SBIR-STTR Award

This project is designed to evaluate a new class of anti-cancer agents for treatment of invasive melanoma, pancreas, lung, and colon carcinomas. The study compounds are small, synthetic molecules that have not previously been used in people, and bind to a surface receptor on tumor cells that has not previously been targeted in cancer. Strong preliminary results indicate that the study compounds potentiate the efficacy of the new immune checkpoint inhibitors that are now the standard of care for metastatic melanoma. In this proposal, we will determine dosing regimens that will maximize the anti-cancer effects, define biomarkers that correlate with tumor response, and determine whether the anti-melanoma synergy between G-1 and ?PD-1 extends to other immune checkpoint inhibitors. Completion of the proposed work will contribute to the completion of IND-enabling work necessary to translate these discoveries to first in human trials.

Public Health Relevance Statement:


Project narrative:
While new immune checkpoint inhibitor pharmaceuticals have resulted in improved outcomes for some metastatic cancer patients, most will still succumb to their tumor, and new therapeutic options are urgently needed. This work will build on promising preliminary data to evaluate a new class of compounds that improve the efficacy of immune checkpoint inhibitors in melanoma, pancreas, lung, and colon carcinomas, as well as identify optimal dosing regimens and biomarker assays. Together, this work will facilitate the completion of IND-enabling work necessary to translate these discoveries to first in human trials.

Project Terms:
advanced disease; Agonist; Antineoplastic Agents; Binding; Biological Assay; Biological Markers; BRAF gene; c-myc Genes; cancer immunotherapy; Cancer Model; Cancer Patient; cancer type; Capital; Cell Differentiation process; Cell Line; cell type; clinical development; Collaborations; Colon Carcinoma; CREB1 gene; Cytotoxic T-Lymphocytes; Data; design; Development; Differentiation Antigens; Disseminated Malignant Neoplasm; Dose; Epigenetic Process; Estrogen Nuclear Receptor; Estrogen Receptor alpha; estrophilin; Event; experimental study; Future; Genetically Engineered Mouse; GTP-Binding Proteins; Half-Life; Hour; Human; Immune; Immune checkpoint blockade; Immune checkpoint inhibitor; Immunohistochemistry; improved; improved outcome; In Vitro; in vivo; interest; Investments; Lung; lung Carcinoma; Malignant Neoplasms; Mediating; melanocyte; melanoma; Memory; Metastatic Melanoma; Modeling; Mus; nanomolar; neoplastic cell; novel therapeutics; Pancreas; Pancreatic carcinoma; PDCD1LG1 gene; Pennsylvania; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; phase I trial; Physiologic pulse; potential biomarker; Privatization; Proteins; Proto-Oncogene Proteins c-myc; receptor; Receptor Activation; Receptor Signaling; Regimen; response; SCID Mice; Serum; Signal Transduction; Small Business Technology Transfer Research; small molecule; standard of care; subcutaneous; Surface; synergism; Technology; Therapeutic; Time; Tissues; Translating; tumor; Tumor Cell Line; tumor growth; Tumor Immunity; Tumor Initiators; Tumor Tissue; Universities; Validation; Work

This project is designed to evaluate a new class of anti-cancer agents for treatment of invasive melanoma, pancreas, lung, and colon carcinomas. The study compounds are small, synthetic molecules that have not previously been used in people, and bind to a surface receptor, G protein- coupled estrogen receptor (GPER) on tumor cells that has not previously been targeted in cancer. Strong preliminary results indicate that the study compounds potentiate the efficacy of the new immune checkpoint inhibitors that are now the standard of care for metastatic melanoma. In this proposal, we will determine the biologically active enantiomer of the GPER agonist G-1, routes of administration that will have the most favorable pharmacokinetics and maximize the anti-cancer effects, assay clinical cancer samples for expression of GPER and downstream signaling molecules. Completion of the proposed work will contribute to the completion of IND-enabling work necessary to translate these discoveries to first in human trials.

Public Health Relevance Statement:


Project narrative:
While new immune checkpoint inhibitor pharmaceuticals have resulted in improved outcomes for some metastatic cancer patients, most will still succumb to their tumor, and new therapeutic options are urgently needed. This work will build on promising preliminary data to evaluate a new class of compounds that improve the efficacy of immune checkpoint inhibitors in melanoma, pancreas, lung, and colon carcinomas, as well as identify routes of administration dosing regimens and analysis of clinical samples. Together, this work will facilitate the completion of IND-enabling work necessary to translate these discoveries to first in human trials.

Project Terms:
Affinity; Agonist; Animals; anti-cancer; anticancer activity; Antineoplastic Agents; Antitumor Response; Archives; Binding; Bioavailable; Biological; Biological Assay; biomarker development; c-myc Genes; Cancer cell line; Cancer Patient; cancer pharmacology; cancer type; Capital Financing; chemical synthesis; Chromatography; Clinical; clinical application; Clinical Trials; clinically relevant; Collaborations; Colon Carcinoma; combinatorial; Combined Modality Therapy; CREB1 gene; Data; design; Development; Disseminated Malignant Neoplasm; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; Elements; enantiomer; Estrogen Receptors; estrophilin; experimental study; first-in-human; Formalin; Formulation; Funding; Future; GPER gene; Grant; GTP-Binding Proteins; Histologic; Human; Immune; Immune checkpoint inhibitor; Immunocompetent; immunogenicity; Immunohistochemistry; Immunotherapy; improved; improved outcome; In complete remission; In Vitro; in vivo; Intravenous; intravenous administration; ITGAM gene; Large Intestine Carcinoma; Life; lung Carcinoma; Malignant Neoplasms; melanoma; Metastatic Melanoma; Modernization; Molecular; Mus; Neoplasm Metastasis; neoplastic cell; new therapeutic target; Non-Small-Cell Lung Carcinoma; novel therapeutics; Oils; Oral; Oral Administration; Organ; Pancreatic carcinoma; Pancreatic Ductal Adenocarcinoma; Paper; Paraffin Embedding; Pathway interactions; Patients; PDCD1LG1 gene; Pennsylvania; personalized medicine; Pharmaceutical Preparations; Pharmacologic Substance; Phase; phase 1 study; Phase I Clinical Trials; Phenotype; potential biomarker; pre-clinical; Pre-Clinical Model; preclinical development; Privatization; prognostic; protein expression; PTPRC gene; receptor; Receptor Activation; receptor binding; receptor expression; Receptor Signaling; Regimen; Resistance; response; Route; Sampling; Signal Transduction; Signaling Molecule; Small Business Innovation Research Grant; Small Business Technology Transfer Research; small molecule; Solid; Solid Neoplasm; Specimen; standard of care; subcutaneous; Surface; targeted treatment; Techniques; Technology; Testing; Therapeutic; Toxic effect; Toxicology; Translating; tumor; tumor growth; Tumor stage; Tumor-infiltrating immune cells; Universities; Work