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Background Little is known about the influence of hepatic artery infusion pump (HAIP) therapy in the setting of chemotherapy resistant hepatic disease in the era of modern systemic therapies. Methods Patients who underwent HAIP therapy for chemotherapy resistant and unresectable colorectal liver metastases (CRLM) were reviewed retrospectively. Results A total of 25 patients met inclusion criteria. 52% had isolated CRLM and 92% had five or more metastatic lesions. Partial response was noted in 40% of patients. Median hepatic progression-free survival (PFS) was 7 months in those with extrahepatic disease versus 6 months in those with isolated CRLM at the time of HAIP placement (p = 0.75). Median overall survival was 8 months in patients with extrahepatic disease and 14 months in patients with isolated CRLM (p = 0.06). Conclusions Our findings are comparable to published data and augment the literature which supports HAIP use in chemotherapy-resistant, liver-predominant metastatic colorectal cancer patients.

Chemotherapy remains the mainstay of treatment in the majority of solid and haematological malignancies. Resistance to cytotoxic chemotherapy is a major clinical problem and substantial research is ongoing into potential methods of overcoming this resistance. One major target, the receptor tyrosine kinase MET, has generated increasing interest with multiple clinical trials in progress. Overexpression of MET is frequently observed in a range of different cancers and is associated with poor prognosis. Studies have shown that MET promotes resistance to targeted therapies, including those targeting EGFR, BRAF and MEK. More recently, several reports suggest that MET also contributes to cytotoxic chemotherapy resistance. Here we review the preclinical evidence of MET’s role in chemotherapy resistance, the mechanisms by which this resistance is mediated and the translational relevance of MET inhibitor therapy for patients with chemotherapy resistant disease.

To study the relationship between temozolomide (TMZ) chemotherapy-resistant cells and stem cells in gliomas.The U251 glioma cell line was exposed to TMZ to generate TMZ-resistant colonies (U251/TMZ cell line) using the pulse drug method. The TMZ sensitivity of U251/TMZ and parental cells was examined using an MTT assay. The cell growth curve was drawn to show the growth of the two kinds of cells. Glioma stem cells (GSCs) were cultured and differentiated in vitro. Immunofluorescence assays were used to identify the expression of CD133, Nestin, and ABCG2 in U251/TM and U251 cells. Western blot analysis was used to analyse protein expression levels.The U251/TMZ cell line was successfully cultured in vitro. The IC50 value of the U251/TMZ cell line is 8.1 times that of the parental U251 cell line (t=-63.28, p=0.00). The doubling time of U251/TMZ cells was long compared with the parental cells. GSC tumour spheres were successfully cultured in vitro, and they differentiated in medium containing serum. The expression of CD133, Nestin, and ABCG2 in U251/TMZ cells was significantly higher than that in the parental U251 cells (t=43.35, p=0.00; t=12.31, p=0.00; t=11.49, p=0.00). Immunofluorescence staining of CD133, Nestin, and ABCG2 was significantly higher in U251/TMZ than in the parental U251 cells (t=43.35, p=0.00; t=12.31, p=0.00; t=11.49, p=0.00). Moreover, Western blot results showed that CD133, Nestin, and ABCG2 expression was significantly higher in U251/TMZ cells than that in the parental U251 cells (t=17.76, p=0.00; t=18.78, p=0.00; t=6.19, p=0.00).The U251/TMZ cell line has the biological characteristics of GSCs. The relationship between GSCs and chemotherapy-resistant cells has been preliminary proven to be partially overlapping, which can provide a new perspective when using appropriate cell subpopulations as targets for glioma.

BackgroundCellular Immunotherapies, which have been transformative in the treatment of liquid tumors, have had extremely limited efficacy in solid tumors to-date, in part due to the challenges of efficiently targeting the tumor heterogeneity. Gamma-delta T cells recognize and immediately respond to stress-induced Natural Killer Group D Ligands (NKG2DL) which can thereby differentiate between healthy and malignant tissue. We designed methylguanine-DNA methyltransferase (MGMT) expressing gamma-delta T cells engineered to be TMZ resistant (DeltEx Drug Resistant Immunotherapy or DRI) which can be administered concurrently with alkylating chemotherapy. This leverages the brief but substantial upregulation of NKG2DL from the pharmacokinetic activity of the chemotherapy. We and others have shown checkpoint inhibitors improve gamma-delta T cell function and can be combined with chemotherapy to target checkpoint mediated tumor cell escape. Further, this approach can be used with DNA damage response (DDR) inhibitors, such as PARP-inhibiters or ATM kinase inhibitors to enhance the upregulation of NKG2DL and amplify the chemotherapy-induced vulnerability of tumor cells.MethodsGlioblastoma cells isolated from patient derived xenografts (PDX) were used to determine if TMZ and blood brain barrier penetrant DDR inhibitors could enhance NKG2D ligands. Three PDX with distinct subtypes and genetic profiles were utilized. GBM PDX-derived cells were propagated with epidermal growth factor (EGF) and fibroblast growth factor (FGF) but without serum to best model parental tumors in vitro. Quantitative real-time PCR was used to determine expression of a panel of NKG2DL under hypoxic and normoxic conditionsResultsWe found a heterogeneous induction of NKG2DL expression with the combination of niraparib + TMZ. While the combinatorial treatment induced stress responses in all cells tested, the specific mRNAs induced, the extent of induction, and the effect of hypoxia varied. Niraparib and TMZ induced >10-fold induction of MICA and MICB in GBM456 cells or ULBP1 in GBM39 cells. The cell type specific inductions of these three targets were reduced by hypoxia and low glucose conditions, suggesting microenvironmental regulation will be important in vivo.ConclusionsThis approach holds promise for solid tumor treatment leveraging the ability of the gamma-delta T cells complex polyclonal receptor repertoire to identify and kill tumor cells with combinational therapeutic treatment to drive increases in NKG2DL. The broad utility of alkylating chemotherapies in solid tumor treatment, suggests that this mechanism could be applicable across multiple indications to drive tumor cell immunogenicity in combination with DeltEx DRI cells to increase cytoxicity and tumor cell killing.

INTRODUCTION AND OBJECTIVE:The use of antibiotics alters gut microbiota and has been reported to impact outcomes in immune checkpoint inhibitor (ICI) treatment in various types of cancer. We invest...

IntroductionTo investigate the effects and mechanisms of all-trans retinoic acid (ATRA) with and without oxaliplatin (OXA) on chemotherapy-resistant hepatocellular carcinoma cell lines.Material and methodsOXA-resistant cell lines (CSQT-2-R and Hep3b-R) and subcutaneous xenograft model were used in this study. MTT assay, flow cytometry, crystal violet assay, transwell assay and western-blotting were conducted to evaluate the effects of co-treatment with ATRA and OXA on OXA-resistant HCC in vivo and in vitro. The differences between two groups were analyzed using ANOVA. All statistical tests in the study were two-sided, and statistical significance was set at PResultsWe established two oxaliplatin-Resistant HCC cell lines (CSQT-2-R and Hep3b-R). The drug resistance ability can be increased up to 100% than their parental cells(CSQT-2 and Hep3b) in certain concentration of OXA. ATRA alone could not inhibited the viability of CSQT-2-R and Hep3b-R, but it can enhance the ability of OXA on apoptosis than OXA alone (75% vs 35%, pConclusionsATRA combined with OXA can elicit cell cycle arrest of CSQT-2-R and Hep3b-R at G2/M phase, thereby inhibiting the proliferation of resistant HCC cell, which provides a new treatment for chemotherapy-resistant HCC.

Cancers are methionine (MET) and methylation addicted, causing them to be highly sensitive to MET restriction. The present study determined the efficacy of restricting MET with oral-recombinant methioninase (o-rMETase) and the DNA methylation inhibitor, azacitidine (AZA) on a chemotherapy-resistant osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model. The osteosarcoma PDOX models were randomized into five treatment groups of six mice: control; doxorubicin (DOX) alone; AZA alone; o-rMETase alone; o-rMETase-AZA combination. Tumor size and body weight were measured during the 14 days of treatment. We found that tumor growth was arrested only by the o-rMETase–AZA combination treatment, as tumors with this treatment exhibited tumor necrosis with degenerative change. This study suggests that o-rMETase-AZA combination has clinical potential for patients with chemoresistant osteosarcoma.

Chemotherapy-resistant osteosarcoma is a recalcitrant disease. It is a frequent cause of death to the patients who are usually adolescent or young adults. The goal of the present study was to determine the efficacy of the combination of olaratumab (OLA), doxorubicin (DOX), and cisplatinum (CDDP) on osteosarcoma, which is resistant to first-line therapy, in a patient-derived orthotopic xenograft (PDOX) model. The osteosarcoma PDOX model was randomized into six treatment groups of six mice: control; CDDP alone; DOX and CDDP; OLA + DOX; OLA + CDDP; and OLA + DOX and CDDP. Tumor size and body weight were measured during 14 days of treatment. Tumor growth was regressed only by the treatment with a combination of OLA + DOX and CDDP. Tumors treated with this three-drug combination had the most tumor necrosis and the lowest Ki-67 index. The present study demonstrates the power of the PDOX model to identify novel effective treatment strategy for chemotherapy-resistant osteosarcoma.

Acute myeloid leukemia (AML) constitutively express growth factors and cytokines for survival. Chemotherapy alters these signals to induce cell death. However, drug resistance in AML remains a major hindrance to successful treatment and early warning is unavailable. Modulation of signaling pathways during chemotherapy may provide a window to detect response and predict treatment outcome. Blood samples collected from AML patients before and at day-3 of induction therapy were compared for changes in expression of CD117, CD34, pro-inflammatory cytokines and mediators of Akt and MAPK pathways, using multi-color flow cytometry. Nine patients were diagnosed as drug-resistant and seven sensitive to chemotherapy. Twelve were paired. Average percentages of CD34 (66.8 ± 11.7% vs. 26.2 ± 5.8%

Background:The emergence of chemotherapy resistant schistosomes necessitates finding new prophylaxis strategies based on immunization by using a modified vaccine candidate. Objective: To assess thepotential of an anti-schistosomal vaccine modified by nanotechnology. Materials and Methods: Soluble adult worm antigen preparation (SWAP) either crude or/and loaded on chitosan nanoparticles (CSNPs)were used. The anti-schistosomal impact was assessed in terms of stools egg count,worm burden and ultrastructural studyof juvenile and adult schistosomes. Results:Chitosan nanoparticles potentiated SWAP efficacy to exceed the impact of crude SWAP.The combination of SWAP loaded on CSNPs and crude SWAP showed the best immunization effects regarding adult worm number andfecundity,as well as morphological and tegumental distortion of juvenile than adult stages. Conclusion:Modified SWAP on CSNPs gave better results in anti-schistosome immunization thancrude SWAP.Immunization by combining different antigens gave the best results.

Background Pemetrexed (MTA) plus cisplatin combination therapy is considered the standard of care for patients with advanced non-small-cell lung cancer (NSCLC). However, in advanced NSCLC, the 5-year survival rate is below 10%, mainly due to resistance to therapy. We have previously shown that the fraction of mesenchymal-like, chemotherapy-resistant paraclone cells increased after MTA and cisplatin combination therapy in the NSCLC cell line A549. Cytidine deaminase (CDA) and thymidine phosphorylase (TYMP) are key enzymes of the pyrimidine salvage pathway. 5′-deoxy-5-fluorocytidine (5′-DFCR) is a cytidine analogue (metabolite of capecitabine), which is converted by CDA and subsequently by TYMP into 5-fluorouracil, a chemotherapeutic agent frequently used to treat solid tumors. The aim of this study was to identify and exploit chemotherapy-induced metabolic adaptations to target resistant cancer cells. Methods Cell viability and colony formation assays were used to quantify the efficacy of MTA and cisplatin treatment in combination with schedule-dependent addition of 5′-DFCR on growth and survival of A549 paraclone cells and NSCLC cell lines. CDA and TYMP protein expression were monitored by Western blot. Finally, flow cytometry was used to analyze the EMT phenotype, DNA damage response activation and cell cycle distribution over time after treatment. CDA expression was measured by immunohistochemistry in tumor tissues of patients before and after neoadjuvant chemotherapy. Results We performed a small-scale screen of mitochondrial metabolism inhibitors, which revealed that 5′-DFCR selectively targets chemotherapy-resistant A549 paraclone cells characterized by high CDA and TYMP expression. In the cell line A549, CDA and TYMP expression was further increased by chemotherapy in a time-dependent manner, which was also observed in the KRAS-addicted NSCLC cell lines H358 and H411. The addition of 5′-DFCR on the second day after MTA and cisplatin combination therapy was the most efficient treatment to eradicate chemotherapy-resistant NSCLC cells. Moreover, recovery from treatment-induced DNA damage was delayed and accompanied by senescence induction and acquisition of a hybrid-EMT phenotype. In a subset of patient tumors, CDA expression was also increased after treatment with neoadjuvant chemotherapy. Conclusions Chemotherapy increases CDA and TYMP expression thereby rendering resistant lung cancer cells susceptible to subsequent 5′-DFCR treatment.

The use of antibiotics alters gut microbiota and has been reported to impact outcomes in immune checkpoint inhibitor (ICI) treatment in various types of cancer. We investigated the impact of antibiotics on patients with metastatic urothelial carcinoma (mUC) treated with pembrolizumab.The data of 67 patients with chemotherapy-resistant mUC who were treated with pembrolizumab were retrospectively evaluated. The patients were classified into groups according to antibiotic status (with-antibiotic and without-antibiotic), and the progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR) were compared between the 2 groups.PFS (median: 1.1 vs. 8.9 months; P0.001) and OS (median: 2.3 vs. 19.5 months; P0.001) were significantly shorter in the with-antibiotic group (n = 15, 22%) than in the without-antibiotic group (n = 52, 78%). Patients in the with-antibiotic group had significantly higher Eastern Cooperative Oncology Group performance status scores (P = 0.042). Multivariable analyses revealed antibiotic use as an independent predictor of PFS (P0.001) and OS (P = 0.002). No patients in the with-antibiotic group achieved a complete response to pembrolizumab. The ORR (complete response (CR) + partial response (PR)) was higher among patients not treated with antibiotics than among patients treated with antibiotics, though the difference was not significant (34.6% vs. 13.3%, P = 0.093). The DCR (CR + PR + stable disease) was also higher among patients in the with-antibiotic group than in the without-antibiotic group (57.7% vs. 20.0%, P = 0.008).The use of antibiotics was negatively associated with outcomes in patients with mUC who are administered pembrolizumab. Baseline performance status was worse for these patients. Further analyses are required to identify associations between antibiotic use, bacterial infection for which it was indicated or its influence on performance status, on treatment outcomes.

Background The indoleamine 2, 3-dioxygenase (IDO) inhibitor 1-methyl-tryptophan (1-MT) is currently being used in clinical trials in patients with relapsed or refractory solid tumors by inhibiting tumor immune escape. A greater understanding of IDO activity is required to begin to understand the molecular mechanism by which drugs work. This study was conducted to investigate of the clinical significance of 1-methyl-tryptophan (1-MT) in treating carboplatin-resistant (CBP-resistant) ovarian cancer and its mechanism of action. Methods Using a medium dose, intermittent treatment method, a clinically relevant CBP-resistant human ovarian cancer cell line (SKOV3/CBP) was established. SKOV3/CBP cells were treated with normal serum (control) or 1-MT (0.25 ng/mL) for 4 h (SKOV3/CBP + 1-MT). Cell proliferation, invasion and IDO expression in SKOV3, SKOV3/CBP and SKOV3/CBP + 1-MT cells were determined by MTT assays, Matrigel invasion chambers assays and ELISAs, respectively. The half-maximal inhibitory concentration (IC50) and resistance index (RI) were also calculated. The killing ability of the NK cells and CD8+ T cells co-cultured with SKOV3, SKOV3/CBP and SKOV3/CBP + 1-MT cells were determined by LDH activity assays and the INF-γcounting method. Results The SKOV3/CBP cell line displayed an increased IC50 compared to the SKOV3 cell line (P 50 and RI of SKOV3/CBP cells. Furthermore, 1-MT treatment not only reduced the invasion ability, but also suppressed IDO expression in the drug-resistant SKOV3/CBP + 1-MT cell line as compared to the SKOV3/CBP cell line. Furthermore, 1-MT enhanced the killing ability of NK cells and the amount of INF-γsecreted from CD8+ T cells which were co-cultured with the SKOV3/CBP cell line. Conclusion Our data suggested that 1-MT inhibits the invasion of CBP-resistant ovarian cancer cells via down-regulation of IDO expression which leads to re-activation of immune cell function. We provide a conceptual foundation for the clinical development of 1-MT as an anti-tumor immunomodulator for chemotherapy resistant ovarian cancer patients.

Background: Ovarian cancer (OC) has the highest mortality among gynecological malignancies, and resistance to chemotherapy drugs is common. We aim to develop a machine learning approach based on gut microbiota to predict the chemotherapy resistance of OC. Methods: The study included patients diagnosed with OC by pathology and treated with platinum and paclitaxel in Shengjing Hospital of China Medical University between 2017 and 2018. Fecal samples were collected from patients, and 16S rRNA sequencing was used to analyze the differences in gut microbiota between OC patients with and without chemotherapy resistance. Nine machine learning classifiers were used to derive the chemotherapy resistance of OC from gut microbiota. Results: A total of 77 chemoresistant OC patients and 97 chemosensitive OC patients were enrolled. The gut microbiota diversity was higher in OC patients with chemotherapy resistance. There were statistically significant differences between the two groups in Shannon indexes (P

INTRODUCTION AND OBJECTIVE:The standard of care for muscle invasive bladder cancer (MIBC) is cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy. Patients with residual MI...

A major impediment to successful cancer treatment is the inability of clinically available drugs to kill drug-resistant cancer cells. We recently identified metabolically stable L-glucosamine-based glycosylated antitumor ether lipids (GAELs) that were cytotoxic to chemotherapy-resistant cancer cells. In the absence of commercially available L-glucosamine, many steps were needed to synthesize the compound and the overall yield was poor. To overcome this limitation, a facile synthetic procedure using commercially available L-sugars including L-rhamnose and L-glucose were developed and the L-GAELs tested for anticancer activity. The most potent analog synthesized, 3-amino-1-O-hexadecyloxy-2R-(O&ndash, &alpha, L-rhamnopyranosyl)-sn- glycerol 3, demonstrated a potent antitumor effect against human cancer cell lines derived from breast, prostate, and pancreas. The activity observed was superior to that observed with clinical anticancer agents including cisplatin and chlorambucil. Moreover, like other GAELs, 3 induced cell death by a non-membranolytic caspase-independent pathway.

Objective: Research has demonstrated that microRNA (miR)-106a is related to cisplatin resistance. We investigated the expression of miR-106a in the serum of patients with non-small cell lung cancer (NSCLC) and their sensitivity to chemotherapy by cisplatin combined with gemcitabine.Methods: Eighty-five NSCLC patients, who completed four cycles of gemcitabine and cisplatin chemotherapy, volunteered for this study and their serum samples were collected. Serum samples from 60 healthy subjects were used as controls. Real-time quantitative polymerase chain reaction (real-time qPCR) was used to quantify the level of miR-106a in the serum. Demographic and survival data of these patients were collected for the analysis.Results: The expression of miR-106a in the serum of NSCLC patients was significantly higher than that of healthy subjects (P < 0.001). The expression of miR-106a was not correlated with patients' gender, age, tumor size, lymphatic metastasis, and pathological types; but was correlated with patients' tumor staging (P = 0.003). After chemotherapy, serum miR-106a expression decreased in patients. The decrease in miR-106a expression in the chemotherapy-sensitive group was much higher than that in the chemotherapy-resistant group. Survival analysis shows that NSCLC patients with high expression of miR-106a have a poorer prognosis. The overall survival of NSCLC patients in the chemotherapy-sensitive group was significantly higher than that in the chemotherapy-resistant group.Conclusions: High expression of miR-106a may be involved in the development of NSCLC. MiR-106a has significance in the prognosis of NSCLC. The level of miR-106a in the serum can be a useful parameter in screening for drug resistance during cisplatin-based chemotherapy.

Despite continued widespread use, the genomic effects of cisplatin-based chemotherapy and implications for subsequent treatment are incompletely characterized. Here, we analyze whole exome sequencing of matched pre- and post-neoadjuvant cisplatin-based chemotherapy primary bladder tumor samples from 30 muscle-invasive bladder cancer patients. We observe no overall increase in tumor mutational burden post-chemotherapy, though a significant proportion of subclonal mutations are unique to the matched pre- or post-treatment tumor, suggesting chemotherapy-induced and/or spatial heterogeneity. We subsequently identify and validate a novel mutational signature in post-treatment tumors consistent with known characteristics of cisplatin damage and repair. We find that post-treatment tumor heterogeneity predicts worse overall survival, and further observe alterations in cell-cycle and immune checkpoint regulation genes in post-treatment tumors. These results provide insight into the clinical and genomic dynamics of tumor evolution with cisplatin-based chemotherapy, suggest mechanisms of clinical resistance, and inform development of clinically relevant biomarkers and trials of combination therapies., The impact of cisplatin-based chemotherapy on tumor genomes is complex. Here, the authors study matched pre- and post-chemotherapy primary samples in muscle-invasive bladder cancer, finding a cisplatin-based mutational signature, and highlighting the impact of intratumor heterogeneity on survival.

Chemotherapy-resistant acute myeloid leukemia (AML) manifesting as primary refractory or relapsed disease carries a dismal prognosis and is often driven by clonal evolution. We have performed a genome-wide CRISPR knockout screen investigating resistance to conventional AML therapy, cytarabine and doxorubicin (AraC/Dox), in 2 independent human AML cell lines. Chemoresistant populations were enriched with gRNAs disrupting cell cycle arrest genes, including cyclin dependent kinase inhibitor 2A (CDKN2A), checkpoint kinase 2 (CHEK2) and TP53. Here, we validate the direct contribution of these genes to chemoresistance and demonstrate that rationally designed therapeutic regimens targeting cell cycle enhances chemotherapy response in AML. Using CRISPR-mediated gene editing, we individually inactivated CDKN2A and CHEK2 in Cas9-expressing OCI-AML3 and MV4-11 cells. CDKN2A- and CHEK2-deficient cells demonstrated proliferative advantage in the presence of AraC/Dox in co-culture competition assays, confirming direct contribution of these gene knockouts to chemoresistance. Nil to modest reductions in apoptosis were seen in CDKN2A- and CHEK2-deficient cells treated with AraC/Dox for 72 hours compared to unedited controls. However, failure of accumulation of cells in the non-cycling G 0/G 1 proportion was seen in these edited cells after chemotherapy, corresponding with maintained DNA synthesis, as measured by BrdU incorporation, and a failure to downregulate phospho-Rb protein expression, indicating ongoing active cell cycling in spite of chemotherapy. These results confirm failure of cell cycle arrest as the major mechanism of resistance with inactivation of CDKN2A or CHEK2. To assess relevance of these genes in chemotherapy response in human AML, we analysed the effect of CDKN2A expression on prognosis. Reduced expression of CDKN2A conferred inferior overall survival in 3 independent clinical cohorts. Additionally, downregulation of CDKN2A and an increase in downstream cell cycling effector, cyclin-dependent kinase 6 (CDK6) was seen at relapse in paired diagnosis-relapse AML samples (Li et al. 2016, Nature Medicine). Further, CHEK2 mutations in clonal hematopoiesis are enriched in patients with solid organ cancers following chemo- or radiotherapy, functionally demonstrating chemoresistance over non-mutated cells. These data suggest CDKN2A and CHEK2 loss-of-function is relevant in promoting chemoresistance in human hematopoiesis. We therefore investigated whether therapeutically targeting cell cycle control pathways that converge on the G 1/S restriction point could synergise with cytotoxic chemotherapy, potentially circumventing chemoresistance. The addition of MDM2 inhibitor, nutlin-3a with AraC/Dox achieved striking synergism in TP53-competent cell lines in reducing viability and promoting apoptosis. Inhibition of CDK4/6 with palbociclib alone induced cell cycle arrest without apoptosis, however combination therapy with AraC/Dox significantly potentiated apoptosis. To functionally validate the role of CDKN2A itself, we examined the inhibitor of histone acetyltransferase KAT6A, WM-1119 (Baell et al. 2018, Nature), which transcriptionally upregulates CDKN2A. WM-1119 had anti-leukemic activity across multiple cell lines, corresponding with down regulation of cell cycling and upregulation of senescence signatures. The anti-leukemic activity was prevented by CDKN2A inactivation, indicating that CDKN2A upregulation is essential for WM-1119's anti-leukemic effect. WM-1119 enhanced activity of AraC/Dox in multiple cell contexts, mediated by cooperative induction of CDKN2A. Its efficacy and synergy with AraC/Dox was further demonstrated in MLL-AF9 primary murine AML ex vivo, demonstrating broader applicability of the approach. Our findings reveal defects in cell cycle arrest pathways as clinically relevant contributors to chemoresistance in AML. Combining agents to target cell cycle components improved in vitro anti-leukemic activity of chemotherapy and warrants further exploration of their translational potential. Disclosures Bullinger: Amgen: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Menarini: Consultancy; Hexal: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bayer: Research Funding; Pfizer: Consultancy, Honoraria; Astellas: Honoraria; Gilead: Consultancy; Daiichi Sankyo: Consultancy, Honoraria; Seattle Genetics: Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Honoraria; Abbvie: Consultancy, Honoraria. Lane: BMS: Consultancy, Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Novartis: Consultancy; Geron: Consultancy.

Background: The use of selective internal radiation therapy with yttrium 90 resin microspheres (SIR-Spheres ® ) in chemotherapy-resistant colorectal cancer liver metastases has been associated with favorable progression-free survival (PFS) and overall survival when given alone or concurrently with chemotherapy. We conducted a single institute retrospective trial to explore the potential impact of SIR-Spheres ® with concurrent chemotherapy vs . SIR-Spheres ® alone on liver PFS in patients with colorectal liver metastases (CRLM). Methods: Patients with 5-fluorouracil-refractory CRLM treated with SIR-Spheres ® between 2009 and 2014 were identified. Patients were excluded if they received any chemotherapy/targeted regimen following radioembolization on which they did not previously progress. This strategy was adopted to minimize the impact of post-SIR-Spheres ® systemic therapy bias on PFS. Results: Twenty-seven patients satisfied inclusion criteria and were included in this analysis. Patients’ demographics were similar between the two treatment arms, except for the median number of prior therapies. No associated ≥ grade 3 toxicities were noted. Liver disease control rates were 84% and 14% on the SIR-Spheres ® plus chemotherapy arms and SIR-Spheres ® alone arms, respectively (P=0.001). Median PFS in the liver was 176 days in the SIR-Spheres ® plus chemotherapy group vs . 91 days in the SIR-Sphere ® alone group (P=0.0009). Median overall survival was 212 days in the SIR-Spheres ® plus chemotherapy group vs . 154 days in the SIR-Spheres ® alone group (P=0.1023). Conclusions: In patients with 5-fluorouracil-refractory disease, SIR-Spheres ® plus chemotherapy is associated with an increased liver disease control rate and a prolonged liver PFS in comparison with SIR-Spheres ® alone.

A metastatic melanoma obtained from the right chest wall of a patient was previously established orthotopically in the right chest wall of nude mice as a patient-derived orthotopic xenograft (PDOX) model. We previously showed that the combination of tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) and chemotherapy was highly effective against the melanoma PDOX. In the present study, we investigated the mechanism of the high efficacy of this combination. Two weeks after implantation, 40 PDOX mouse models were randomized into 4 groups of 10 mice each: untreated control (n = 10); treated with S. typhimurium A1-R (5 × 107 CFU/100μl, i.v., once a week for 2weeks, n = 10); treated with temozolomide (TEM) (25mg/kg, p.o. for 14 consecutive days) combined with S. typhimurium A1-R (5 × 107 CFU/100μl, i.v., once a week for 2weeks, n = 10); treated with vemurafenib (VEM) (30mg/kg, p.o., for 14 consecutive days) combined with S. typhimurium A1-R (5 × 107 CFU/100μl, i.v., once a week for 2weeks) (n = 10). On day 14 from initiation, all treatments significantly inhibited tumor growth compared with untreated control (S. typhimurium A1-R: p < 0.01; TEM combined with S. typhimurium A1-R: p < 0.01; VEM combined with S. typhimurium A1-R: p < 0.01). Combination therapy with S. typhimurium A1-R was significantly more effective on tumor growth than S. typhimurium A1-R alone (with TEM: p < 0.01; with VEM: p < 0.01). Combination therapy significantly increased S. typhimurium A1-R tumor targeting alone (S. typhimurium A1-R + TEM: p < 0.01, S. typhimurium A1-R + VEM: p < 0.01), relative to S. typhimurium A1-R alone, respectively. In conclusion, chemotherapy drugs promoted targeting of S. typhimurium A1-R of melanoma, thereby enhancing efficacy against the melanoma PDOX.

Within the neuroendocrine tumors of the pancreas, insulinomas are tumors of generally benign behavior and cause of endogenous hyperinsulinism. We present the case of an adult patient with prolonged hypoglycemia secondary to malignant insulinoma with regional dissemination and poor cellular differentiation, besides a review of the diagnostic and therapeutic approach of this type of tumors. Keywords: Malignant insulinoma, Pancreatic neuroendocrine tumor, Hypoglycemia

Primary mediastinal nonseminomatous germ cell tumors (PMNSGCT) frequently become refractory to chemotherapy, and no effective salvage therapy exists. We performed genomic profiling on a series of 44 PMNSGCT and compared the results with those from chemorefractory, metastatic pure seminomatous (Sem, n = 22) and nonseminomatous (NS, n = 86) testicular germ cell tumors. Archival tissues were sequenced by a hybrid capture-based technology (FoundationONE; Foundation Medicine, Inc., Cambridge, MA). Microsatellite instability (MSI) and tumor mutational burden (TMB, mutations [mut]/Mb) were determined. Statistically significant differences in genomic alterations (GA) of PMNSGCT versus NS included higher TP53 pathway GA (p < .0001), PIK3CA pathway GA (p < .0001), and lower cell-cycle pathway GA (p = .0004). There were no MSI-high PMNSGCT cases. Mean TMB was similar between the groups, but there were more ≥10 mut/Mb in the PMNSGCT group versus NS (11.4% vs. 4.6%). The GA identified in PMNSGCT were similar to the findings from NS, with differential opportunities for targeted therapies and immunotherapies. Further study of precision treatments appears warranted.

A subset of pancreatic ductal adenocarcinomas (PDACs) is highly resistant to systemic chemotherapy, but no markers are available in clinical settings to identify this subset. In this study, we evaluate the role of sTRA, a glycan biomarker for PDAC, in predicting chemotherapeutic responses. We tested the correlation between chemosensitivity and glycan expression in PDACs in multiple systems including sets of cell lines, organoids, and isogenic cell lines; primary tumors; and blood plasma from human subjects. The sTRA-expressing models tended to have stem-like gene expression and the capacity for mesenchymal differentiation, in contrast to the non-expressing models. The sTRA cell lines also had significantly increased resistance to seven different chemotherapeutics commonly used against pancreatic cancer. Patients with primary tumors that were positive for a gene-expression classifier for sTRA received no statistically significant benefit from adjuvant chemotherapy, in contrast to those negative for the signature. In another cohort, based on direct measurements of sTRA in tissue microarrays, the patients who were high in sTRA again had no statistically significant benefit from adjuvant chemotherapy. Furthermore, a blood-plasma test for the sTRA glycan identified the PDACs that showed rapid relapse following neoadjuvant chemotherapy. This research demonstrates that a glycan biomarker could have value to detect chemotherapy resistant PDAC in clinical settings. This capability could aid in the development of stratified treatment plans and facilitate biomarker-guided trials targeting resistant PDAC. Citation Format: ChongFeng Gao, Luke Wisniewski, Ying Liu, Ben Staal, Ian Beddows, Dennis Plenker, Mohammed Aldakkak, Johnathan Hall, Daniel Barnett, Mirna Kheir Gouda, Peter Allen, Richard Drake, Amer Zureikat, Ying Huang, Douglas Evans, Aatur Singhi, Randall Brand, David Tuveson, Susan Tsai, Brian Haab. Detection of chemotherapy-resistant pancreatic cancer using a glycan Biomarker [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-002.

Background The management of uterine-serous-carcinoma (USC) no longer amenable to treatment with surgery, radiation and/or chemotherapy remains dismal. Alternative therapeutic options are desperately needed. Case We describe the case of a heavily pretreated 74-year-old patient with a recurrent USC overexpressing HER2/neu at 3 + level by IHC treated with the anti-HER2/neu antibody-drug-conjugate (ADC) trastuzumab-emtansine (TDM-1-Kadcyla-Genentech/Roche). She experienced a remarkable clinical response to TDM-1 with a complete resolution of a large metastatic, radiation/chemotherapy resistant tumor deposit in her abdominal wall muscle confirmed by multiple CAT scans and a prolonged systemic control of her disease. Conclusion TDM-1 may represent a novel treatment option for recurrent/metastatic HER2/neu-positive USC patients refractory to salvage-treatment., Highlights • USC patients have limited therapeutic options when the disease becomes resistant to chemotherapy. • About 35% of USC overexpress the HER2/neu receptor at 3 + level by IHC and/or are c-erbB2 gene amplified. • Trastuzumab emtansine (T-DM1, Kadcyla) is a novel antibody-drug conjugate. • T-DM1 may represent a novel treatment modality in USC patients with recurrent, HER2/neu + disease.

Gestational trophoblastic neoplasia (GTN) is a highly responsive to chemotherapy, but sometimes can be resistant, or relapse and require salvage chemotherapy with or without surgery. We use descriptive studies with case series to determine prognosis patient GTN with chemotherapy resistant manage with surgical procedure in Sardjito Hospital, Yogyakarta. GTN-resistant chemotherapy patients that undergoing hysterectomy showed significant decreases in hCG levels. Hysterectomy also help us to stop vaginal bleeding. However, complications from continuous bleeding can worsen patient condition. The decision to take a hysterectomy action varies depending on the patient's condition. At the Sardjito hospital, the patient was diagnosed with the fastest hysterectomy within the first 12 hours of treatment due to continuous bleeding, and shortly after 4 years of treatment with 5 different types of chemotherapy.

Angiosarcomas are rare malignant tumors derived from endothelial cells and occur most commonly in the scalp and the face. The prognosis is poor. Therefore, spontaneous regression of angiosarcoma is a rare phenomenon.We describe a case of a 73-year-old man with multiple metastatic angiosarcoma.In the present case, weekly paclitaxel therapy had an effect, but could not be continued because of interstitial pneumonia (IP). Weekly docetaxel therapy did not have an effect, but further chemotherapy was not carried out because aggravation of the IP was a concern.The primary lesion and other metastatic lesions were inconspicuous on the positron emission tomography/computed tomography scan performed in one year and two months after best supportive care.We reported an extremely rare case of spontaneous regression of therapy-resistant metastases of angiosarcoma that has remained controlled for 40 months since the initial diagnosis.

101 Background: Targeted gene delivery in vivo has long been considered the “Holy Grail” of gene therapy. Methods: We reviewed long-term data of patients with advanced chemotherapy-resistant malignancies, previously-treated patients with two tumor-targeted retrovectors: (1) encoding cytotoxic dominant negative cyclin G1, DeltaRex-G (formerly Rexin-G), and (2) encoding cytokine GMCSF plus suicide gene HStk, DeltaVax (formerly Reximmune-C). Results: Ninety-nine patients received > 5,000 intravenous infusions of DeltaRex-G; another 16 patients received 288 intravenous infusions of DeltaRex-G + 96 infusions of DeltaVax followed by valacyclovir p.o. No therapy-related bone marrow suppression, organ dysfunction or delayed treatment related adverse events were observed. Survival analysis showed 5.0% 10-year overall survival rate for patients who received DeltaRex-G alone, and 18.8% for DeltaRex-G + DeltaVax. Conclusions: Data analysis indicates that tumor-targeted gene delivery in vivo, represented by cytocidal DeltaRex-G, with or without immuno-stimulatory DeltaVax, has induced prolonged ( > 10 years) sustained remissions in cancer patients presenting with advanced chemotherapy-resistant solid and hematologic malignancies—plausibly due to safety, selectivity, and immune modulation. While the curative potential of precision targeted genetic medicine necessarily remains an academic question; it is clear that these initial long-term, cancer-free ( > 10 year) survivors represent a major milestone in both cancer therapy and immunotherapy. Phase 2-3 clinical trials are planned for these hard-to treat malignancies.