Kenta Masuda

mTOR-mediated p62/SQSTM1 stabilization confers a robust survival mechanism for ovarian cancer

Over 50 % of patients with high-grade serous carcinoma (HGSC) are homologous recombination proficient, making them refractory to platinum-based drugs and poly (ADP-ribose) polymerase (PARP) inhibitors. These patients often develop progressive resistance within 6 months after primary treatment and tend to die early, thus new therapies are urgently needed. In this study, we comprehensively investigated this tumor type by leveraging a combination of machine learning analysis of a large published dataset and newly developed genetically engineered HGSC organoid models from murine fallopian tubes. Aberrant activation of RAS/PI3K signaling was a signature of poor prognosis in BRCA1/2 wild-type ovarian cancer, and mTOR-induced elevated p62 expression was a robust marker of chemotherapy-induced mTOR-p62-NRF2 signal activation. mTOR inhibition with everolimus decreased p62 and enhanced sensitivity to conventional chemotherapy, indicating that p62 serves as an important biomarker for therapeutic intervention. Combination therapy with conventional chemotherapy and mTOR inhibitors is a promising therapeutic strategy for refractory HGSC, with p62 as a biomarker.

Current status of hereditary breast and ovarian cancer practice among gynecologic oncologists in Japan: a nationwide survey by the Japan Society of Gynecologic Oncology (JSGO)

The practices pertaining to hereditary breast and ovarian cancer (HBOC) in Japan have been rapidly changing owing to the clinical development of poly(ADP-ribose) polymerase inhibitors, the increasing availability of companion diagnostics, and the broadened insurance coverage of HBOC management from April 2020. A questionnaire of gynecologic oncologists was conducted to understand the current status and to promote the widespread standardization of future HBOC management. A Google Form questionnaire was administered to the members of the Japan Society of Gynecologic Oncology. The survey consisted of 25 questions in 4 categories: respondent demographics, HBOC management experience, insurance coverage of HBOC management, and educational opportunities related to HBOC. A total of 666 valid responses were received. Regarding the prevalence of HBOC practice, the majority of physicians responded in the negative and required human resources, information sharing and educational opportunities, and expanded insurance coverage to adopt and improve HBOC practice. Most physicians were not satisfied with the educational opportunities provided so far, and further expansion was desired. They remarked on the psychological burdens of many HBOC managements. Physicians reported these burdens could be alleviated by securing sufficient time to engage in HBOC management, creating easy-to-understand explanatory material for patients, collaboration with specialists in genetic medicine, and educational opportunities. Gynecologic oncologists in Japan are struggling to deal with psychological burdens in HBOC practice. To promote the clinical practice of HBOC management, there is an urgent need to strengthen human resources and improve educational opportunities, and expand insurance coverage for HBOC management.