Medicon — Department of Health and Human Services SBIR Phase I: 102

Description

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 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 years Thus the development of efficacious and safe agents for EOC is an unmet and pressing medical need Q 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 Q showed rapid tumor regression reduction in tumor load compared to its baseline and 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 Q ihhibits the growth of platinum and doxorubicin resistant cells with identical potency as the parent cell line Finally Q inhibits mutant K Ras and suppresses VEGF a molecule critical to the introperitoneal spread of EOC Our hypothesis is that Q 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 Determine the efficacy and safety of Q in EOC Aim Determine the pharmacokinetics and biodistribution of Q And Aim Determine in vitro and in vivo the mechanism of action of Q in EOC Q 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 Q 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 EOCNARRATIVE Ovarian cancer is the most lethal gynecological malignancy Most women present with advanced cancer which is treated with surgery and chemotherapy to which many patients become resistant One of the reasons for the high mortality of ovarian cancer is the lack of efficacious therapeutic agents The development of efficacious and safe agents for this cancer is an unmet medical need Q is a proprietary anti cancer agent that we hypothesize to be efficacious and safe for the treatment of ovarian cancer We propose studies to evaluate this hypothesis