New targetable vulnerabilities for the treatment of chemoresistant breast and ovarian BRCA1/2-mutated tumors

Our team aims at bridging the fundamental scientific bases of genome stability maintenance with patient needs that regard cancer treatment; our ultimate goal is to foster the discovery and development of new chemotherapeutics. More specifically, we investigate DNA repair and synthetic lethal interaction in BRCA-mutated breast and ovarian cancer. Unraveling the function and structure of these mechanisms will facilitate the identification of new targets and ultimately the development of new molecules for the tailored treatment of these cancers.

In this PhD project, we aim to discover and study new targetable vulnerabilities for the treatment of chemoresistant breast and ovarian BRCA1/2-mutated tumors.

Here to find alternative curative options for PARPi-resistant HRD tumors, we aim at identifying PARP1-independent DNA repair mechanisms essential for the survival of BRCA- mutated tumors. To do so, will employ two independent yet complementary high-throughput approaches (Step 1). We will perform genome-wide CRISPR-mediated screens and proteomic analyses by mass-spectrometry in several PARPi-naive and -resistant BRCA- mutated tumor cells to identify genes whose knockout kills PARPi-resistant tumor cells specifically.

The most promising hits arising from unbiased screens will be selected for further studies. Here each hits will be evaluated for its impact on genome stability maintenance and DNA repair by using live microscopy, immunofluorescence and sequencing (Step 2).

To evaluate the potential of these hits as new druggable target for the treatment of BRCA-mutated tumors, we will take advantage of the large collection of PARPi naive and resistant BRCA-mutated patients derived xenograft (PDXs) available at Institut Curie. We will measure whether inhibition of top hits can reduce PARPi-resistant tumor growth in vivo (Step 3). Finally, best hits (new targetable vulnerabilities) will be enroll in a drug development program to initiate, in collaboration with chemists and structural biologists, the development of small- molecule inhibitors (Step 4).

Deficiency in homologous recombination (HR)-mediated DNA repair occurs mainly through genetic inactivation of the BRCA1 and BRCA2 (BRCA) genes. HR-

deficiency (HRD) plays a role in the initiation and progression of many tumor types, including breast, ovarian and pancreatic tumors. Importantly, about 50% of basal like breast tumors and ovarian serous carcinomas show defect in HR. HRD tumors (or BRCA-mutated tumors) exhibit increased genomic instability and dependence on alternative DNA repair mechanisms for survival, setting the stage for synthetic lethality-based targeted therapies. A prime example is the extreme sensitivity of HRD tumors to poly (ADP-ribose) polymerase inhibitors (PARPi). However, PARPi and other chemotherapeutics have shown limited effectiveness in achieving HRD cancer remission, notably because of the emergence of drug resistance. Hence, no therapeutic options are left for patients suffering from HRD cancers, and many succumb to the disease, stressing the need for alternative curative options. Providing with new curative options for the treatment of these tumors is the final goal of our team (Step 5).

Any medical doctor with a strong interest in basic research and especially tumor biology. A knowledge of breast and ovarian tumors will be considered as a plus.