Development of an Orally Available and Low-Toxic Chemotherapy for Improved Ovarian Cancer Therapy
Abstract
Background: The overall survival (OS) rate of ovarian cancer (OC) patients diagnosed with metastatic OC remains dismal. Chemotherapeutic drugs, including Taxol (paclitaxel) and Platinol (cisplatin or carboplatin), are often used to treat OC patients. While they show initial anticancer activity, the clinical efficacy of these currently FDA-approved chemotherapeutic drugs are limited by several factors. First, these drugs are often actively pumped out of cancer cells by proteins known as efflux pumps. Upon prolonged treatment with these drugs, cancer cells will produce excessive levels of drug efflux pumps and the body will effectively clear these drugs before they can kill the cancer cells, leading to therapeutic resistance and disease progression. Escalating the dose of these chemotherapy drugs is not currently possible, because it leads to high toxicity. Second, the use of these drugs is frequently associated with neurotoxicity, including persistent peripheral neuropathy after therapy ends, particularly if used with other agents that are neurotoxic. Third, these drugs must be administered using the intravenous route (i.v.) by infusion, and cannot be taken orally. This could increase patient exposures to potential environmental infections (e.g., COVID-19 as an extreme example). It is especially important since existing chemotherapies often weaken cancer patients’ immune systems and thus increases their risk of infection. Therefore, there is an urgent need to develop new oral therapies that are not susceptible to drug resistance mechanisms (i.e., drug efflux) and are less toxic in order to improve quality of life and to reduce the morbidity and mortality associated with metastatic OC. Rationale, Objectives, and Aims: Our overarching objective is to design novel therapies to make metastatic OC a manageable, chronic disease (no evidence of disease NED). We discovered a new class of tubulin inhibitors represented by our investigational new drug VERU-111 (Sabizabulin) that can be taken orally (PO per oral once per day under current clinical trials) and effectively bypasses many of the known resistance mechanisms associated with the prolonged use of existing chemotherapy for OC. VERU-111 also shows substantially less neurotoxicity in preclinical mouse and dog studies and the ongoing clinical trials. Preliminary evaluation using VERU-111 in highly metastatic, orthotopic human models of OC in mice clearly demonstrated that it suppresses ovarian tumor growth and metastases. Currently, VERU-111 is in late-stage human clinical trials for breast cancer and prostate cancer. A phase 3 trial for hospitalized COVID-19 patients was stopped early due to overwhelming efficacy and an Emergence Use Approval (EUA) application was submitted to the FDA on June 7. We have also developed a new generation of VERU-111, represented by our best new compound SHIP-216, which showed improved efficacy and maintains the ability to circumventing drug resistance to existing chemotherapy. Our technical goals in this project are to rigorously de-risk SHIP-216 as a potential future clinical candidate and comprehensively evaluate both VERU-111 and SHIP-216 in chemotherapy-resistant, well-characterized preclinical mouse models that develop lethal metastatic OC disease. If successful, such preclinical data will allow our industry partner, Veru, Inc., who licensed these patent portfolios, to have solid foundations and optimal designs to initiate phase 2 trials in OC patients within the next 4 years, with the goal to provide a more efficacious therapy for metastatic and chemoresistant OC patients. Overarching Challenges Addressed: To revolutionize treatment regimens by overcoming current clinical limitations by replacing the use of existing FDA approved tubulin inhibitor treatment regimens with a new generation of orally available tubulin inhibitors that are more effective and less toxic and will increase overall survival (OS). A secon
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310216
Entities
People
- Wei Li
Organizations
- United States Army
- University of Tennessee Health Science Center