R01CA266207

Small molecule enhancers of tumor immunity targeting the LPA5 GPCR - lysophosphatidic acid (LPA) GPCR subtype 5 (LPAR5) is abundantly expressed by human and murine CD8 cytotoxic T lymphocytes (CTLs) and functions as an inhibitory receptor that represses T cell receptor (TCR) signaling leading to inhibition of tumor immunity.

Specifically, stimulation of LPAR5 by physiological levels of LPA significantly impedes antigen-specific TCR-induced Ca2+ mobilization, T cell activation, proliferation, and cytolytic tumor cell killing functions, resulting in an impaired anti-tumor immune response.

Indeed, CD8+ T cells lacking LPAR5 expression are more effective at reducing the growth rate of EG7 lymphoma and B16 melanoma tumors in mice compared to wild type (WT) CD8+ T cells.

Moreover, LPAR5 -/- mice have an 85% reduction in the incidence of B16 melanoma-derived lung metastasis compared to WT littermates, with a robust CD8+ CTL infiltration observed in the LPAR5 -/- mice that developed few lung metastasis.

These data highlight a unique role for LPAR5 as an immune checkpoint molecule regulating immune surveillance and cytotoxic effector function.

The objective of this proposal is to identify small molecule inhibitors of LPAR5 as clinically applicable immunomodulators for cancer treatment.

A virtual screening (VS) of 2 million compounds using validated LPAR models identified more than 300 hits, of which 90 were selective for LPAR5 antagonist compounds with diverse scaffolds.

In addition, a high throughput screening (HTS) campaign of 200K compounds and secondary analyses of 19 validated hits have already resulted in the identification of two distinct molecular scaffolds.

The most promising hit, SRI-42730, demonstrated LPAR5 antagonism in five independent assays: β-arrestin recruitment, Ca2+ mobilization, TGFA-shedding, IL-2 production implemented in HTS platform, and in vivo efficacy in the B16 murine melanoma metastasis model.

The novel hits and analogs we have already identified will be used as tool compounds in the following proposed studies:

1) Perform hit-to-lead medicinal chemistry optimization of LPAR5 antagonists. Computational approaches will include scaffold hopping on HTS hits and the generation of a pharmacophore model to aid synthetic optimization of potency and selectivity of newly designed analogs.

2) Determine the specificity of novel antagonists at LPA GPCR subtypes and autotaxin lysophospholipase enzyme.

3) Rank specific antagonist hits by potency in boosting antigen-specific TCR activation and IL-2 production in the presence of LPA.

4) Eight key compounds will then be evaluated in cellular assays, from which three compounds will undergo PK analysis prior to in vivo tox studies and animal efficacy studies.

5) Determine efficacy of nominated three potential lead compounds in boosting tumor immunity using murine and allogeneic human in vitro tumor killing assays and in vivo murine metastasis seeding and progression models.

The impact of this research will be the identification and nomination of a single lead compound and a pool of structurally diverse LPAR5 antagonists for further preclinical development.

University Of Tennessee

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]

Memphis, Tennessee 381034902 United States

Single Zip Code

Assay development and screening for discovery of chemical probes, drugs or immunomodulators (R01 Clinical Trial Not Allowed) (PAR-20-271)

Amendment Since initial award the total obligations have increased 261% from $861,845 to $3,114,085.