Ovarian cancer (OC) is the deadliest gynecological cancer with an overall survival of less than 40%. Although most patients respond well to the initial taxol/platin treatment, recurrence of the disease is observed in most patients, indicating the urgent need for the development of new treatment strategies. One of the most popular approaches for treating cancer is targeted therapy. Targeted therapy consists of the use of drugs that exploits specific weaknesses of cancer cells and that have a limited effect on normal cells. Unfortunately, in many cases the cancer cells adapt to the drug and become resistant.
In the case of OC treatment, several targeted therapy drugs that inhibit a protein called poly (ADP-ribose) polymerase (PARP) have been developed. PARP protein is involved in DNA damage repair and, thus, the use of PARP inhibitors leads to the accumulation of DNA damage. Since OC cells often display defects in the mechanisms of DNA damage repair, the use of PARP inhibitors (PARPi) is very efficient in the killing of the cancer cells. Although several clinical trials have shown the efficacy of PARPi in OC by improving the disease free survival, a rapid development of drug resistance was observed in many patients. To increase the clinical benefits of PARPi, several groups, including ours, have suggested the use of PARPi in combination with a drug that would target the adaptive response of the cells to the stress induced by the PARPi. Previous studies have shown that the PI3K signaling pathway helps cancer cells survive PARPi. Targeting this pathway with a drug in combination with PARPi have been shown to act synergistically in the killing of cancer cells, but the underlying mechanisms are yet to be elucidated. The goal of this project are to identify molecular mechanisms and protein networks involved in the synthetic lethality induced by the combination of PARPi and PI3K pathway inhibitors and to provide methods to identify patients who will benefit as well as mechanisms of resistance that could be targeted.
To address these questions, we will use pre and post treatment tumor samples from patients treated with a PARPi in combination with a PI3K pathway inhibitor. Pre and post treatment samples from responders and non-responders will be compared through the analysis of DNA, RNA and proteins. Furthermore, we will use a panel of sensitive and resistant ovarian cancer cell lines that we will treat with PARPi and PI3K inhibitors. We will characterize protein networks involved in the response to these drugs. This project will help predict which patients would benefit a PARP and PI3K inhibitors combination and understand molecular mechanism involved in the response to this drug combination.
This grant was made possible in part by a generous donation from Ruth and Steve Anderson, in honor of Shea Anderson Gerlinger.