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Principal Investigator: Christine Anne Pratilas
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $541,365
Funding agency: National Cancer Institute
PROJECT SUMMARY/ ABSTRACT
There has been little advancement in overall survival for patients with malignant peripheral nerve sheath tumor
(MPNST), despite decades of research and many clinical trials, and thus novel therapies are needed. While loss
of NF1 GTPase-activating protein function suggests that targeting RAS may be a logical therapeutic approach,
there is currently no approved drug that effectively and directly targets wild-type RAS. The design of novel
therapeutic combinations requires a deep understanding of the signaling pathways regulated by hyperactive
RAS and feedback that conditions the response to their inhibition. MEK, SHP2, and CDK4/6 are critical nodes
in RAS effector signaling in MPNST tumors, and combinations of small molecule inhibitors that target them may
have synergistic anti-tumor activity. Further, adaptive signaling changes in response to RAS effector pathway
inhibition occurs not only in tumor cells but also in cells that comprise the tumor immune micro-
environment (TIME). Thus, the characterization of the TIME in our murine model of MPNST, and its modulation
via small-molecule inhibitors of the RAS pathway, will identify key immune pathways leading to the
reprogramming of intratumoral myeloid cells, enhancing endogenous immune responses.
We propose three Aims: 1. Identify and functionally validate mechanisms of acquired resistance to SHP2
inhibitors in MPNST in order to develop novel therapeutic combinations. We will determine how tumors become
resistant to SHP2i, as well as to SHP2i +CDK4/6i in combination, and will perform genetic manipulation studies
in order to functionally validate priority hits. 2. Determine the efficacy and tolerability of combination small-
molecule inhibitors of RAS signaling, particularly SHP2i + CDK4/6i, in in vitro, patient-derived xenografts (PDX),
and immune-competent syngeneic Nf1 -/-/Ink4a/Arf -/- mouse models. We will test the effects of SHP2i and
CDK4/6i single agents or combinations as tools to probe the biochemical and biological changes that occur upon
pathway perturbation, and will determine the mechanism and anti-tumor activity of these combinations, with a
priority focus on the SHP2i+CDK4/6i combination, based on our advanced preliminary data. 3. Reprogram the
intratumoral pathological myeloid cells via treatment with the combination of SHP2i and CDK4/6i in murine
MPNST. Our preliminary data suggest that the landscape of MPNST is densely populated by tumor infiltrating
myeloid cells. To evaluate the effects of these agents and their combinations on the TIME, we will utilize single
cell transcriptional analysis, multiparameter flow cytometry and multiplex immunohistochemistry to decipher the
specific effects of these drugs on cell types that comprise the tumor, including both immune-infiltrating and
primary tumor cells. By determining the efficacy and mechanism of these rationally-designed therapeutic
strategies in both PDX and immune-competent mouse models, our studies will provide mechanism-based,
promising combinatorial approaches that may be rapidly and successfully translated to the clinic, and will inform
effective patient selection strategies and the development of novel clinical trials for patients with MPNST.
Terms: <Affect><Animal Model><Animal Models and Related Studies><Anti-Oncogenes><Antioncogenes><Assay><Bioassay><Biochemical><Biological><Biological Assay><Biological Markers><CDK4><CDK4 gene><Cancer Suppressor Genes><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Division Kinase 4><Cell Signaling><Cells><Chemotherapy and Radiation><Chemotherapy and/or radiation><Clinic><Clinical><Clinical Trials><Combined Modality Therapy><Conditioned Reflex><Cyclin-Dependent Kinase 4><Data><Development><Dimensions><Disease><Disorder><Drugs><Elements><Emerogenes><Feedback><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Future><GAP Proteins><GTPase-Activating Proteins><Gene Transcription><Genetic Transcription><Genomics><Human><Immune><Immune infiltrates><Immune mediated therapy><Immune response><Immunes><Immunocompetent><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Immunological response><Immunologically Directed Therapy><Immunomodulation><Immunotherapeutic agent><Immunotherapy><In Vitro><In vivo analysis><Infiltration><Intracellular Communication and Signaling><Investigation><Knowledge><Location><MEK inhibition><MEKs><Malignant Peripheral Nerve Sheath Tumor><Malignant Schwannoma><Malignant Soft Tissue Neoplasm><Mediator><Medication><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Modeling><Modern Man><Molecular Target><Morbidity><Morbidity - disease rate><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Myelogenous><Myeloid><Myeloid Cells><Myeloid-derived suppressor cells><NF-1><NF-1 Protein><NF-1 encoded protein><NF1><NF1 GRP><NF1 Protein><NF1 gene><NF1-GAP-Related Protein><Neoplasm Metastasis><Neurilemma Cell><Neurilemmal Cell><Neurofibromatosis 1 Genes><Neurofibromatosis Type 1 Gene Product><Neurofibromatosis Type 1 Protein><Neurofibromin><Neurofibromin 1><Neurofibrosarcoma><Neurogenic Sarcoma><Non-Receptor Type 11 Protein Tyrosine Phosphatase><Onco-Suppressor Genes><Oncogenes-Tumor Suppressors><Oncogenic><Operative Procedures><Operative Surgical Procedures><PDX model><PSK-J3><PTK Receptors><PTP-2 enzyme><PTP2C><PTPN11><PTPN11 gene><Pathologic><Pathway interactions><Patient Selection><Patient derived xenograft><Patients><Persons><Pharmaceutical Preparations><Pre-Clinical Model><Preclinical Models><Predisposition><Primary Neoplasm><Primary Tumor><Protein Tyrosine Phosphatase 2C><Protein-Tyrosine Phosphatase 2C><Proteomics><RNA Expression><Ras Inhibitor><Receptor Protein-Tyrosine Kinases><Receptor Tyrosine Kinase Gene><Recessive Oncogenes><Reporting><Research><Resistance><Role><SHP2><SHP2 Phosphatase><SHPTP2><Safety><Sarcoma><Schwann Cells><Secondary Neoplasm><Secondary Tumor><Shp-2 tyrosine phosphatase><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Surgical><Surgical Interventions><Surgical Procedure><Susceptibility><Technology><Testing><Therapeutic><Time><Toxic effect><Toxicities><Transcription><Translating><Transmembrane Receptor Protein Tyrosine Kinase><Tumor Cell><Tumor Immunity><Tumor Suppressing Genes><Tumor Suppressor Genes><Tumor-infiltrating immune cells><Tyrosine Kinase Linked Receptors><Tyrosine Kinase Receptors><Tyrosine Phosphatase SHP2><Up-Regulation><Upregulation><Validation><anti-tumor immunity><antitumor immunity><bio-markers><biologic><biologic marker><biological signal transduction><biomarker><cancer immunity><cancer metastasis><cancer microenvironment><cancers that are rare><cell culture><cell cultures><cell type><check point inhibition><checkpoint inhibition><chemo/radiation therapy><chemotherapy><chemotherapy and radiotherapy><combination therapy><combinatorial><combined modality treatment><combined treatment><conditioned response><design><designing><determine efficacy><developmental><drug/agent><early clinical trial><early phase clinical trial><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><flow cytophotometry><gene manipulation><genetic manipulation><genetically manipulate><genetically perturb><guanosinetriphosphatase activating protein><host response><hyperactive Ras><hypoimmunity><immune cell infiltrate><immune cell infiltration of tumors><immune cells infiltrating the tumor><immune cells that infiltrate the tumor><immune check point inhibition><immune checkpoint inhibition><immune competent><immune deficiency><immune drugs><immune microenvironment><immune modulation><immune regulation><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapeutics><immune-based therapies><immune-based treatments><immuno therapy><immunodeficiency><immunologic reactivity control><immunologic therapeutics><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunosuppressive microenvironment><immunosuppressive myeloid cells><immunosuppressive tumor microenvironment><immunotherapeutics><immunotherapy agent><improved><in vivo evaluation><in vivo testing><infiltration of tumors by immune cells><inhibitor><intervention design><intratumoral immune cell><intratumoral immune infiltrate><loss of function><malignant soft tissue tumor><model of animal><mouse model><multi-modal therapy><multi-modal treatment><murine model><myeloid suppressor cells><myeloid-derived suppressive cells><neoplastic cell><neurofibromatosis type 1 gene><neurofibromatosis type 1 protein/gene><new drug class><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapeutics><new therapy><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><next generation therapeutics><nf 1 Genes><novel><novel drug class><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapeutics><novel therapy><novel therapy approach><novel therapy target><oncosuppressor gene><pathway><patient derived xenograft model><patient response><patient specific response><pre-clinical><preclinical><programs><protein function><radiation or chemotherapy><rare cancer><rare malignancy><rare tumor><ras GTPase-Activating Proteins><ras-GAPs><rational design><resistance mechanism><resistant><resistant mechanism><response><responsive patient><small molecular inhibitor><small molecule inhibitor><small molecule therapeutics><social role><suppressive myeloid cells><surgery><targeted agent><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapy design><tool><transcriptomics><treatment design><tumor><tumor cell metastasis><tumor immune cell><tumor immune infiltrate><tumor immune microenvironment><tumor infiltration of immune cells><tumor microenvironment><tumor-immune system interactions><validations>