u-104 and Melanoma

Mesenchymal stem cells (MSC) take part to solid tumour-associated stroma and critically influence progression of malignancy. Our study represents a striking example of melanoma progression to a more malignant and resistant phenotype promoted by MSC and the possibility to contrast this diabolic liaison using CAIX inhibitors. In particular, we demonstrated that melanoma cells exposed to a MSC-conditioned medium switch to a more malignant phenotype, characterised by resistance to programmed cell death and endowed with an epithelial-to-mesenchymal transition and stem cell characteristics. These effects were reversed abrogating MSC CAIX activity using SLC-0111, a CAIX inhibitor. Moreover, the acquisition by melanoma cells of a Vemurafenib-resistant phenotype upon MSC-conditioned medium exposure was removed when MSC were treated with SLC-0111. Therefore, MSC may profoundly reprogramme melanoma cells towards a wide resistant phenotype through CAIX involvement, as the use of SLC-0111 is able to contrast the development of this highly risky adaptation for disease progression.

Topics: Carbonic Anhydrase Inhibitors; Carbonic Anhydrase IX; Cell Line, Tumor; Cell Survival; Culture Media, Conditioned; Humans; Melanoma; Mesenchymal Stem Cells; Phenylurea Compounds; Skin Neoplasms; Sulfonamides

Treatment strategies involving immune-checkpoint blockade (ICB) have significantly improved survival for a subset of patients across a broad spectrum of advanced solid cancers. Despite this, considerable room for improving response rates remains. The tumor microenvironment (TME) is a hurdle to immune function, as the altered metabolism-related acidic microenvironment of solid tumors decreases immune activity. Here, we determined that expression of the hypoxia-induced, cell-surface pH regulatory enzyme carbonic anhydrase IX (CAIX) is associated with worse overall survival in a cohort of 449 patients with melanoma. We found that targeting CAIX with the small-molecule SLC-0111 reduced glycolytic metabolism of tumor cells and extracellular acidification, resulting in increased immune cell killing. SLC-0111 treatment in combination with immune-checkpoint inhibitors led to the sensitization of tumors to ICB, which led to an enhanced Th1 response, decreased tumor growth, and reduced metastasis. We identified that increased expression of

Topics: Animals; Antineoplastic Agents, Immunological; Apoptosis; Breast Neoplasms; Carbonic Anhydrases; Cell Proliferation; CTLA-4 Antigen; Drug Therapy, Combination; Enzyme Induction; Female; Gene Expression Regulation, Enzymologic; Humans; Hypoxia; Lung Neoplasms; Melanoma; Mice; Mice, Inbred C57BL; Phenylurea Compounds; Prognosis; Programmed Cell Death 1 Receptor; Sulfonamides; Survival Rate; Tumor Cells, Cultured; Tumor Microenvironment