# Targeting BMP signaling to treat advanced melanoma and suppress therapeutic resistance

> **NIH NIH F31** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $12,688

## Abstract

PROJECT SUMMARY
Melanoma is the leading cause of skin cancer death in the United States, with the 5-year survival rate of 20%
for patients with advanced disease1,2. Despite improvements in therapy, many patients receive minimal survival
benefit and often develop resistance to standard-of-care therapies3–8. Furthermore, a population of patients exist
who do not have the appropriate mutations or tumor characteristics to be eligible for new targeted and
immunotherapies. In order to provide adequate treatment options for patients who develop resistance or are
ineligible for current cutting-edge therapies, new therapeutic targets must be identified. Our lab has discovered
a novel melanoma oncogene, growth differentiation factor 6 (GDF6), a secreted bone morphogenetic protein
(BMP) ligand that promotes melanoma by regulating expression of specific neural crest factors, which has the
dual effect of preventing differentiation and suppressing apoptosis9. In addition to these specific factors, we found
GDF6 more broadly promotes a gene expression signature that mimics that of the embryonic neural crest. Neural
crest identity has previously been identified as a key feature involved in melanoma initiation, progression, and
therapeutic resistance5,6,10,11. Our studies show knockdown of GDF6 suppresses expression of many of these
neural crest genes. Taken together, these data indicate GDF6 is an optimal target for melanoma therapy. As a
secreted extracellular protein, GDF6 is amenable to targeting by antibodies. We produced a panel of monoclonal
antibodies to target the C-terminal binding region of GDF6 and developed multiple in vitro and in vivo assays to
assess candidate antibodies with the most potent action against GDF6 and evaluate their effectiveness as
potential melanoma therapeutics. I hypothesize that a subset of antibodies will effectively block GDF6 activity
leading to increase differentiation and cell death of melanoma cells in vitro and in vivo. I further hypothesize that
blocking GDF6 will suppress neural crest identity in melanoma cells, leading to less aggressive tumor cell
characteristics and sensitizing previously resistant cells to standard-of-care therapy. I will evaluate a pre-
screened panel of 42 monoclonal antibodies for in vitro and in vivo activity against GDF6 in melanoma cells to
identify top candidates with the most potent activity, in parallel with characterizing pharmacokinetic and dynamic
properties of the antibodies in vivo. I will further characterize the effects of GDF6 inhibition by these antibodies
on neural crest expression profiles and key features of advanced melanoma such as therapeutic resistance,
invasiveness, and anchorage independent growth. Additionally, I will analyze potential combinatorial therapies
in vitro and in vivo to assess changes in pathway activity for known therapeutic resistance mechanisms. Results
of this study will identify lead candidate anti-GDF6 antibodies for first-in-human (FIH) studies and pro...

## Key facts

- **NIH application ID:** 9877953
- **Project number:** 5F31CA239478-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Alec Kragie Gramann
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $12,688
- **Award type:** 5
- **Project period:** 2019-02-15 → 2020-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9877953

## Citation

> US National Institutes of Health, RePORTER application 9877953, Targeting BMP signaling to treat advanced melanoma and suppress therapeutic resistance (5F31CA239478-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9877953. Licensed CC0.

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