SBIR-STTR Award

Development of MTX-211 for the Treatment of KRAS Mutant Colorectal Cancer
Profile last edited on: 5/15/2020

Program
STTR
Agency
NIH | NCI
Total Award Amount
$2,086,575
Award Phase
2
Principal Investigator
Christopher Emil Whitehead
Activity Indicator

Company Information

MEKanistic Therapeutics LLC

U-M Venture Accelerator 1600 Huron Parkway:Huron Parkway
Ann Arbor, MI 48109
Multiple Locations:   
Congressional District:   12
County:   Washtenaw

Phase I

Phase I year
2017
Phase I Amount
$225,000
Mekanistic Therapeutics seeks to design, discover, and develop anti-cancer agents that selectively inhibit multiple oncogenic pathways. Its lead agent MTX-211 was discovered in collaboration with the Leopold laboratory at University of Michigan. MTX-211 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-211 to treat KRAS mutant colorectal cancers. Every year >130,000 new patients are diagnosed with colorectal cancer. At the time of diagnosis, approximately 20% of these patients present with metastatic disease. Patients diagnosed with metastatic colorectal cancer (mCRC) have a very poor prognosis, with 5 year survival rates of less than 15%. 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 50% 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-211 is a first-in-class dual inhibitor of PI3K and EGFR kinases with demonstrated in vivo anticancer activity against multiple KRAS mutant colorectal tumors. MTX-211 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-211 is highly selective for EGFR and PI3K 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 1, we will scale up synthesis of MTX-211 at the 20 gram scale to generate sufficient materials for Specific Aim 2. In Specific Aim 2, we propose to evaluate the efficacy of MTX-211 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 30% in this pilot trial would be followed by a Phase II plan to conduct an expanded mouse trial of MTX-211 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/PI3K pathways with MTX-211. Combined Phase I and II applications will provide pivotal data necessary to justify completing an investigative new drug (IND) package.

Public Health Relevance Statement:
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-211 represents a novel experimental agent that is the first reported selective inhibitor of EGFR and PI3 kinase, which are key signaling molecules implicated in the progression of KRAS mutant colorectal cancer. This project is focused on evaluation of MTX-211 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.

Project Terms:
1-Phosphatidylinositol 3-Kinase; Advanced Development; anticancer activity; Antineoplastic Agents; Assimilations; Cancer Etiology; Cancer Prognosis; Capital; Cessation of life; Cetuximab; Chemistry; chemotherapy; Clinical; clinical development; Clinical Trials; Collaborations; colon cancer patients; Colorectal; Colorectal Cancer; Colorectal Neoplasms; Combined Modality Therapy; commercial application; commercialization; Custom; Data; design; Development; Diagnosis; Disease; Dose; Drug Interactions; Economics; effective therapy; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Evaluation; exome sequencing; Family member; fluoropyrimidine; Funding; Genomics; Goals; HCT116 Cells; Heterogeneity; Histology; Impairment; improved; in vivo; Individual; inhibitor/antagonist; innovation; Investments; irinotecan; kinase inhibitor; KRAS2 gene; Laboratories; Lead; Lipids; Malignant Neoplasms; Measures; metastatic colorectal; Michigan; Modeling; Monoclonal Antibodies; Mus; mutant; Mutation; mutational status; neoplastic cell; Newly Diagnosed; novel; novel therapeutics; Oncogenes; Oncogenic; Outcome; outcome forecast; oxaliplatin; panitumumab; Pathway interactions; patient population; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; phase 2 study; Phosphotransferases; PIK3CG gene; pilot trial; pre-clinical; precision medicine; Process; Prognostic Marker; Protein Isoforms; prototype; PTEN gene; Public Health; receptor; Refractory; Regimen; Reporting; response; Risk; Route; scale up; Signal Transduction; Signaling Molecule; single molecule; Small Business Technology Transfer Research; Solid; Specimen; success; Survival Rate; targeted treatment; Testing; Therapeutic; therapeutic development; therapy development; therapy outcome; Time; Toxic effect; Toxicology; tumor; Tyrosine; United States; Universities; Validation; Vertebral column; Xenograft Model; Xenograft procedure

Phase II

Phase II year
2019 (last award dollars: 2020)
Phase II Amount
$1,861,575
Mekanistic Therapeutics seeks to design, discover, and develop anti-cancer agents that selectively inhibit multiple oncogenic pathways. Its lead agent MTX-211 was discovered in collaboration with the Leopold laboratory at University of Michigan. The overall objective of this project is to expediently advance MTX- 211 into development for the treatment of KRAS mutant colorectal cancer (CRC). Every year >130,000 new patients are diagnosed with colorectal cancer. At the time of diagnosis, approximately 20% of these patients present with metastatic disease. Currently, there are no approved treatments for metastatic CRC patients with activating mutations in KRAS. MTX-211 is a first-in-class highly selective dual inhibitor of PI3K and EGFR kinases, designed to attack KRAS oncogenic signaling using two orthogonal mechanisms. As such, it embodies a combination approach in a single molecule. Phase I aims focused on optimizing the synthetic process to scale-up production of MTX-211 and conducting a pilot mouse trial of primary xenograft models established from six different patients diagnosed with KRAS mutant CRC. All milestones were achieved providing preclinical proof-of-concept for pursuit of a clinical development path for MTX-211 that specifically targets the KRAS mutant CRC population. In Phase II, we propose to test a broader panel of KRAS mutant CRC models in an expanded efficacy trial that incorporates molecular profiling to identify prognostic markers that correlate with therapeutic outcome. At the same time, we propose to carry out early safety studies to further de-risk MTX-211 and strengthen the case for moving forward to future IND-enabling toxicology studies.

Public Health Relevance Statement:
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 KRAS mutant disease is especially poor. This project is focused on evaluation of MTX-211, a novel first-in-class agent, that selectively targets EGFR and PI3 kinase, key signaling molecules implicated in the progression of KRAS mutant colorectal cancer.

Project Terms:
1-Phosphatidylinositol 3-Kinase; Achievement; active control; Advanced Development; Antineoplastic Agents; base; Cancer Model; Cancer Prognosis; candidate marker; Capital; Chemistry; Chemotherapy-Oncologic Procedure; Clinical; clinical development; Clinical Trials; Collaborations; colon cancer patients; Colorectal Cancer; colorectal cancer treatment; Combined Modality Therapy; commercial application; Data; design; Development; Diagnosis; Disease; Dose; effective therapy; efficacy trial; Epidermal Growth Factor Receptor; Evaluation; Fluorouracil; follow-up; Funding; Future; Immunotherapy; improved; improved outcome; In Vitro; inhibitor/antagonist; interest; Investments; KRAS2 gene; Laboratories; Lead; lead candidate; MAP Kinase Gene; Maximum Tolerated Dose; MEK inhibition; MEKs; metastatic colorectal; Michigan; Mismatch Repair; Mitogen-Activated Protein Kinases; Modeling; Molecular Profiling; Molecular Target; Mus; mutant; Mutation; novel; Oncogenic; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; phase 2 study; Phosphotransferases; Play; Population; pre-clinical; preclinical study; Process; Production; Prognostic Marker; Public Health; resistance mechanism; response; response biomarker; Risk; Role; Safety; safety study; scale up; Signal Transduction; Signaling Molecule; single molecule; Small Business Innovation Research Grant; Survival Rate; targeted agent; Testing; Therapeutic; therapy development; therapy outcome; Time; Toxicology; trial design; tumor; Universities; Up-Regulation; Xenograft Model