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Principal Investigator: Suzie Chen
Organization: VA NEW JERSEY HEALTH CARE SYSTEM
Fiscal Year: 2024
Funding agency: Veterans Affairs
Much has been learned about the molecular pathology of melanoma in recent years and significant progress
has been made towards its treatment, yet late-stage melanoma still remains one of the least curable cancers
with high metastatic propensity. The brain is a common site of metastasis for patients with various neoplasia
including melanoma, breast cancer, lung cancer, and colorectal cancer. The mainstay for treatment of brain
metastasis has been radiation therapy; sometimes surgery and chemotherapeutic agents have been included.
Most clinical trials usually excluded patients with brain metastases because of the unlikelihood these patients
will benefit from such regiment, however, recently a few trials have included melanoma patients with or without
brain metastases. Preliminary results from these trials are suggestive that similar responsiveness was observed
for patients with or without brain metastases, and further trials are needed to confirm these results. Despite these
improvements, patients with multiple brain metastases from solid tumors often show progression in the brain
contributing to neurological deterioration, decreased quality of life, and poor survival.
Mouse models reflecting human cancers are important tools towards the translation of basic science discoveries
to clinical therapies. However, rapidly evolving technologies within the last few years require further refining
current approaches that enable models to be more suitable in robust translational applications to provide
consistent information to meet patients’ needs. In our studies of melanoma, we discovered that >65% of human
melanoma cell lines and melanoma biopsies express metabotropic glutamate receptor 1 (GRM1), independent
of N-RAS/B-RAF genotypes, while normal human melanocytes do not. Based on this discovery, our group was
the first to propose the link between GRM1-mediated glutamatergic signaling and melanoma. In recent clinical
trials, we observed that >90% of all enrolled patients expressed GRM1 within their late-stage melanomas.
However, the conventional mouse models of melanoma do not mimic this genetic alteration common to
melanoma patients. Therefore, we developed mouse models (MASS and TGS) where the ectopic expression of
GRM1 in previously normal melanocytes leads to consistent, wide-spread development of melanocytic lesions
and metastasis to various organs including the lung and brain, two common metastatic sites for human
melanoma. In this application, we propose to characterize the ability of these two different but complementary
innovative models that mimic human melanoma with brain metastases and fill the gap, to expand, improve, and
transform the utility of mammalian tumor models for translational research. Completion of this proposed work is
an essential step towards establishing fundamentally important and relevant animal models of human cancer
that will improve and save cancer patient lives.
Terms: <2-Amino-6-trifluoromethoxybenzothiazole><Active Oxygen><Allografting><Amyotrophic Lateral Sclerosis><Amyotrophic Lateral Sclerosis Motor Neuron Disease><Animal Model><Animal Models and Related Studies><Animals><Apoptosis><Apoptosis Pathway><Appearance><Archives><Automobile Driving><Autoregulation><BBB crossing><Basic Research><Basic Science><Biologic Models><Biological Models><Biopsy><Blood><Blood Reticuloendothelial System><Brain><Brain Metastasis><Brain Nervous System><Breast Cancer><CNS Nervous System><Cancer Patient><Cancer Treatment><Cancers><Causality><Cell Body><Cell Communication and Signaling><Cell Cycle Arrest><Cell Line><Cell Signaling><Cell Transplantation><CellLine><Cells><Central Nervous System><Characteristics><Checkpoint inhibitor><Clinic><Clinical><Clinical Trials><Colorectal Cancer><Critical Paths><Critical Pathways><Cysteine><DNA Damage><DNA Injury><Deterioration><Development><Disease><Disorder><Drug Therapy><Ectopic Expression><Encephalon><Etiology><Exclusion><Experimental Models><Experimental Therapies><Extracellular Signal-Regulated Kinase Gene><FDA approved><Family><GPRC1A><GRM1><GRM1 gene><GRM1A><Gehrig's Disease><General Population><General Public><Genes><Genetic Alteration><Genetic Change><Genetic defect><Genotype><Glutamate Receptor><Glutamates><Half-Cystine><Heterograft><Heterologous Transplantation><Homeostasis><Human><Immune><Immune Evasion><Immune checkpoint inhibitor><Immune mediated therapy><Immune response><Immunes><Immunocompetent><Immunologic Model><Immunological Models><Immunological response><Immunologically Directed Therapy><Immunotherapy><In Vitro><Interruption><Intracellular Communication and Signaling><Investigational Therapies><Investigational Treatments><L-Cysteine><L-Glutamate><Lab Findings><Laboratory Finding><Learning><Lesion><Ligands><Link><Longitudinal Studies><Lou Gehrig Disease><Luciferase Immunologic><Luciferases><Lung><Lung Respiratory System><MAP Kinase Gene><MAPK><MGLUR1><MGLUR1A><Malignant Breast Neoplasm><Malignant Melanoma><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Mediating><Melanoma><Melanoma Cell><Melanoma Metastasis><Melanoma patient><Metabotropic 1 Glutamate Receptor><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Melanoma><Metastatic Neoplasm><Metastatic Neoplasm to the Brain><Metastatic Tumor><Metastatic Tumor to the Brain><Metastatic malignant neoplasm to brain><Mice><Mice Mammals><Mitogen-Activated Protein Kinase Gene><Model System><Modeling><Modern Man><Modification><Monitor><Murine><Mus><Mutate><Mutation><N-RAS><NRAS gene><Neoplasm Metastasis><Neoplasms><Nerve Cells><Nerve Unit><Neural Cell><Neuraxis><Neuroblastoma RAS viral oncogene><Neurocyte><Neurologic><Neurological><Neurons><Operative Procedures><Operative Surgical Procedures><Organ><Oxygen Radicals><PI-3K/AKT><PI3K/AKT><Paraffin><Paraffin waxes and Hydrocarbon waxes><Pathway interactions><Patients><Pharmacotherapy><Physiological Homeostasis><Population><Position><Positioning Attribute><Primary Neoplasm><Primary Tumor><Pro-Oxidants><Prognosis><Programmed Cell Death><Property><Pulmonary Cancer><Pulmonary malignant Neoplasm><QOL><Quality of life><Radiation><Radiation therapy><Radiotherapeutics><Radiotherapy><Reactive Oxygen Species><Reduced Glutathione><Relapse><Resistance><Riluzole><Sampling><Secondary Neoplasm><Secondary Tumor><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Site><Solid Neoplasm><Solid Tumor><Strains Cell Lines><Surgical><Surgical Interventions><Surgical Procedure><Technology><Therapeutic><Toxic effect><Toxicities><Transgenic Mice><Transgenic Model><Translating><Translational Research><Translational Science><Translations><Tumor Cell><Work><Xenograft><Xenograft procedure><Xenotransplantation><anti-cancer research><anti-cancer therapy><biological signal transduction><blood-brain barrier crossing><bloodbrain barrier crossing><brain micrometastasis><cancer metastasis><cancer microenvironment><cancer progression><cancer research><cancer therapy><cancer-directed therapy><causation><cellular transplant><chemotherapeutic agent><combinatorial><cultured cell line><cytokine><design><designing><determine efficacy><developmental><disease causation><driving><drug treatment><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><experimental therapeutic agents><experimental therapeutics><genome mutation><glutamate signaling><glutamatergic><glutamatergic dendrodendritic synapses><glutamatergic signaling><host response><human model><humanized mice><humanized mouse><immune check point inhibitor><immune competent><immune evasive><immune reconstitution><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunoresponse><improved><improved outcome><in vivo><inhibitor><innovate><innovation><innovative><long-term study><longitudinal outcome studies><longterm study><lung cancer><mGlu1><malignancy><malignant breast tumor><melanocyte><metabotropic glutamate receptor type 1><military veteran><model of animal><model of human><molecular pathology><mouse model><multidisciplinary><murine model><neo-antigen><neo-epitopes><neoantigens><neoepitopes><neoplasia><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic growth><neoplastic progression><neuronal><new approaches><non-invasive monitor><noninvasive monitor><novel approaches><novel strategies><novel strategy><participant enrollment><pathway><patient enrollment><patient response><patient specific response><peripheral blood><pre-clinical><pre-clinical study><preclinical><preclinical study><prevent><preventing><progression biomarker><progression marker><pulmonary><radiation treatment><resistant><response><response biomarker><response markers><response to therapy><response to treatment><responsive patient><small molecule><surgery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic response><therapeutically effective><therapy response><tool><transgenic trait><translation><translation research><translational applications><translational investigation><translational model><treatment response><treatment responsiveness><treatment with radiation><tumor><tumor cell metastasis><tumor microenvironment><tumor progression><veteran population><xeno-transplant><xeno-transplantation>