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Pro-tumorigenic activity of beta-galactosylceramidase: a novel player in cutaneous melanoma

Titolo: Pro-tumorigenic activity of beta-galactosylceramidase: a novel player in cutaneous melanoma

Abstract:

Background

Usually resistant to both chemotherapy and radiotherapy, metastatic melanoma represents the most lethal form of skin cancer. The expression of various sphingolipid-metabolizing enzymes has been associated to melanoma cell proliferation, survival and metastatization related to changes in the intracellular levels of ceramide. Beta-Galactocerebrosidase (GALC) is a lysosomal enzyme that catalyzes the removal of galactose from galactosylceramide and other sphingolipids. Preliminary observations indicate that GALC is involved in melanoblast/melanocyte development in zebrafish and is highly expressed in murine B16-F10 melanoma, its downregulation leading to inhibition of melanoma cell growth in vitro and in vivo. Further, data mining indicates that GALC expression in human melanoma is related to tumor progression and survival.

Hypothesis

Preliminary data support the hypothesis that GALC plays a role in melanocyte differentiation and neoplastic progression and that the GALC enzyme may represent a druggable target for melanoma therapy.

Aims

We will attempt to establish the role of GALC in melanoma and we will address the possibility that GALC may represent a druggable target in melanoma monotherapy and/or in combination with immune checkpoint inhibitors or MAPK pathway inhibitors. We will use hypothesis-driven and data-driven approaches applied to genetic zebrafish and murine melanoma models and to human melanoma cell lines. The possibility that anti-GALC compounds may act as “two compartment” inhibitors by targeting both the stromal/endothelial and tumor cell compartments of melanoma represents a further aim of the project.

Experimental Design

We will use zebrafish and murine melanoma models and human melanoma cell lines. These platforms will allow combined in vitro and in vivo experimentation to evaluate the role of GALC in melanocyte differentiation and transformation in zebrafish and in the tumorigenic, angiogenic and metastatic activity of murine and human melanoma cell lines by gene knockdown and knockout approaches. We will capitalize our preliminary results to assess the effect of GALC silencing on melanoma lipidome and sphingolipid metabolism. Selective suicide substrate GALC inhibitor(s) will be used to evaluate in pre-clinical settings the effect of the pharmacologic inhibition of GALG activity on melanoma cells and genetic zebrafish and murine melanoma models in monotherapy and/or in combination with immune checkpoint inhibitors or MAPK pathway inhibitors. Finally, the effect of GALG inhibition on endothelial/stromal melanoma components will be also evaluated.

Expected Results

 

We expect that the data will demonstrate the role of GALC in melanoma progression via alterations of its sphingolipid metabolism and we anticipate that selective suicide substrate GALC inhibitor(s) may exert an oncosuppressive effect on melanoma in monotherapy and/or in combination with immune checkpoint inhibitors or MAPK pathway inhibitors. Such anti-GALC molecules may act as “two compartment” inhibitors by targeting both the stromal and tumor cell compartments of human melanoma.

Impact on Cancer

This project focuses on the sphingolipid-metabolizing enzyme GALC as a novel druggable target in melanoma. Our findings will provide valuable information for the development of novel “two compartment” GALC inhibitors with therapeutic implications for human melanoma. In addition, elucidation of the mechanism of action of GALC in melanoma may pave the way for further studies about the role of this enzyme in different malignancies.

Coordinatore del Progetto: Prof. Marco Presta

marco.presta@unibs.it

Dipartimento di Medicina Molecolare e Traslazionale

Durata progetto: 5 anni

Ruolo: Capofila

Costo totale: € 133.000,00

Contributo AIRC per UNIBS : € 133.000,00

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