The Translational Development of a Therapeutic For Triple Negative Breast Cancer

DESCRIPTION provided by applicant Triple negative breast cancer TNBC accounts for of all diagnosed breast cancers worldwide TNBC carries a poorer prognosis and lower survival rate compared to other breast cancer subtypes Identifying novel targets and new therapeutics to treat patients diagnosed with TNBC remains a significant priority of the National Institutes of Health Product and Long Term Goal Nanometics is developing an orally available and targeted therapeutic dubbed andquot MTDIAandquot for the treatment of TNBC MTDIA inhibits a novel target methylthioadenosine phosphorylase MTAP and selectively disrupts the epigenetic development of cancer cells Technical Innovation MTAP is the sole enzyme responsible for metabolizing methylthioadenosine MTA in humans which facilitates recycling of S adenosylmethionine AdoMet MTAP is a promising target for cancer therapeutics because it is linked to various anticancer pathways MTDIA is a powerful transition state inhibitor of MTAP Ki pM and a single oral dose causes systemic MTAP inhibition and a disruption in MTA AdoMet homeostasis that impairs the epigenetic development of cancer cells Phase I SBIR Equivalent Outcomes Once daily oral doses of MTDIA are effective against eight cell line derived xenograft CDX models of six different human cancers Once daily dosing with MTDIA inhibits MTAP for andgt h causes whole body increases in MTA levels up to fold in plasma suppresses the growth rate of TNBC primary tumors and causes dramatic regression of large TNBC tumors Escalating dose studies in mice demonstrate a lack of observable toxicity for MTDIA up to mg kg day for days Pharmacokinetic pharmacodynamic and genomic analyses provide strong evidence for the MTDIA mechanism of action Direct Phase II Objectives Demonstrate that oral doses of MTDIA are effective in patient derived xenograft PDX models of TNBC and optimize the multi kilogram synthesis of MTDIA phosphate Expected Outcomes Demonstration of efficacy in PDX models and optimization of the multi kilogram synthesis is expected to de risk the program for human clinical trials Commercial Application The global market for breast cancer therapeutics is forecast to reach $ billion by Because the treatment options for metastatic relapse of TNBC are limited there remains a significant need for new drugs that work through novel modes of action PUBLIC HEALTH RELEVANCE Triple negative breast cancer TNBC is a deadly disease that accounts for of diagnosed breast cancers worldwide Identifying novel drug therapies and new targets to improve treatment for patients diagnosed with TNBC remains a significant priority This project seeks to advance the use of a novel small molecule transition state inhibito for the treatment of TNBC