Building a Personalized Medicine Infrastructure for Gynecological Oncology Patients in a High-Volume Hospital

Gynecological cancers require complex intervention since patients have specific needs to be addressed. Centralization to high-volume centers improves the oncological outcomes of patients with gynecological cancers. Research in gynecological oncology is increasing thanks to modern technologies, from the comprehensive molecular characterization of tumors and individual pathophenotypes. Ongoing studies are focusing on personalizing therapies by integrating information across genomics, proteomics, and metabolomics with the genetic makeup and immune system of the patient. Hence, several challenges must be faced to provide holistic benefit to the patient. Personalized approaches should also recognize the unmet needs of each patient to successfully deliver the promise of personalized care, in a multidisciplinary effort. This may provide the greatest opportunity to improve patients’ outcomes. Starting from a narrative review on gynecological oncology patients’ needs, this article focuses on the experience of building a research and care infrastructure for personalized patient management

Dual inhibition of CDK12 and CDK13 uncovers actionable vulnerabilities in patient-derived ovarian cancer organoids

Abstract Background High grade serous ovarian cancer (HGSOC) is highly lethal, partly due to chemotherapy resistance and limited availability of targeted approaches. Cyclin dependent kinases 12 and 13 (CDK12/13) are promising therapeutic targets in human cancers, including HGSOC. Nevertheless, the effects of their inhibition in HGSOC and the potential synergy with other drugs are poorly known. Methods We analyzed the effects of the CDK12/13 inhibitor THZ531 in HGSOC cells and patient-derived organoids (PDOs). RNA sequencing and quantitative PCR analyses were performed to identify the genome-wide effects of short-term CDK12/13 inhibition on the transcriptome of HGSOC cells. Viability assays with HGSOC cells and PDOs were performed to assess the efficacy of THZ531 as single agent or in combination with clinically relevant drugs. Results The CDK12 and CDK13 genes are deregulated in HGSOC and their concomitant up-regulation with the oncogene MYC predicts poor prognosis. HGSOC cells and PDOs display high sensitivity to CDK12/13 inhibition, which synergizes with drugs in clinical use for HGSOC. Transcriptome analyses revealed cancer-relevant genes whose expression is repressed by dual CDK12/13 inhibition through impaired splicing. Combined treatment with THZ531 and inhibitors of pathways regulated by these cancer relevant genes (EGFR, RPTOR, ATRIP) exerted synergic effects on HGSOC PDO viability. Conclusions CDK12 and CDK13 represent valuable therapeutic targets for HGSOC. We uncovered a wide spectrum of CDK12/13 targets as potential therapeutic vulnerabilities for HGSOC. Moreover, our study indicates that CDK12/13 inhibition enhances the efficacy of approved drugs that are already in use for HGSOC or other human cancers