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Principal Investigator: IRINA AGOULNIK
Organization: UNIVERSITY OF SOUTH FLORIDA
Fiscal Year: 2024
Award: $199,856
Funding agency: National Cancer Institute
The therapeutics efficacy of an anticancer treatment is often restricted by tumor fibrous tissue and tumor
microenvironment. Stromal matrix barriers create a sanctuary for breast cancer, while the prolonged pro-fibrotic
stimuli facilitate cancer cell growth and survival by establishing an immunosuppressive environment. Relaxin, a
small peptide hormone, demonstrated dual anti-fibrotic and pro-immunogenic effects in various disease models
including several solid cancers. Treatment with relaxin significantly reduced the expression of major tumor
extracellular matrix components such as collagens, fibronectin, and elastin. The degradation of fibrotic tumor
matrix following relaxin treatment led to reduced cancer cell drug resistance. Additionally, it was shown that
relaxin can change tumor macrophage population from pro-inflammatory to pro-resolution enabling T cell-
mediated cancer cell killing and macrophage phagocytosis. However, due to a short half-life in vivo, delivery of
recombinant relaxin requires continuous infusion. Relaxin signals through its cognate G protein-coupled receptor
RXFP1, which is expressed in tumor associated fibroblasts and infiltrating immune cells. We propose targeting
the integrity of the tumor microenvironment with the first-in-class small molecule agonist of RXFP1 developed in
our laboratories. The lead compound, ML290, shows high activity, oral bioavailability, in vivo stability, and
excellent pharmacological properties. It is well tolerated by animals, shows no toxicity in vivo, and does not
increase cancer cell proliferation and invasiveness nor does it affect extracellular matrix remodeling in healthy
tissues. Our preliminary data indicate that the ML290 treatment of mice with HER2-positive breast cancer
reduces tumor size and tumor fibrotic content. The overall goal of this project is to demonstrate anticancer activity
of relaxin receptor agonist, ML290, in preclinical models of breast cancer, regardless of cancer subtype. We will
test the anti-cancer efficacy of ML290 in primary and metastatic breast cancer models, analyze changes in tumor
ECM composition, recruitment of immune cells, and genomic/proteomic response in stromal and cancer cells to
treatment. We will analyze the effect of combination treatment of ML290 with immune checkpoint blockade and
anti-HER2 immunotherapeutics. The pharmacological re-programing of stromal cancer microenvironment by
ML290 will provide a new therapeutic approach for breast cancer suppression.
Terms: <4T1><Abscission><Affect><Agonist><Allografting><American><Animal Model><Animal Models and Related Studies><Animals><Anti-Cancer Agents><Antibodies><Antibody Therapy><Antiinflammatory Effect><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><B7-H1><B7H1><BALB C Mouse><BALB/c><Bioavailability><Biological Availability><Body Tissues><Breast Cancer><Breast Cancer Model><Breast Cancer Treatment><Breast Cancer therapy><Breast Neoplasms><Breast Tumors><Breast tumor model><CD274><Cancer Cell Growth><Cancer Drug><Cancer Model><Cancer Patient><CancerModel><Cancers><Cell Body><Cell Communication and Signaling><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Protection><Cell Signaling><Cell Survival><Cell Viability><Cell-Extracellular Matrix><Cell-Mediated Lympholytic Cells><Cells><Cellular Proliferation><Characteristics><Chronic><Clinical Treatment Moab><Cold-Insoluble Globulins><Collagen><Combined Modality Therapy><Continuous Infusion><Cytolytic T-Cell><Cytoprotection><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><Data><Development><Diagnosis><Dose><Drug Kinetics><Drug Targeting><Drug Therapy><Drug resistance><Drug usage><ECM><ERBB2><ERBB2 gene><Elastin><Endocrine Gland Secretion><Environment><Excision><Extirpation><Extracellular Matrix><FN1><Fibroblasts><Fibronectin 1><Fibronectins><Fibrosis><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GPCR><Generalized Growth><Genomics><Goals><Growth><HER -2><HER-2><HER2><HER2 Genes><HER2/neu><Half-Life><Hormones><Immune><Immune infiltrates><Immune mediated therapy><Immune response><Immunes><Immunocompetent><Immunological response><Immunologically Directed Therapy><Immunotherapeutic agent><Immunotherapy><Inbred BALB C Mice><Inflammatory><Intracellular Communication and Signaling><LETS Proteins><Laboratories><Laboratory Research><Large External Transformation-Sensitive Protein><Lead><Macrophage><Malignant Breast Neoplasm><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Mammary Cancer><Mammary Neoplasms><Mediating><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Metastatic breast cancer><Mice><Mice Mammals><Modification><Monoclonal Antibodies><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Mφ><NEU Oncogene><NEU protein><Neoplasm Metastasis><Neoplastic Disease Chemotherapeutic Agents><Oncogene ErbB2><Opsonic Glycoprotein><Opsonic alpha(2)SB Glycoprotein><Oral><PD-L1><PDL-1><PDL1><PK/PD><Pathway interactions><Patients><Pb element><Penetration><Peptide Hormone Gene><Peptides><Phagocytosis><Pharmacodynamics><Pharmacokinetics><Pharmacotherapy><Physiologic Availability><Population><Pre-Clinical Model><Preclinical Models><Primary Neoplasm><Primary Tumor><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Property><Proteomics><Recombinants><Relaxin><Removal><Reporting><Resolution><Route><Secondary Neoplasm><Secondary Tumor><Signal Transduction><Signal Transduction Systems><Signaling><Solid><Stimulus><Stromal Cells><Stromal Neoplasm><Stromal Tumor><Surgical Removal><T cell infiltration><T-Cells><T-Lymphocyte><TKR1><Testing><Therapeutic><Therapeutic Hormone><Tissue Growth><Tissues><Toxic effect><Toxicities><Transgenic Mice><Transgenic Model><Translating><Treatment Efficacy><Tumor-Specific Treatment Agents><Woman><aPD-L1><aPDL1><alpha 2-Surface Binding Glycoprotein><anti programmed cell death ligand 1><anti programmed cell death protein ligand 1><anti-PD-(L)1><anti-PD-L1><anti-PDL-1><anti-PDL1><anti-cancer><anti-cancer drug><anti-cancer treatment><anti-inflammatory effect><antiPD-L1><antiPDL1><antibody based therapies><antibody treatment><antibody-based therapeutics><antibody-based treatment><anticancer activity><biological signal transduction><c-erbB-2><c-erbB-2 Genes><c-erbB-2 Proto-Oncogenes><cancer cell><cancer invasiveness><cancer metastasis><cancer microenvironment><cancer sub-types><cancer subtypes><cell killing><check point blockade><checkpoint blockade><combination therapy><combined modality treatment><combined treatment><cytoprotective><developmental><disease model><disorder model><drug resistant><drug treatment><drug use><erbB-2 Genes><experiment><experimental research><experimental study><experiments><expression subtypes><heavy metal Pb><heavy metal lead><herstatin><host response><immune cell infiltrate><immune check point><immune check point blockade><immune checkpoint><immune checkpoint blockade><immune competent><immune drugs><immune microenvironment><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><immunecheckpoint><immuno therapy><immunogenic><immunologic therapeutics><immunoresponse><immunosuppressive microenvironment><immunosuppressive tumor microenvironment><immunotherapeutics><immunotherapy 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pharmacodynamics><pharmacologic><pre-clinical><preclinical><prevent><preventing><programmed cell death ligand 1><programmed cell death protein ligand 1><protein death-ligand 1><recruit><relaxin receptor><resection><resistance to Drug><resistant to Drug><resolutions><response><side effect><small molecule><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic efficacy><therapy efficacy><thymus derived lymphocyte><transgenic trait><tumor><tumor cell metastasis><tumor growth><tumor immune microenvironment><tumor microenvironment><tumor-immune system interactions><αPD-L1><αPDL1>