# Impact of N-Acetylgalactosamine-4-Sulfatase (Arylsulfatase B) on the Progression of Melanoma

> **NIH VA I01** · JESSE BROWN VA MEDICAL CENTER · 2024 · —

## Abstract

The morbidity and mortality of malignant melanoma are significant problems for veterans, their families,
and the general public. Progress has been made in early diagnosis and in treatment, in particular with advances
in checkpoint inhibition therapy. However, not all patients respond to this approach and the treatment has major
toxicity. There is a continuing unmet need for improvement in treatment of melanoma. This project presents a
novel and potentially breakthrough treatment approach, based on the impact of the enzyme N-
acetylgalactosamine-4-sulfatase, also known as arylsulfatase B (ARSB). This enzyme removes sulfate groups
from chondroitin 4-sulfate (C4S) and dermatan sulfate and is required for the degradation of these sulfated
glycosaminoglycans. Our previous work has shown that lower ARSB activity is associated with more aggressive
melanomas. Also, decline in ARSB leads to increased expression of the melanoma proteoglycan chondroitin
sulfate proteoglycan (CSPG)4 and of the matrix metalloproteinase pro-MMP2 which facilitates invasion. Other
experiments have shown increase in PD-L1 expression in melanoma cells following ARSB silencing.
 In this project, we will determine the transcriptional mechanism by which decline in ARSB increases
expression of PD-L1 in normal melanocytes and melanoma cells. Experiments will show how decline and
increase in ARSB affect melanoma cell survival and intracellular signaling. The impact of anti-PD1 treatment on
melanoma cell survival will be tested in live cell co-culture with immune cells following ARSB silencing. Other
studies in the B16F10 and YUMM mouse models of melanoma and in a humanized mouse xenograft model will
show the impact of modulation of ARSB in association with checkpoint inhibitor treatment on the progression of
primary and metastatic melanomas. This project is based on over 30 publications in which Dr. Tobacman and
collaborators have identified biological consequences of decline in ARSB. A previous report with project
collaborator, Arkadiusz Dudek, M.D., Ph.D., a distinguished oncologist and investigator with strong interest,
background, and clinical experience in immuno-oncology, identified decline in ARSB with increasing
aggressiveness of melanoma cell lines, as well as significant increases in expression CSPG4 and pro-MMP2.
 Inborn deficiency of ARSB is present in the lysosomal storage disease Mucopolysaccharidosis (MPS) VI,
in which mutations lead to marked reduction of ARSB activity. In malignant cells from prostate, breast, colon,
and liver, as well as in melanoma cells and tissue, we have shown that expression and activity of ARSB are
reduced, compared to normal melanocytes and tissue. Decline in ARSB leads to accumulation of the sulfated
glycosaminoglycans chondroitin 4-sulfate and dermatan sulfate, from which ARSB normally removes the 4-
sulfate group at the non-reducing end and is required to initiate their degradation. With decline in ARSB, C4S
accumulates and its interactions w...

## Key facts

- **NIH application ID:** 10881735
- **Project number:** 5I01BX005342-04
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** Joanne Kramer Tobacman
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881735

## Citation

> US National Institutes of Health, RePORTER application 10881735, Impact of N-Acetylgalactosamine-4-Sulfatase (Arylsulfatase B) on the Progression of Melanoma (5I01BX005342-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10881735. Licensed CC0.

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