The growing use of neoadjuvant chemotherapy to treat advanced stage high-grade serous ovarian cancer (HGSOC) creates an opportunity to better understand chemotherapy-induced mutational and gene expression changes. Here we performed a cohort study including 34 patients with advanced stage IIIC or IV HGSOC to assess changes in the tumor genome and transcriptome in women receiving neoadjuvant chemotherapy. RNA sequencing and panel DNA sequencing of 596 cancer-related genes was performed on paired formalin-fixed paraffin-embedded specimens collected before and after chemotherapy, and differentially expressed genes (DEG) and copy-number variations (CNV) in pre- and post-chemotherapy samples were identified. Following tissue and sequencing quality control, the final patient cohort consisted of 32 paired DNA and 20 paired RNA samples. Genomic analysis of paired samples did not reveal any recurrent chemotherapy-induced mutations. Gene expression analyses found that most DEGs were upregulated by chemotherapy, primarily in the chemotherapy-resistant specimens. AP-1 transcription factor family genes (FOS, FOSB, FRA-1) were particularly upregulated in chemotherapy-resistant samples. CNV analysis identified recurrent 11q23.1 amplification, which encompasses SIK2. In vitro, combined treatment with AP-1 or SIK2 inhibitors with carboplatin or paclitaxel demonstrated synergistic effects. These data suggest that AP-1 activity and SIK2 copy-number amplification are induced by chemotherapy and may represent mechanisms by which chemotherapy resistance evolves in HGSOC. AP-1 and SIK2 are druggable targets with available small molecule inhibitors and represent potential targets to circumvent chemotherapy resistance. Significance: Genomic and transcriptomic analyses identify increased AP-1 activity and SIK2 copy-number amplifications in resistant ovarian cancer following neoadjuvant chemotherapy, uncovering synergistic effects of AP-1 and SIK2 inhibitors with chemotherapy.
PURPOSE: The COVID-19 pandemic has created new challenges for ovarian cancer survivors. This study aims to evaluate the psychologic morbidity and alterations in medical care caused by the pandemic. METHODS: Advanced-stage ovarian cancer survivors at our institution were contacted for participation in a cross-sectional telephone-based quantitative survey study assessing pandemic-related psychologic morbidity. Psychologic domains using validated measures were explored: health-related quality of life (HRQOL; functional assessment of cancer therapy [FACT-G7]), anxiety (generalized anxiety disorder-7 [GAD7]), depression (Patient Health Questionnarie-2 [PHQ2]), global health Patient-Reported Outcomes Measurement Information System - Global Physical Health/Global Mental Health (PROMIS-GMH/GPH), resilience (brief resilience scale), and loneliness (English Longitudinal Study on Aging). Novel COVID-19 pandemic questions were drawn from a larger survey developed in our department. RESULTS: Fifty-nine percent (61 of 104) of contacted patients completed the survey. One quarter of respondents had high resilience, with only 10% reporting low resilience. Only one patient screened positive for depression, and two for anxiety. Increased loneliness was reported by 43% of respondents. Patients' overall HRQOL was good (median = 21; range = 6-28). Few patients experienced treatment delays, with only four experiencing chemotherapy interruption and two reporting surgical delays. Multiple regression analyses revealed that high FACT-G7 HRQOL was predicted by age > 65 years, high self-reported mental health, high resilience, and being off chemotherapy. Lower COVID-19 concern was predicted by recurrent cancer and high resilience. CONCLUSION: Despite the far-reaching impact of the COVID-19 pandemic, ovarian cancer survivors' HRQOL has been maintained. Older age, high resilience, high mental health, and being off chemotherapy predicted better HRQOL. Ovarian cancer survivors remain resilient in the face of the pandemic, and the support of clinicians to preserve this invaluable personal resource is critical for well-being.
Chemotherapy is often ineffective in advanced stage and aggressive histologic subtypes of endometrial cancer. Overexpression of the receptor tyrosine kinase AXL has been found to be associated with therapeutic resistance, metastasis, and poor prognosis. However, the mechanism of how inhibition of AXL improves response to chemotherapy is still largely unknown. Thus, we aimed to determine whether treatment with AVB-500, a selective inhibitor of GAS6-AXL, improves endometrial cancer cell sensitivity to chemotherapy particularly through metabolic changes. We found that both GAS6 and AXL expression were higher by immunohistochemistry in patient tumors with a poor response to chemotherapy compared to tumors with a good response to chemotherapy. We showed that chemotherapy resistant endometrial cancer cells (ARK1, uterine serous carcinoma and PUC198, grade 3 endometrioid adenocarcinoma) had improved sensitivity and synergy with paclitaxel and carboplatin when treated in combination with AVB-500. We also found that in vivo intraperitoneal models with ARK1 and PUC198 cells had decreased tumor burden when treated with AVB-500 + paclitaxel compared to paclitaxel alone. Treatment with AVB-500 + paclitaxel decreased AKT signaling which resulted in a decrease in basal glycolysis. Finally, multiple glycolytic metabolites were lower in the tumors treated with AVB-500 + paclitaxel than in tumors treated with paclitaxel alone. Our study provides strong pre-clinical rationale for combining AVB-500 with paclitaxel in aggressive endometrial cancer models
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