Proteolysis targeting chimera against nuclear receptor NR4A1 for melanoma therapy

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Principal Investigator: Keiran  Smalley
Organization: UNIVERSITY OF FLORIDA
Fiscal Year: 2024
Award: $678,605
Funding agency: National Cancer Institute

Project Summary-Abstract
Tumor microenvironment (TME) consists of many cell types that co-exist to promote tumor progression. Most
cancer therapeutics are designed to target one molecule in one defined cell type. For example, vemurafenib
(BRAF inhibitor) kills melanoma cells through targeting mutated BRAF; whereas pembrolizumab (anti-PD-1
antibody) blocks PD-1 on T cells, re-activating anti-tumor immunity. Our overarching goal is to identify targetable
molecules/pathways that are critical for multiple cell types within the TME. Using the published single cell
RNAseq (scRNAseq) datasets, we searched for these molecules/pathways meeting the following criteria: 1) they
should have important functions in cancer cells and immune suppressive cell types such as regulatory T cells
(Tregs), exhausted T cells (Texh), and myeloid-derived suppressor cells (MDSCs) etc.; 2) they are not important
for effector function of major immune cells such as effect T cells (CD4+ or CD8+ Teff) or nature killer cells (NK);
3) they should be targetable with known inhibitors. NR4A1 fits all 3 criteria and represents a valid target for
cancer immunotherapy. In the current proposal, we intend to use proteolysis-targeting chimera (PROTAC)
technology to develop a first-of-its-kind NR4A1 degrader for melanoma therapy. Aim 1. Rational design of novel
celastrol-based NR4A1-Ps by modifying celastrol and linkers. Aim 2. Determine cellular and molecular
mechanisms by which NR4A1-Ps work to inhibit melanoma. Aim 3. Explore the therapeutic potential of NR4A1-
Ps as a single agent or in combination. The outcome is to define the rationale for the future clinical translation of
NR4A1-Ps to enhance ICI therapy responses in melanoma.

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Cancer><Endometrial Carcinoma><Endometrium Cancer><Endometrium Carcinoma><Environment><Eragrostis><Exhibits><Family member><Future><Generalized Growth><Goals><Growth><Immune><Immune checkpoint inhibitor><Immunes><Immunomodulation><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><In Vitro><Indoles><Infiltration><K Cells><K lymphocyte><Keytruda><Kidney Cancer><Kidney Carcinoma><Killer Cells><LYT3><Lead><Ligands><Literature><MEKs><Malignant Breast Neoplasm><Malignant Cell><Malignant Melanoma><Malignant Neoplasms><Malignant Tumor><Marrow monocyte><Mediating><Medication><Melanoma><Melanoma Cell><Metabolic><Mice><Mice Mammals><Modeling><Modification><Molecular><Molecular Interaction><Murine><Mus><Mutate><Myeloid-derived suppressor cells><NK Cells><Natural Killer Cells><Nature><Nuclear Orphan Receptor><Nuclear Receptors><Outcome><PD 1><PD-1><PD-1 antibody><PD-1/PD-L1><PD-1/PDL1><PD1><PD1 antibody><PD1-PD-L1><PD1/PD-L1><PD1/PDL1><PRO2286><Pathway 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