Development of MTX for the Treatment of KRAS Mutant Colorectal Cancer

PROJECT SUMMARY Mekanistic Therapeutics seeks to design discover and develop anti cancer agents that selectively inhibit multiple oncogenic pathways Its lead agent MTX was discovered in collaboration with the Leopold laboratory at University of Michigan MTX is a novel kinase inhibitor showing early promise for its therapeutic potential against solid cancers refractory to current treatment options The goal of this STTR application is to demonstrate the scientific merit and therapeutic feasibility of developing MTX to treat KRAS mutant colorectal cancers Every year andgt new patients are diagnosed with colorectal cancer At the time of diagnosis approximately of these patients present with metastatic disease Patients diagnosed with metastatic colorectal cancer mCRC have a very poor prognosis with year survival rates of less than A small percentage of these patients respond to first line treatment with EGFR monoclonal antibodies cetuximab or panitumumab However these agents confer no benefit to the of the mCRC patient population whose tumors harbor a mutation in the KRAS oncogene Currently there are no approved treatments for mCRC patients with activating mutations in KRAS MTX is a first in class dual inhibitor of PI K and EGFR kinases with demonstrated in vivo anticancer activity against multiple KRAS mutant colorectal tumors MTX is innovative because it attacks KRAS oncogenic signaling using two orthogonal mechanisms serving as a combination approach in a single molecule Unlike previously reported dual receptor tyrosine and lipid kinase inhibitors MTX is highly selective for EGFR and PI K family members As such it has limited off target toxicity and a broad therapeutic window The long term goal of this proposal is to improve the clinical outcome of patients diagnosed with metastatic colorectal cancer with activating mutations in KRAS In Specific Aim we will scale up synthesis of MTX at the gram scale to generate sufficient materials for Specific Aim In Specific Aim we propose to evaluate the efficacy of MTX against six KRAS mutant CRC PDX models The histology of all six models has been confirmed to recapitulate that of the original patient specimen and all have been fully profiled by whole exome sequencing Successful demonstration of an overall response rate of in this pilot trial would be followed by a Phase II plan to conduct an expanded mouse trial of MTX against a broader CRC PDX panel The expected outcome of a precision medicine focused Phase II proposal would be a clearly defined patient enrichment strategy and identified prognostic markers that track therapeutic outcome in response to dual inhibition of EGFR PI K pathways with MTX Combined Phase I and II applications will provide pivotal data necessary to justify completing an investigative new drug IND package PROJECT NARRATIVE Public Health Impact There is an urgent need to develop more effective therapies to improve the low survival rate for metastatic colorectal cancer where the prognosis for patients diagnosed with tumors that harbor a KRAS mutation is especially poor MTX represents a novel experimental agent that is the first reported selective inhibitor of EGFR and PI kinase which are key signaling molecules implicated in the progression of KRAS mutant colorectal cancer This project is focused on evaluation of MTX in KRAS mutant colorectal tumor models established from patient specimens and has been designed to provide preclinical proof of concept for clinical development of this agent for this therapeutic indication