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