Platinum-based agents are the core chemotherapeutic for treatment of ovarian cancer. Based on the initial response to platinum-based chemotherapy, ovarian cancer patients are classified into three categories: platinum-refractory, platinum-resistant, and platinum-responsive. Platinum-refractory patients do not respond to platinum-based therapy and show progression during the course of the therapy. Meanwhile, platinum-resistant tumors can recur within 6 months of cisplatin treatment, and although considered incurable, are still responsive to chemotherapy to variable degrees. Lastly, the platinum-responsive patients initially respond to therapy, and their treatment-free interval lasts between 6 months to several years. However, when these patients present with recurrent disease, the tumors are typically not responding to platinum. Given the range of resistance to platinum-based therapy, new treatments effective against platinum-refractory and -resistant ovarian cancers are urgently needed to increase cure rates of ovarian cancers. After rigorous preliminary experiments, we have identified one such novel drug, N7-73, that targets platinum-resistant high-grade serous ovarian cancers.

The drug N7-73 was identified after phenotypic screening of 650 active compounds on four high-grade serous ovarian cancer cell lines and chemoresistant 3D spheroid cell models. In order to test its ability to target chemoresistant cells in patient samples, N7-73 was tested on patient-derived ovarian cancer stem cell spheroids, where it was found to be effective across 10 patient tumors. These data encouraged us in this proposal to conduct preclinical testing of N7-73 for its ability to kill platinum-resistant ovarian cancers while sparing normal ovarian cells. By using 3D spheroids generated from ovarian cancer cell lines and ovarian cancer patient-derived xenografts that have developed platinum resistance, we will identify the cellular targets of N7-73 and perform in-depth mechanistic studies to better understand the single-agent activity of N7-73. Further, we will identify the analogues of N7-73 that possess enhanced potency and selectivity toward cancer cells and test them on 3D chemoresistant ovarian cancer cell line spheroids and on spheroids derived from tumor cells from patients. Using the potent analogues of N7-73, we will also identify the chemoresistance pathways in ovarian cancer cells that survive after the N7-73 treatment and utilize them to find new druggable targets. Finally, we will validate the efficacy of N7-73 as a single agent or in combination with carboplatin in the patient-derived spheroids xenograft in vivo model.

Short-term impact: We have assembled an outstanding team, which has been efficiently collaborating together for over three years, with complementary expertise in the proposed areas. Together, we will test the efficacy of the novel drug N7-73, either as a single agent or in combination therapies, to target platinum-resistant ovarian cancers. With our physiologically relevant novel approach, we will establish the effectiveness of N7-73 across multiple subtypes of ovarian cancers, by performing screens on patient-derived ovarian cancer spheroids generated from several patient samples, with the aim of establishing effective N7-73 dosage for each patient sample. By optimizing concurrent and sequential chemotherapeutic strategy with N7-73 or its combination with carboplatin, we will reduce tumor growth. Our integrated platform (3D in vitro and in vivo) is high-throughput amenable and can be easily adopted by both basic or clinical oncology researchers.

Long-term impact: This work has the possibility to inform future clinical combinations and the potential to identify specific therapies of benefit for the patients with platinum-refractory and -resistant ovarian cancers. With the screening of N7-73 analogues, ovarian cancer patient cells can be screened for effective individualized therapy, to control or eliminate ovarian cancer. By combining a physiologically relevant model that preserves ovarian cancer patient heterogeneity with genetic analysis after N7-73 treatment, we will enhance the predictive potency of preclinical drug testing. After successful completion of the proposed project, we hope to establish a clinical trial to directly assess the efficacy of N7-73 in platinum-refractory and platinum-resistant ovarian cancers. By creating individualized therapies catering to the unique needs of each ovarian cancer patient, we hope to contribute to elimination of ovarian cancers.