Roberto Vargas

Gram-positive targeting antibiotics are associated with progression and death in women with platinum-sensitive recurrent high grade epithelial ovarian cancer

A working group report from the 2024 National Cancer Institute / Gynecologic Cancer Steering Committee endometrial cancer clinical trials planning meeting: refining the approach to endometrial cancer in the immunotherapy era

Abstract Endometrial cancer is now the leading cause of gynecologic cancer death in the United States. Recognizing the urgent need to improve outcomes for patients diagnosed with endometrial cancer, the National Cancer Institute Gynecologic Cancer Steering Committee convened a clinical trials planning meeting, Refining the Approach to Endometrial Cancer in the Immunotherapy Era, on January 8 and 9, 2024. Multidisciplinary experts were charged with addressing critical challenges to optimize treatment of endometrial cancer in the new immunotherapy landscape. As part of the clinical trials planning meeting, working groups were assembled to address several important aspects of clinical trial design. Working group 1 focused on translational science and was tasked with reviewing the scientific literature for data on validated discriminants of response to immunotherapy to inform trial concept development by the therapy-focused groups. The working group established that molecular subtyping of endometrial cancer is now the standard approach for classifying endometrial tumors. Molecular subtyping for prognostic and predictive applications should be considered when assessing biomarkers as well as therapeutic targets. Additionally, strategies to improve immune response like incorporation of radiation as well as therapy sequencing considerations should continue to be explored. A major key observation from working group 1 was lack of validated discriminants for immunotherapy response beyond mismatch repair status, and tumor mutational burden and exploration of additional discriminants of response and resistance will be critical with the increasing use of immunotherapy in endometrial cancer.

Bridging the Gap from Bench to Bedside: A Call for In Vivo Preclinical Models to Advance Endometrial Cancer and Cervical Cancer Immuno-oncology Research

Abstract Advanced-stage endometrial and cervical cancers are associated with poor outcomes despite contemporary advances in surgical techniques and therapeutics. Recent clinical trial results have led to a shift in the treatment paradigm for both malignancies, in which immunotherapy is now incorporated as the standard of care up front for most patients with advanced endometrial and cervical cancers as the standard of care. Impressive response rates have been observed, but unfortunately, a subset of patients do not benefit from immunotherapy, and survival remains poor. Continued preclinical research and clinical trial development are crucial for our understanding of resistance mechanisms to immunotherapy and maximization of therapeutic efficacy. In this setting, syngeneic models are preferred over xenograft models as they allow for the evaluation of the tumor–immune interaction in an immunocompetent host, most closely mimicking the tumor–immune interaction in patients with cancer. Unfortunately, significant disparities exist about syngeneic models in gynecologic malignancy, in which queries from multiple large bioscience companies confirm no commercial availability of endometrial or cervical cancer syngeneic cell lines. Published data exist about the recent development of several endometrial and cervical cancer syngeneic cell lines, warranting further investigation. Closing the disparity gap for preclinical models in endometrial and cervical cancers will support physician scientists, basic and translational researchers, and clinical trialists who are dedicated to improving outcomes for our patients with advanced disease and poor prognosis.

Disruption of the Gut Microbiota Confers Cisplatin Resistance in Epithelial Ovarian Cancer

Abstract Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer death. Despite initial responses to intervention, up to 80% of patient tumors recur and require additional treatment. Retrospective clinical analysis of patients with ovarian cancer indicates antibiotic use during chemotherapy treatment is associated with poor overall survival. Here, we assessed whether antibiotic (ABX) treatment would impact growth of EOC and sensitivity to cisplatin. Immunocompetent or immunocompromised mice were given untreated control or ABX-containing (metronidazole, ampicillin, vancomycin, and neomycin) water prior to intraperitoneal injection with EOC cells, and cisplatin therapy was administered biweekly until endpoint. Tumor-bearing ABX-treated mice exhibited accelerated tumor growth and resistance to cisplatin therapy compared with control treatment. ABX treatment led to reduced apoptosis, increased DNA damage repair, and enhanced angiogenesis in cisplatin-treated tumors, and tumors from ABX-treated mice contained a higher frequency of cisplatin-augmented cancer stem cells than control mice. Stool analysis indicated nonresistant gut microbial species were disrupted by ABX treatment. Cecal transplants of microbiota derived from control-treated mice was sufficient to ameliorate chemoresistance and prolong survival of ABX-treated mice, indicative of a gut-derived tumor suppressor. Metabolomics analyses identified circulating gut-derived metabolites that were altered by ABX treatment and restored by recolonization, providing candidate metabolites that mediate the cross-talk between the gut microbiome and ovarian cancer. Collectively, these findings indicate that an intact microbiome functions as a tumor suppressor in EOC, and perturbation of the gut microbiota with ABX treatment promotes tumor growth and suppresses cisplatin sensitivity. Significance: Restoration of the gut microbiome, which is disrupted following antibiotic treatment, may help overcome platinum resistance in patients with epithelial ovarian cancer. See related commentary by Hawkins and Nephew, p. 4511