Targeted Docetaxel-Nanocolloid for the Treatment of Ovarian Cancer

DESCRIPTION (provided by applicant): PROJECT SUMMARY This proposal is a Phase 1 proposal in response to The National Institute of Health Small Business Innovation Research (SBIR) Program call for proposals for the Cancer Diagnostics and Therapeutic AgentsEnabled By Nanotechnology (SBIR [U43/U44]) [Program Announcement Number: PA-10-286]. Nemucore Medical Innovation, Inc.'s (NMI) goal for this Phase 1 SBIR proposal is to fully determine the controlled release, targeting, cytotoxicity, pharmacokinetics, andefficacy profile for a novel integrins v3 and v5 targeted docetaxel (DTX) encased in a nanocolloid created with a proprietary layer-by-layer manufacturing process, designated NMI-700, for treatment of integrin expressing ovarian cancers. NMI's long- termgoal is to couple NMI-700 with a companion diagnostic utilizing AutoGenomic's INFINITI platform to screen for integrin expressing ovarian tumors in order to stratify patients into a cohort who would most benefit from this unique treatment. Part of the challenge with standard chemotherapeutic agents is the retention and distribution of the agent, which can be solved with the use of the NMI's long circulating nanocolloid technology developed for encapsulating poorly soluble drugs, such as DTX. Integrin targeting is highly applicable for ovarian cancer because most of ovarian cancers differentially express integrins compared to other adult tissues. Therefore design of NMI-700 incorporates a number of key attributes, which respond to physical limitations of DTXby mitigating solubility issues and to clinical observations that limiting systemic exposure that reduces drug toxicity, clearance, and inactivation through targeting and controlled release of sequestered DTX. For newly diagnosed ovarian cancer patients,a majority of whom rapidly progress to a chemoresistant state, NMI's nanomedicine offers a solution that is urgently needed for treating patients with refractory disease, which is generally incurable, and the goal of further treatment changes from one ofcure to one of palliation. It is anticipated that the pre-clinical studies will advance to subsequent clinical trials where patients will be segregated into potential responders using the companion INFINITI diagnostic. By the end of the grant period NMIshould have much of the data needed to proceed to the next stage of preclinical development and to further the advancement of this unique integrin-targeted/DTX nanomedicine into the clinic. NMI anticipates that development of NMI-700 product will provide the following benefits: Provide a new highly cytotoxic treatment for tumors of a patient population in desperate need for a clinical solution. Advance the development of nanomedicine, a key compliment to the promise of personalized medicine. Commercialize a new method of manufacture for solubilizing poorly soluble drugs. PUBLIC HEALTH RELEVANCE PROJECT NARRATIVE Nemucore Medical Innovations, Inc. (NMI) is developing a nanomedicine product that addresses major unmet clinical needs for the treatment ofovarian cancer. With an estimated 22,000 new cases in 2008 and approximately 15,000 deaths, ovarian cancer is the most lethal of gynecologic cancers in the USA. In general ovarian cancers respond to conventional therapy, but eventually regrow and are resistant to further standard anticancer drugs. In most cases patients experience severe side effects because the anticancer drugs, not only interact tumors, but other organs in the body, thus, adversely affecting the quality of life of the cancer patient. Additionally, the standard anti-cancr drugs may be rapidly cleared from the body and inactivated in the blood or organs, other than the tumor; these actions decrease the overall amount of active drug that reaches the tumor and limit the effectiveness of the therapy. To overcome these characteristics of drug therapy physicians generally give high doses of standard drugs to treat tumors, but such treatment simultaneously induces debilitating toxic side effects in patients which have to be mitigated by lowering the dose. The promise of nanomedicine circumvents drug inactivation as it circulates through the body with a concomitant decrease in side effects, increases anticancer drug accumulation in tumors and improves treatment of cancer. NMI designed a nanomedicine, which contains the anticancer drug, docetaxel (DTX) encased in a nanosized vehicle. The vehicle is decorated with protein that specifically binds to the target v3 and v5 integrins and has stealth properties to evade the body's normal inactivation and clearance mechanisms. Moreover ovarian cancers the selective expression of integrins v3 and v5, which play a significant role in angiogenesis and in metastasis provide a natural target for drawing the DTX-carrying nanosized vehicle to theses tumors providinga means for DTX to preferentially accumulate in the tumors and increasing the effectiveness of eradicating the tumors. Long term, and not part of this proposal, NMI plans to develop with its strategic partner AutoGenomics Inc. a diagnostic that will aid in the selection of the patients who would benefit from the integrin tar