DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Discovery of Orally Bioavailable Tubulin Inhibitors to Overcome Taxane Resistance in Metastatic Breast Cancer

Principal Investigator: LI, WEI
Institution Receiving Award: TENNESSEE, UNIVERSITY OF, HEALTH SCIENCE CENTER
Program: BCRP
Proposal Number: BC190092
Award Number: W81XWH-20-1-0011
Funding Mechanism: Breakthrough Award - Funding Level 2 - Partnering PI Option
Partnering Awards: BC190092P1
Award Amount: $1,271,866.00
Period of Performance: 3/1/2020 - 2/29/2024


PUBLIC ABSTRACT

Background: The overall survival rate of breast cancer patients diagnosed with metastatic breast cancer (MBC) remains dismal. Among the different molecular types of MBC, triple-negative breast cancer (TNBC) cells do not express estrogen receptor (ER), progesterone receptor (PR), and human epithermal growth factor 2 (HER2). Thus, patients with TNBC do not response to hormonal or Herceptin® (trastuzumab)-based targeted therapy. Therefore, chemotherapeutic drugs, including Taxol® (paclitaxel) or Taxotere® (docetaxel), are often used to treat TNBC. These drugs, in the general class called tubulin inhibitors, work mainly by inhibiting the critical function of a cytoskeleton protein called tubulin and by cutting blood/nutrition supplies to tumor cells. While they show initial anticancer activity, the clinical efficacy of these currently Food and Drug Administration (FDA)-approved taxane 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 taxanes, 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 taxane 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, both Taxol and Taxotere have very poor water solubility, such that potentially harmful surfactants, such as Cremophor EL, are needed to keep the drug in solution. Lastly, these drugs must be administered using the intravenous route (i.v.) by infusion and cannot be taken orally. Therefore, there is an urgent need to develop new tubulin inhibitor therapies that are not susceptible to drug resistance mechanisms (like drug efflux) and are less toxic in order to improve quality of life and to reduce the morbidity and mortality associated with MBC.

Rationale, Objectives, and Aims: Our overarching objective is to design novel therapies to make MBC a manageable, chronic disease (“no evidence of disease”). We discovered a new class of tubulin inhibitors represented by our lead compound VERU-111 that can be taken by mouth (likely once per day) and effectively bypasses many of the known taxane resistance mechanisms associated with the prolonged use of paclitaxel. The VERU-111 scaffold also shows substantially less neurotoxicity in preclinical mouse and dog studies. Preliminary evaluation using VERU-111 in two highly metastatic human models of TNBC in mice clearly demonstrated that it suppresses tumor growth and lung/lymph node metastases, with comparable efficacy to Taxol. In a known taxane-resistant TNBC model, VERU-111 also repressed tumor growth and inhibited the growth of established metastases (present prior to treatment). While VERU-111 is highly promising, improving its anticancer potency and metabolic stability would allow lower drug doses with a higher treatment (therapeutic) index to ensure success in eradicating or suppressing metastatic disease. We have solved the structural puzzle of how tubulin protein binds to VERU-111, pointing to new directions where careful drug design approaches are likely to improve the potency and drug-like properties of VERU-111. Our technical goals are to perform focused structural optimization utilizing X-ray crystallography and computer-aided drug design to produce a first-in-class, highly potent, metabolically stable, orally bioavailable tubulin inhibitor to reverse taxane resistance, with low toxicity, to be tested in well-characterized preclinical mouse models that develop lethal metastatic disease.

Overarching Challenges Addressed: To revolutionize treatment regimens by overcoming current clinical limitations by replacing the use of existing FDA-approved taxane treatment regimens with a new generation of orally available tubulin inhibitors that are more effective, less toxic, and will increase overall survival. A second challenge is to eliminate the mortality associated with MBC.

Clinical Benefits and Projected Timing of Impact: Our research plan will result in an improved lead compound as a new generation of tubulin inhibitor to be used in future clinical trials in breast cancer, particularly for patients who have failed taxanes. Our current lead compound, VERU-111, has been licensed by a biotech company (Veru, Inc.) for commercial development to treat metastatic prostate cancer; Phase 1b/2 clinical trials for men with metastatic prostate cancer started in 11/2018. Due to the high attrition rate of early-stage drugs during trials, it is highly risky to rely on only one compound in a drug pipeline, another rationale to further develop VERU-111 derivatives. Within 5 years (2024), it is feasible that we will bring a safer, more stable and more effective tubulin inhibitor into the clinic to benefit patients with MBC. Since tubulin inhibitors are widely used in other types of metastatic solid tumors, including prostate, ovarian, and lung cancers, project success could have a broader impact to improve the clinical outcomes for these cancer patients and to reduce toxicities.