an-ex-vivo-brain-slice-model-to-study-target-breast-cancer-brain

An <em>Ex Vivo</em> Brain Slice Model to Study and Target Breast Cancer Brain Metastatic Tumor Growth

Brain metastasis is a serious consequence of breast cancer for women as these tumors are difficult to treat and are associated with poor clinical ...

Drexel University College of Medicine

Thomas Jefferson University

Epigenetic agents such as bromodomain and extra-terminal region inhibitors (BETi) slow tumor growth via tumor intrinsic alterations; however, their effects on antitumor immunity remain unclear. A recent advance is the development of next-generation BETi that are potent and display a favorable half-life. Here, we tested the BETi, PLX51107, for immune-based effects on tumor growth in BRAF V600E melanoma syngeneic models. PLX51107 delayed melanoma tumor growth and increased activated, proliferating, and functional CD8+ T cells in tumors leading to CD8+ T-cell-mediated tumor growth delay. PLX51107 decreased Cox2 expression, increased dendritic cells, and lowered PD-L1, FasL, and IDO-1 expression in the tumor microenvironment. Importantly, PLX51107 delayed the growth of tumors that progressed on anti-PD-1 therapy; a response associated with decreased Cox2 levels, decreased PD-L1 expression on non-immune cells, and increased intratumoral CD8+ T cells. Thus, next-generation BETi represent a potential first-line and secondary treatment strategy for metastatic melanoma by eliciting effects, at least in part, on antitumor CD8+ T cells.

The next-generation BET inhibitor, PLX51107, delays melanoma growth in a CD8-mediated manner.

Combinations of BRAF inhibitors and MEK inhibitors (BRAFi + MEKi) are FDA-approved to treat  -mutant melanoma. Efficacy of BRAFi + MEKi associates with cancer cell death and alterations in the tumor immune microenvironment; however, the links are poorly understood. We show that BRAFi + MEKi caused durable melanoma regression in an immune-mediated manner. BRAFi + MEKi treatment promoted cleavage of gasdermin E (GSDME) and release of HMGB1, markers of pyroptotic cell death. GSDME-deficient melanoma showed defective HMGB1 release, reduced tumor-associated T cell and activated dendritic cell infiltrates in response to BRAFi + MEKi, and more frequent tumor regrowth after drug removal. Importantly, BRAFi + MEKi-resistant disease lacked pyroptosis markers and showed decreased intratumoral T-cell infiltration but was sensitive to pyroptosis-inducing chemotherapy. These data implicate BRAFi + MEKi-induced pyroptosis in antitumor immune responses and highlight new therapeutic strategies for resistant melanoma. SIGNIFICANCE: Targeted inhibitors and immune checkpoint agents have advanced the care of patients with melanoma; however, detailed knowledge of the intersection between these two research areas is lacking. We describe a molecular mechanism of targeted inhibitor regulation of an immune-stimulatory form of cell death and provide a proof-of-principle salvage therapy concept for inhibitor-resistant melanoma...

Mutant BRAF and MEK Inhibitors Regulate the Tumor Immune Microenvironment via Pyroptosis.

Prior to metastasis, modern therapeutics and surgical intervention can provide a favorable long-term survival for patients diagnosed with many types of cancers. However, prognosis is poor for patients with metastasized disease. Melanoma is the deadliest form of skin cancer, yet i and localized, thin melanomas can be biopsied with little to no postsurgical follow-up. However, patients with metastatic melanoma require significant clinical involvement and have a 5-year survival of only 34% to 52%, largely dependent on the site of colonization. Melanoma metastasis is a multi-step process requiring dynamic changes in cell surface proteins regulating adhesiveness to the extracellular matrix (ECM), stroma, and other cancer cells in varied tumor microenvironments. Here we will highlight recent literature to underscore how cell adhesion molecules (CAM) contribute to melanoma disease progression and metastasis.

Article	Year
The next-generation BET inhibitor, PLX51107, delays melanoma growth in a CD8-mediated manner. Pigment cell & melanoma research\| PubMed ID: 31063649	2019
Mutant BRAF and MEK Inhibitors Regulate the Tumor Immune Microenvironment via Pyroptosis. Cancer discovery\| PubMed ID: 31796433	2020
Cell Adhesion Molecules in Plasticity and Metastasis. Molecular cancer research : MCR\| PubMed ID: 33004622	2021

Edward J. Hartsough

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