Topic: Memory of Franco Muggia：Drug Resistance in Female Cancer

In the 1940s, women with ovarian cancer seldom survived for over a year in spite of tantalizing responses to chemotherapy following surgery. In the 1970s, cisplatin’s dramatic efficacy pointed to the cancer’s inability to repair platinum-DNA adducts leading to efforts in antiemetics and nephro- and neuro-toxicity protection, coupled with developing analogs either less toxic (e.g., carboplatin) or active against cisplatin-resistant models (e.g., oxaliplatin).  Identification of mutant BRCA genes in 1990s conferring high lifetime risks of developing breast and ovarian cancers proved insightful: BRCA1, BRCA2 and downstream genes were key players in homologous recombination (HR) repair of double strand breaks. Risk-reducing salpingo-oophorectomies in mutation carriers showed nearly 10% of premalignant and invasive serous “ovarian” cancers arising in Fallopian tube fimbriae – some already with peritoneal dissemination. Moreover, these cells lacking HR BRCA function exhibited synthetic lethality upon exposure to poly(ADP-ribose) polymerase inhibitors (i.e., PARPi) interfering with repair of single strand DNA breaks. Platinum-based induction regimens for such cancers are now poised to enhance future curative strategies –until now they have been largely unfulfilled. Paths towards prolonged survival now exploit targeting cellular DNA repair mechanisms beyond platinums. Results since 2018 leveraging oral PARP inhibitors after completion of platinum doublets – emphasize the timely introduction to active drugs forestalling recurrences with heightened resistance.

31 Dec 2021