Search

Ovarian cancer is the deadliest gynecologic cancer. Although human epidermal growth factor receptor-2 (HER2) overexpression, a poor prognostic molecular marker in ovarian cancer, is found in almost 30% of ovarian cancer cases, there are no established therapies for HER2-overexpressing ovarian cancer. In this study, we investigated the efficacy of combined samfenet, a biosimilar compound of trastuzumab, and natural killer (NK) cells in preclinical model of HER2-overexpressing ovarian cancer. Firstly, we screened the HER2 expression in three ovarian cancer cell lines and eight ovarian cancer patient-derived tumor xenograft (PDTX) samples. Then, immunohistochemistry and silver in situ hybridization (SISH) were performed following clinical criteria. HER2-overexpressing cells exhibited the highest sensitivity to samfenet compared with low-HER2-expressing cells. In addition, the combination of samfenet with natural killer (NK) cells resulted in significantly enhanced sensitivity to HER2-overexpressing cells and showed a significant antitumor effect on PDTX mice compared with monotherapy. It is known that anti-HER2-humanized IgG1 monoclonal antibodies, including trastuzumab, induce antibody-dependent cellular cytotoxicity (ADCC). Consequently, the combination of samfenet with NK cells demonstrated NK cell-mediated ADCC, as confirmed using an in vitro NK cytotoxicity assay and in vivo antitumor efficacy. A transferase dUTP nick end labeling (TUNEL) assay using xenografted tumors further supported the ADCC effects based on the increase in the number of apoptotic cells in the combination group. Furthermore, high HER2 expression was associated with shorter progression-free survival and overall survival based on public mRNA expression data. In this study, we demonstrated that the combination of samfenet and NK cell therapy could be a promising treatment strategy for patients with HER2-overexpressing ovarian cancer, through ADCC effects. Therefore, this study supports a rationale for further clinical studies of the combination of samfenet and NK cells as a therapy for patients with HER2-overexpressing ovarian cancer. [ABSTRACT FROM AUTHOR]

Poly (ADP-ribose) polymerase (PARP) inhibitors are effective against BRCA1/2-mutated cancers through synthetic lethality. Unfortunately, most cases ultimately develop acquired resistance. Therefore, enhancing PARP inhibitor sensitivity and preventing resistance in those cells are an unmet clinical need. Here, we investigated the ability of paraspeckle component 1 (PSPC1), as an additional synthetic lethal partner with BRCA1/2, to enhance olaparib sensitivity in preclinical models of BRCA1/2-mutated breast and ovarian cancers. In vitro, the combined olaparib and PSPC1 small interfering RNA (siRNA) exhibited synergistic anti-proliferative activity in BRCA1/2-mutated breast and ovarian cancer cells. The combination therapy also demonstrated synergistic tumor inhibition in a xenograft mouse model. Mechanistically, olaparib monotherapy increased the expressions of p-ATM and DNA-PKcs, suggesting the activation of a DNA repair pathway, whereas combining PSPC1 siRNA with olaparib decreased the expressions of p-ATM and DNA-PKcs again. As such, the combination increased the formation of γH2AX foci, indicating stronger DNA double-strand breaks. Subsequently, these DNA-damaged cells escaped G2/M checkpoint activation, as indicated by the suppression of p-cdc25C (Ser216) and p-cdc2 (Tyr15) after combination treatment. Finally, these cells entered mitosis, which induced increased apoptosis. Thus, this proves that PSPC1 inhibition enhances olaparib sensitivity by targeting DNA damage response in our preclinical model. The combination of olaparib and PSPC1 inhibition merits further clinical investigation to enhance PARP inhibitor efficacy. [ABSTRACT FROM AUTHOR]

Simple Summary: Paclitaxel-based chemotherapy is the standard front-line therapy for advanced or metastatic endometrial cancer. However, paclitaxel resistance eternally develops. Based on the high prevalence of PIK3CA mutation, reaching 50%, in endometrial cancer, we preclinically investigated the effectiveness of a combination of a PI3K inhibitor with eribulin, a post-paclitaxel therapy for breast cancer, in treating paclitaxel-resistant, PIK3CA-mutated endometrial cancer. Based on our in vitro and in vivo results, we suggest that paclitaxel resistance is associated with the activation of the PIK3/AKT pathway in PIK3CA-mutated endometrial cancer, and the combination of a PI3K inhibitor and eribulin merits further clinical investigation. Endometrial cancer stands as the predominant gynecological malignancy in developed nations. For advanced or recurrent disease, paclitaxel-based chemotherapy is the standard front-line therapy. However, paclitaxel resistance eternally develops. Based on the high prevalence of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation, reaching 50%, in endometrial cancer, we preclinically investigated the effectiveness of a combination of a phosphatidylinositol 3-kinase (PI3K) inhibitor with eribulin, a post-paclitaxel therapy for breast cancer, in treating paclitaxel-resistant, PIK3CA-mutated endometrial cancer. We generated paclitaxel-resistant cell lines from PIK3CA-mutated endometrial cancer cell lines by gradually increasing the concentration of paclitaxel in cell cultures. We observed that the PI3K/AKT and epithelial–mesenchymal transition (EMT) pathways in paclitaxel-resistant cells were significantly upregulated compared with those in parental cells. Then, we demonstrated that the combination of alpelisib (a PI3K inhibitor) and eribulin more effectively suppressed the cellular growth of paclitaxel-resistant cells in in vitro and in vivo xenograft models. Mechanistically, we demonstrated that the effect of the combination could be enhanced by inhibiting both the PI3K/AKT and EMT pathways. Therefore, we suggest that paclitaxel resistance is associated with the activation of the PIK3/AKT pathway in PIK3CA-mutated endometrial cancer, and the combination of a PI3K inhibitor and eribulin merits further clinical investigation. [ABSTRACT FROM AUTHOR]

Background: Standard intravenous (IV) paclitaxel is associated with hypersensitivity/toxicity. Alternative IV formulations have improved tolerability but still require frequent hospital visits and IV infusion. DHP107 is a novel oral formulation of paclitaxel that is approved in South Korea for the treatment of gastric cancer. Methods: This multicenter, phase II study using a Simon's two-stage design investigated the efficacy and safety of DHP107 200 mg/m2 administered orally twice daily on days 1, 8, and 15 every 4 weeks for the first-line treatment of recurrent or metastatic HER2-negative breast cancer. Results: Thirty-six patients were enrolled and 31 were assessable for efficacy. Patient median age was 57 years (range = 34–81) and 11 (31%) had triple-negative disease. A median of seven cycles (range = 1–28) of DHP107 was administered. Objective response rate was 55% (17 patients), all partial responses, according to the investigator's decision and independent central review (ICR), and 44% (4/9 patients) in those with triple-negative disease. Disease control rate (partial response and stable disease) was 74% (23 patients) according to the investigator's decision and ICR. In the intention-to-treat (ITT) population of all enrolled participants, the objective response rate was 50% (18/36 patients). Median progression-free survival was 8.9 months [95% confidence interval [CI]: 5.2–12.3) and median time to treatment failure was 8.0 months (95% CI: 4.2–10.0). DHP107 had an acceptable toxicity profile. All patients experienced treatment-emergent adverse events; the most common adverse events were decreased neutrophil count (81% all grades and 78% grade ⩾ 3) followed by peripheral sensory neuropathy (61% all grades and 8% grade 3). However, there was no febrile neutropenia or sepsis. Conclusion: DHP107 showed promising efficacy and acceptable tolerability in this phase II study and is currently being investigated in the OPTIMAL phase III study (NCT03315364). Trial registration: This trial was registered with ClinicalTrials.gov identifier: NCT03315364. [ABSTRACT FROM AUTHOR]

Eflapegrastim (Rolontis®) is a novel, long‐acting hematopoietic growth factor consisting of a recombinant human granulocyte‐colony stimulating factor (rhG‐CSF) analog conjugated to a human IgG4 Fc fragment via a short polyethylene glycol linker. We report results from a second pivotal, randomized, open‐label, Phase 3 study comparing the efficacy and safety of eflapegrastim to pegfilgrastim for reducing the risk of chemotherapy‐induced neutropenia. Patients with Stage I to IIIA early‐stage breast cancer (ESBC) were randomized 1:1 to fixed‐dose eflapegrastim 13.2 mg (3.6 mg G‐CSF) or pegfilgrastim (6 mg G‐CSF) administered one day after standard docetaxel/cyclophosphamide (TC) therapy for four cycles. The primary objective was to demonstrate noninferiority (NI) of eflapegrastim compared to pegfilgrastim in mean duration of severe neutropenia (DSN; Grade 4) in Cycle 1. A total of 237 eligible patients were randomized 1:1 to receive either eflapegrastim (n = 118) or pegfilgrastim (n = 119). Cycle 1 severe neutropenia was observed in 20.3% (n = 24) of patients receiving eflapegrastim and 23.5% (n = 28) receiving pegfilgrastim. The DSN of eflapegrastim in Cycle 1 was noninferior to pegfilgrastim with a mean difference of −0.074 days (NI P‐value <.0001). Noninferiority was maintained throughout the four treatment cycles (P <.0001 in all cycles). Other efficacy endpoints results were comparable between treatment arms, and adverse events, irrespective of causality and grade, were comparable between treatment arms. The results demonstrate noninferior efficacy and comparable safety for eflapegrastim, at a lower G‐CSF dose, vs pegfilgrastim. The potential for the increased potency of eflapegrastim to deliver improved clinical benefit warrants further clinical study. [ABSTRACT FROM AUTHOR]

Deregulation of the cyclin D‐CDK4/6‐INK4‐RB pathway leading to uncontrolled cell proliferation, is frequently observed in breast cancer. Currently, three selective CDK4/6 inhibitors have been FDA approved: palbociclib, ribociclib and abemaciclib. Despite promising clinical outcomes, intrinsic or acquired resistance to CDK4/6 inhibitors has limited the success of these treatments; therefore, the development of various strategies to overcome this resistance is of great importance. We highlight the various mechanisms that are directly or indirectly responsible for resistance to CDK4/6 inhibitors, categorizing them into two broad groups; cell cycle‐specific mechanisms and cell cycle‐nonspecific mechanisms. Elucidation of the diverse mechanisms through which resistance to CDK4/6 inhibitors occurs, may aid in the design of novel therapeutic strategies to improve patient outcomes. This review summarizes the currently available knowledge regarding mechanisms of resistance to CDK4/6 inhibitors, and possible therapeutic strategies that may overcome this resistance as well. [ABSTRACT FROM AUTHOR]

We evaluated the preliminary efficacy and feasibility of a next-generation sequencing (NGS)-based targeted anticancer therapy in refractory solid tumors at a Korean institution. Thirty-six patients with advanced cancer underwent molecular profiling with NGS with the intent of clinical application of available matched targeted agents. Formalin-fixed paraffin-embedded (FFPE) tumors were sequenced using the Comprehensive Cancer Panel (CCP) or FoundationOne in the Clinical Laboratory Improvement Amendments-certified laboratory in the USA. Response evaluations were performed according to RECIST v1.1. Four specimens did not pass the DNA quality test and 32 specimens were successfully sequenced with CCP (n = 31) and FoundationOne (n = 1). Of the 32 sequenced patients, 10 (31.3%) were ≤40 years. Twelve patients (37.5%) had received ≥3 types of prior systemic therapies. Of 24 patients with actionable mutations, five were given genotype-matched drugs corresponding to actionable mutations: everolimus to PIK3CA mutation in parotid carcinosarcoma (partial response) and tracheal squamous cell carcinoma (stable disease; 21% reduction), sorafenib to PDGFRA mutation in auditory canal adenocarcinoma (partial response), sorafenib to BRAF mutation in microcytic adnexal carcinoma (progressive disease), and afatinib to ERBB2 mutation in esophageal adenocarcinoma (progressive disease). Nineteen of 24 patients with actionable mutations could not undergo targeted therapy based on genomic testing because of declining performance status (10/24, 41.7%), stable disease with previous treatment (5/24, 20.8%), and lack of access to targeted medication (4/24, 16.7%). NGS-based targeted therapy may be a good option in selected patients with refractory solid tumors. To pursue this strategy in Korea, lack of access to clinical-grade NGS assays and a limited number of genotype-matched targeted medications needs to be addressed and resolved. [ABSTRACT FROM AUTHOR]

Background: EGFR mutation-induced cell proliferation causes changes in tumor biology and tumor metabolism, which may reflect tumor marker concentration and 18F-FDG uptake on PET/CT. Direct aspirates of primary lung tumors contain different concentrations of tumor markers than serum tumor markers, and may correlate better with EGFR mutation than serum tumor markers. The purpose of this study is to investigate an association between cytologic tumor markers and FDG uptake with EGFR mutation status in non-small cell lung cancer (NSCLC).Methods: We prospectively collected tumor aspirates of 61 patients who underwent EGFR mutation analysis. Serum and cytologic CYFRA 21-1, CEA, and SCCA levels were measured and correlated with EGFR gene mutations. FDG PET/CT was performed on 58 patients for NSCLC staging, and SUV was correlated with EGFR mutation status.Results: Thirty (50%) patients had EGFR mutation and 57 patients had adenocarcinoma subtype. Univariate analysis showed that female gender, never smoker, high levels of cytologic CYFRA 21-1 (c-CYFRA) and lower maximum standard uptake value (SUVmax) were correlated with EGFR mutations. ROC generated cut-off values of 20.8 ng/ml for c-CYFRA and SUVmax of 9.6 showed highest sensitivity for EGFR mutation detection. Multivariate analysis revealed that female gender [hazard ratio (HR): 18.15, p = 0.025], higher levels of c-CYFRA (HR: 7.58, and lower SUVmax (HR: 0.08, p = 0.005) were predictive of harboring EGFR mutation.Conclusions: The cytologic tumor marker c-CYFRA was positively associated with EGFR mutations in NSCLC. EGFR mutation-positive NSCLCs have relatively lower glycolysis compared with NSCLCs without EGFR mutation. [ABSTRACT FROM AUTHOR]

Background: This study evaluated the efficacy and safety of S-1 combined with docetaxel (SD) following doxorubicin plus cyclophosphamide (AC) as neoadjuvant therapy in patients with HER2-negative, stage II-III breast cancer.Methods: Patients received AC every 3 weeks for four cycles followed by S-1 (30 mg/m2 orally b.i.d. on days 1-14) and docetaxel (75 mg/m2 i.v. on day 1) every 3 weeks for four cycles. The primary endpoint was the pathological complete response (pCR) rate in breast and axillary lymph nodes.Results: The study included 49 patients with a median age of 43 years. The median breast tumor size was 4.0 cm by palpation. All patients were positive for involvement of axillary lymph node and five patients also had supraclavicular lymph node metastasis, which was confirmed by histological examination. In total, 85.4% of patients (41/49) completed eight cycles of therapy and 95.9% of patients (47/49) received curative surgery. The pCR rate was 22.5% (n = 11). The clinical response rate was 67.4%. During SD chemotherapy, the most frequent grade 3-4 toxicity was neutropenia (8.5% by cycle). There was a single treatment-related mortality from severe neutropenia. Grade 3 S-1 specific toxicities such as epigastric pain (12.2% by person), stomatitis (4.1% by person), and diarrhea (2.0% by person) were also observed. In particular, gastrointestinal discomfort led to dose reduction of S-1 in 45.8% of patients.Conclusions: Given all axillary lymph node positive diseases, neoadjuvant S-1 combined with docetaxel following AC showed a favorable anti-tumor activity but gastrointestinal discomfort should be carefully considered for future studies.Trial Registration: NCT00994968. [ABSTRACT FROM AUTHOR]

Simple Summary: Cyclin-dependent kinase (CDK) 4/6 inhibitors, in combination with endocrine therapies, are now the standard of care for patients with metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer. Despite the effectiveness of CDK4/6 inhibitors, acquired resistance occurs in almost all cases. We developed and used a palbociclib-resistant preclinical model and studied the overcoming strategies, using FDA-approved chemotherapy in combination with a CDK4/6 inhibitor. We demonstrated that sequential abemaciclib treatment following eribulin-enhanced anti-tumor activity in vitro and in vivo on the CDK4/6 inhibitor-resistant cells by more effectively inhibiting the G2/M cell cycle phase. The sequential combination of abemaciclib following eribulin could be an effective treatment strategy in overcoming resistance to CDK4/6 inhibitors in HR-positive breast cancer. Breast cancer remains a leading cancer burden among women worldwide. Acquired resistance of cyclin-dependent kinase (CDK) 4/6 inhibitors occurs in almost all hormone receptor (HR)-positive subtype cases, comprising 70% of breast cancers, although CDK4/6 inhibitors combined with endocrine therapy are highly effective. CDK4/6 inhibitors are not expected to cooperate with cytotoxic chemotherapy based on the basic cytotoxic chemotherapy mode of action that inhibits rapidly proliferating cells. The palbociclib-resistant preclinical model developed in the current study investigated whether the combination of abemaciclib, CDK4/6 inhibitor with eribulin, an antimitotic chemotherapy could be a strategy to overcome palbociclib-resistant HR-positive breast cancer. The current study demonstrated that sequential abemaciclib treatment following eribulin synergistically suppressed CDK4/6 inhibitor-resistant cells by inhibiting the G2/M cell cycle phase more effectively. The current study showed the significant association of the pole-like kinase 1 (PLK1) level and palbociclib resistance. Moreover, the cumulative PLK1 inhibition in the G2/M phase by each eribulin or abemaciclib proved to be a mechanism of the synergistic effect. The synergistic antitumor effect was also supported by in vivo study. The sequential combination of abemaciclib following eribulin merits further clinical trials to overcome resistance to CDK4/6 inhibitors in HR-positive breast cancer. [ABSTRACT FROM AUTHOR]

Recently, cyclin-dependent kinase (CDK) 4/6 inhibitors have been widely used to treat advanced hormone receptor-positive breast cancer. Despite promising clinical outcomes, almost all patients eventually acquire resistance to CDK4/6 inhibitors. Here, we screened genes associated with palbociclib resistance through genomics and transcriptomics in preclinical breast cancer models. Palbociclib-resistant cells were generated by exposing hormone receptor-positive breast cancer cell lines to palbociclib. Whole-exome sequencing (WES) and a mRNA microarray were performed to compare the genomic and transcriptomic landscape between both palbociclib-sensitive and resistant cells. Microarray analysis revealed 651 differentially expressed genes (DEGs), while WES revealed 107 clinically significant mutated genes. Furthermore, pathway analysis of both DEGs and mutated genes revealed immune pathway deregulation in palbociclib-resistant cells. Notably, DEG annotation revealed activation of type I interferon pathway, activation of immune checkpoint inhibitory pathway, and suppression of immune checkpoint stimulatory pathway in palbociclib-resistant cells. Moreover, mutations in NCOR1, MUC4, and MUC16 genes found in palbociclib-resistant cells were annotated to be related to the immune pathway. In conclusion, our genomics and transcriptomics analysis using preclinical model, revealed that deregulated immune pathway is an additional mechanism of CDK4/6 inhibitor resistance besides the activation of cyclin E-CDK2 pathway and loss of RB, etc. Further studies are warranted to evaluate whether immune pathways may be a therapeutic target to overcome CDK4/6 inhibitor resistance. [ABSTRACT FROM AUTHOR]

Epithelial ovarian cancer remains the leading cause of mortality among all gynecologic malignancies owing to recurrence and ultimate development of chemotherapy resistance in the majority of patients. In the chemotherapy-resistant ovarian cancer preclinical model, we investigated whether AZD6738 (an ataxia telangiectasia and Rad3-related (ATR) inhibitor) could synergize with belotecan (a camptothecin analog and topoisomerase I inhibitor). In vitro, both chemotherapy-resistant and chemotherapy-sensitive ovarian cancer cell lines showed synergistic anti-proliferative activity with a combination treatment of belotecan and AZD6738. The combination also demonstrated synergistic tumor inhibition in mice with a chemotherapy-resistant cell line xenograft. Mechanistically, belotecan, a DNA-damaging agent, increased phospho-ATR (pATR) and phospho-Chk1 (pChk1) in consecutive order, indicating the activation of the DNA repair system. This consequently induced G2/M arrest in the cell cycle analysis. However, when AZD6738 was added to belotecan, pATR and pChk1 induced by belotecan alone were suppressed again. A cell cycle analysis in betotecan showed a sub-G1 increase as well as a G2/M decrease, representing the release of G2/M arrest and the induction of apoptosis. In ascites-derived primary cancer cells from both chemotherapy-sensitive and -resistant ovarian cancer patients, this combination was also synergistic, providing further support for our hypothesis. The combined administration of ATR inhibitor and belotecan proved to be synergistic in our preclinical model. This combination warrants further investigation in a clinical trial, with a particular aim of overcoming chemotherapy resistance in ovarian cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are widely used to treat metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer. Despite the effectiveness of CDK4/6 inhibitors, acquired resistance occurs in almost all cases. Strategies to address this issue have not been developed yet. We investigated mechanisms of resistance to CDK4/6 inhibitor in breast cancer and potential therapeutic strategies. We found that cyclin E-CDK2 mediated phosphorylation of C-MYC is responsible for resistance to CDK4/6 inhibitor by suppressing C-MYC induced senescence. On the contrary, the synergistic anti-proliferative effect of the combined inhibition of CDK2 and CDK4/6 overcomes acquired resistance to CDK4/6 inhibitors by enhancing senescence. Our findings could pave the way for the development CDK2-specific kinase inhibitor for the treatment of breast cancers that are resistant to CDK4/6 inhibitor. Breast cancer represents the number one global cancer burden in women and the hormone receptor (HR)-positive subtype comprises approximately 70% of breast cancers. Unfortunately, acquired resistance ultimately occurs in almost all cases, even though cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are a highly effective therapy for HR-positive/human epidermal growth factor receptor 2-negative subtype. Here, we investigated mechanisms of resistance to CDK4/6 inhibitor and potential therapeutic strategies using our palbociclib-resistant preclinical model. We observed that cyclin E was significantly overexpressed in palbociclib-resistant cells, and similar association was also confirmed in pleural effusion samples collected from HR-positive breast cancer patients. After confirmation of cyclin E-CDK2 interaction by co-immunoprecipitation, we demonstrated CDK2 inhibition combined with palbociclib synergistically suppressed proliferation of palbociclib-resistant cells and growth of palbociclib-resistant xenograft in mice. We also proved that enhancing C-MYC-mediated senescence is a novel mechanism behind the synergism created by targeting both CDK2 and CDK4/6. Furthermore, the clinical relevance of cyclin E as a therapeutic target was supported by significant association between CCNE1 overexpression and poor prognosis based on large-scale public gene expression data sets in HR-positive breast cancer patients. Therefore, we propose cyclin E-CDK2 signaling as a promising therapeutic target for overcoming cyclin E-associated resistance to CDK4/6 inhibitor. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to investigate whether the quantitative parameters of dual-energy computed tomography (DECT) can predict the effects of chemotherapy in advanced adenocarcinoma based on the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines.Materials and Methods: A total of 90 patients (59 males, 31 females, age 61.4 ± 12.3 (23-85)) with unresectable lung adenocarcinoma (TNM stage IIIB or IV) who underwent DECT before chemotherapy were prospectively included in this study. By comparing baseline studies with the best response achieved during 1 st line chemotherapy, patients were divided into two groups according to RECIST (version 1.1) guidelines as follows; responders (CR or PR) and non-responders (SD or PD). Quantitative measurements were performed on baseline DECT, and a logistic regression model was used to evaluate predictive factors for a response to chemotherapy.Results: Among 90 patients, 38 were categorized as responders, while 52 patients were non-responders. The mean iodine concentration measurements were significantly higher in responders compared with non-responders (1.81 ± 0.51 vs 1.33 ± 0.76 mg/ml, p < 0.001). On multivariate analysis, EGFR mutation (odds ratio (OR): 3.116, 95% confidential interval (CI):1.182-8.213, p = .019) and iodine concentration (OR: 1.112, 95% CI:1.034-1.196, p = .006) were found to be significant for predicting a treatment response.Conclusions: Dual-energy CT using a quantitative analytic method based on iodine concentration measurements can be used to predict the effects of chemotherapy in patients with advanced adenocarcinoma. [ABSTRACT FROM AUTHOR]