Targeting Ligand-Dependent BMP Signaling in Melanoma
Abstract
Introduction Melanoma is the deadliest skin cancer, killing over 7,200 Americans annually and 60,700 people worldwide. A majority of these patients will ultimately die from metastatic disease, their tumors spreading and exhibiting resistance to one or more therapies. Substantial efforts in academic and industry settings have been undertaken to improve the efficacy of current melanoma therapies. These efforts have defined several mechanisms responsible for resistance to these drugs. However, efforts to combat such drug resistance in the clinic have resulted in minor improvements in patient outcomes. Additionally, clinical trials using combinations of these drugs have been undertaken and have shown meaningful, but modest, improvements in patient survival. For these reasons, it has become apparent that orthogonal approaches that complement existing therapies are likely to have the best impact on patient outcome. In this proposal we aim to develop a treatment that inhibits the GDF6 protein, which would cause death of melanoma cells and lead to tumor regression. GDF6 is expressed in nearly 80% of melanomas at all stages of the disease, and its inhibition could lead to clinical benefit for a large fraction of melanoma patients. Furthermore, an anti-GDF6 treatment would inhibit a newly-discovered, essential target in melanoma and would be entirely complementary to existing therapies. Scientific Objective and Rationale In a series of prior studies, we found that the GDF6 protein is secreted by melanoma cells, and it then acts on these same cells to promote tumor growth. It does so by altering the state of melanoma cells, endowing them with properties of highly proliferative embryonic cells. Blocking GDF6 and the signaling it stimulates causes melanoma cells to become less embryonic and proliferative, then ultimately die. GDF6 is an excellent therapeutic target for several reasons. Its inhibition leads to melanoma cell death and tumor regression. It is present in melanoma cells but absent from normal tissues, which makes toxicity caused by inhibition of GDF6 in normal tissues unlikely. And it can be targeted by a tried-and-true monoclonal antibody approach. Monoclonal antibodies are highly specific to their targets and are the basis for several currently approved cancer therapies, including Herceptin, Opdivo, Yervoy, and Rituxan. We know that GDF6 can be targeted in common cutaneous melanomas, those that grow on hairy skin, and preliminary data suggest it also can be targeted in rarer subtypes such as acral melanomas that grow on hairless palms and soles, as well as melanomas that grow on mucosal surfaces. Thus far we have generated monoclonal antibodies against GDF6 and have shown that these antibodies kill melanoma cells in culture. This proposal seeks to test whether these monoclonal antibodies can shrink common cutaneous and rarer melanoma tumors, thus providing a strong impetus for clinical trials. Impact and Relationship to Fiscal Year 2019 (FY19) Melanoma Research Program Challenge Statement and Focus Areas This proposal addresses the FY19 MRP Challenge Statement by focusing on the prevention of melanoma progression. GDF6 is present in the earliest primary stage melanomas, and its presence is correlated with metastatic progression of these lesions. Therefore, in addition to shrinking late-stage tumors, an anti-GDF6 therapy could also be used to prevent metastatic progression of earlier lesions, potentially when administered as adjuvant therapy with surgery. GDF6 is a target in a large fraction of common cutaneous melanomas, and the studies in this proposal will also determine whether rare acral and mucosal melanomas, which are often refractory to current therapies, are also sensitive to GDF6 inhibition. The studies described in this proposal would speed the development of an anti-GDF6 therapy, which could have beneficial effects to a large proportion of melanoma patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010288
Entities
People
- Craig J Ceol
Organizations
- United States Army
- University of Massachusetts Medical School