Monday, April 28, 2025
4/28/2025
A Novel Agent for Ovarian Cancer - ABSTRACT Epithelial ovarian cancer (EOC) is the main subgroup of ovarian cancer, the most lethal gynecological malignancy. EOC encompasses high-grade serous epithelial ovarian carcinoma, fallopian tubal, and peritoneal carcinomas, which are considered a single clinical entity due to their shared clinical behavior, treatment and pathogenesis. Most women (75%) present with advanced EOC which is treated with cytoreductive surgery and chemotherapy consisting of a platinum salt plus a taxane. While most patients respond to first-line chemotherapy, many become platinum resistant. The high mortality of EOC is attributed to the late diagnosis of the disease and the lack of efficacious therapeutic agents; rates of survival have not changed in the last 20 years. Thus the development of efficacious and safe agents for EOC is an unmet and pressing medical need. Q922 is a proprietary anti-cancer agent that in preliminary studies showed broad anticancer properties and remarkable safety. In a mouse model of stage III EOC, Q922 showed rapid tumor regression (53% reduction in tumor load compared to its baseline and 153% reduction compared to vehicle control). This result is highly promising as in the vast majority of EOC patients at both initial diagnosis and tumor recurrence the cancer is confined to the peritoneal cavity. Additional preliminary data indicate safety, a favorable PK pattern and a novel mechanism of action. The pivotal mechanistic event is induction of strong oxidative stress that activates several downstream signaling pathways, leading to a profound cytokinetic effect (suppressed proliferation, induction of apoptosis, and cell cycle block) that, in turn, results in tumor regression. Using cis-platinum and doxorubicin resistant ovarian cell lines we demonstrated that Q922 ihhibits the growth of platinum and doxorubicin resistant cells with identical potency as the parent cell line. Finally, Q922 inhibits mutant K-Ras, and suppresses VEGF, a molecule critical to the introperitoneal spread of EOC. Our hypothesis is that Q922 is an efficacious and safe agent for the treatment of EOC acting predominantly through a redox-based mechanism. We propose to evaluate our hypothesis by pursuing three specific aims: Aim #1: Determine the efficacy and safety of Q922 in EOC. Aim #2: Determine the pharmacokinetics and biodistribution of Q922. And Aim #3: Determine in vitro and in vivo the mechanism of action of Q922 in EOC. Q922, is an outstanding drug candidate for EOC, based on its efficacy, safety, favorable PK, low cost and ability to inhibit the growth of drug-resistant EOC cells. Our preliminary data support the strong therapeutic potential of Q922. By assessing key aspects of the pharmacology of this promising agent, the proposed work will provide the foundation for its further development as an efficacious and safe treatment for EOC
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