and paclitaxel, notably reduced the motility of hypoxic triple-negative breast cancer cells. In conclusion, we identified novel drug combinations that can potentially combat triple-negative breast cancer by inhibiting hypoxia signaling and hindering cell migration and metastasis formation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background/aim: Non-small-cell lung cancer (NSCLC) is the most frequently diagnosed malignancy and the first cause of cancer-related death. Thus, finding alternative therapeutic options is crucial. Drug repurposing offers therapeutic options in a simplified and affordable manner, especially to cancer patients in developing countries. Several drugs including antihistamines and beta-adrenergic receptor blockers (beta-blockers) display antiproliferative properties on cancer cells. Interestingly, NSCLC patients who had used either antihistamines or beta-blockers showed improved response to chemotherapy or reduced mortality in comparison to non-users of any of these drugs. However, combination therapy is gaining substantial interest in many cancers including non-EGFR mutated NSCLC. Here, we investigated the antineoplastic effect of the combination of the antihistamine loratadine, the beta-blocker nebivolol, and the tyrosine-kinase inhibitor gefitinib on NSCLC cell lines., Materials and Methods: A-549 and NCI-H1975 cell lines were used. The effect of nebivolol, gefitinib, and loratadine on the metabolic activity was studied using the MTT assay. The inhibitory concentrations (IC 20 and IC 50 ) were calculated and used in the drug-combination experiments. Apoptosis was investigated using flow cytometry; and cell survival using the colony formation assay., Results: The combination nebivolol-loratadine-gefitinib produced a significant synergistic effect on inhibiting the metabolic activity and colony formation, as well as on promoting apoptosis in both cell lines. Noteworthy, the effect on the cell line carrying the EGFR mutation (NCI-H1975) was very similar to the cell line that does not exhibit such mutation (A-549 cells)., Conclusion: The nebivolol-gefitinib-loratadine combination may be a promising alternative for lung cancer treatment., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)