U01CA252048

Understanding and Targeting MAPK Pathway Activation in NF1-Deficient Malignant Peripheral Nerve Sheath Tumor (MPNST) - Project Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) represent a group of highly aggressive soft tissue sarcomas that occur in distinct clinical settings: neurofibromatosis 1 (NF1)-associated (45%), sporadic (45%), or radiotherapy (RT)-associated (10%). MPNSTs metastasize early and are resistant to radiotherapy and systemic chemotherapy, resulting in poor prognosis. Regardless of the clinical setting, MPNSTs share the same molecular pathway inactivation in NF1 (>90%, hence NF1-deficient), polycomb repressive complex 2 (PRC2), and CDKN2A through biallelic genetic alterations, suggesting that they can be molecularly targeted similarly.

NF1-deficient plexiform neurofibroma responds well to MEK inhibitor (MEKI) treatment clinically. However, NF1-deficient MPNSTs arising from plexiform neurofibromas are universally resistant to MEKI, suggesting intrinsic resistance in the more aggressive form of peripheral nerve sheath tumors. Using MPNST patient tumor samples and preclinical MPNST models, we have uncovered that PRC2-loss leads to PDGRA upregulation. MEKI treatment resulted in feedback upregulation of PDGFRB irrespective of the PRC2 status. The convergence of the PDGFR pathway activation by different mechanisms points to a novel therapeutic opportunity to target the PDGFR pathway to overcome MEKI resistance in MPNST. Combination of a novel PDGFRA/B inhibitor, ripretinib, with a MEKI leads to synergistic growth inhibition of MPNST in vitro and in vivo. We hypothesize that PDGFRA/B pathway activation represents a central resistance mechanism to MEKI, and combined targeting of the PDGFR and MAPK pathways with ripretinib (pan-PDGFRA/B inhibitor) and binimetinib (MEKI) may present an effective therapeutic strategy in NF1-deficient MPNST.

Here, we propose to investigate the tumor heterogeneity and cellular plasticity involved in tumor evolution and adaptive resistance to binimetinib and the combination of ripretinib and binimetinib. We will use well-defined preclinical MPNST in vitro and in vivo model systems and single-cell analysis, including single-cell RNA-seq (scRNA-seq) and a novel barcoding system. Additionally, we propose a collaborative clinical investigation between CCR/NCI (Drs. Widemann/Sheren) and MSKCC (Dr. Chi) to conduct a proof-of-concept Phase I/II study of the combination of ripretinib and binimetinib in patients with NF1-deficient MPNST. In this trial, we will assess and optimize the evaluation of MAPK pathway inhibition to the ripretinib/binimetinib combination therapy using traditional ERK phosphorylation and a newly established custom PEA3-family ETS-regulated MAPK signature. Furthermore, we will also investigate the tumor heterogeneity and cellular plasticity in tumor evolution and resistance mechanisms to the ripretinib/binimetinib combination using targeted NGS, scRNA-seq, and integrative analysis.

The proposal leverages the synergistic expertise and resources at MSKCC and CCR/NCI. We believe that these studies will generate mechanistic insight into therapeutic resistance and provide pivotal clinical and translational information for future definitive trials, with the potential to change the clinical practice in MPNST.

Sloan-Kettering Institute For Cancer Research

TO DEVELOP THE MEANS TO CURE AS MANY CANCER PATIENTS AS POSSIBLE AND TO CONTROL THE DISEASE IN THOSE PATIENTS WHO ARE NOT CURED. CANCER TREATMENT RESEARCH INCLUDES THE DEVELOPMENT AND EVALUATION OF IMPROVED METHODS OF CANCER TREATMENT THROUGH THE SUPPORT AND PERFORMANCE OF BOTH FUNDAMENTAL AND APPLIED LABORATORY AND CLINICAL RESEARCH. RESEARCH IS SUPPORTED IN THE DISCOVERY, DEVELOPMENT, AND CLINICAL TESTING OF ALL MODES OF THERAPY INCLUDING: SURGERY, RADIOTHERAPY, CHEMOTHERAPY, AND BIOLOGICAL THERAPY INCLUDING MOLECULARLY TARGETED THERAPIES, BOTH INDIVIDUALLY AND IN COMBINATION. IN ADDITION, RESEARCH IS CARRIED OUT IN AREAS OF NUTRITIONAL SUPPORT, STEM CELL AND BONE MARROW TRANSPLANTATION, IMAGE GUIDED THERAPIES AND STUDIES TO REDUCE TOXICITY OF CYTOTOXIC THERAPIES, AND OTHER METHODS OF SUPPORTIVE CARE THAT MAY SUPPLEMENT AND ENHANCE PRIMARY TREATMENT. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.395 - Cancer Treatment Research

National Cancer Institute (NCI) [HHS - NIH]

New York, New York 100656007 United States

Single Zip Code

National Cancer Institute's Investigator-Initiated Early Phase Clinical Trials for Cancer Treatment and Diagnosis (R01 Clinical Trials Required) (PAR-18-560)

Amendment Since initial award the total obligations have increased 394% from $622,197 to $3,076,366.