Development of Rational Combination Therapy Strategies for the Treatment of Metastatic Melanoma
Abstract
This research project is focused on melanoma, an aggressive form of skin cancer. In particular, we are interested in exploring novel treatment avenues to close currently existing gaps in melanoma treatment that affect both the general population and that also have a profound impact on military health. Melanoma is a devastating disease that is responsible for a disproportionate number of cancer-related deaths relative to the number of newly diagnosed cases. Indeed, according to the National Cancer Institute, melanoma is the fifth most prevalent in the United States whereby an estimated 76,900 Americans are expected to be diagnosed with melanoma in 2014 and today, even with better detection and therapeutic strategies, roughly 10,000 individuals are expected to die from the disease. A critical health concern is the alarming and steady increase in the rate of newly diagnosed cases due to prolonged sun exposure. This issue is pertinent to military personnel, in which the risk of developing melanoma is higher among active duty personnel relative to the civilian population. The scientific community has made steady gains in our ability to treat melanoma, particularly over the past decade with the discovery of distinct types of melanoma with unique molecular features. One type in particular, called B-RAF mutant melanoma, harbors activating mutations in genes that control an intracellular pathway (called RAF/MEK/MAPK), which stimulates melanoma tumor growth. Importantly, B-RAF mutant tumors constitute roughly 40%-50% of all newly diagnosed melanomas and are associated with reduced survival of melanoma patients. In 2011, there was a major breakthrough in treatment options for patients with B-RAF mutant melanoma owing to the development of targeted drugs that specifically target mutant B-RAF, which is only expressed in melanoma cells and not normal cells. Patients treated with these B-RAF inhibitors experienced very impressive rates of remission, which were unfortunately also accompanied by rapid relapse rates owing to the development of therapeutic resistance. Thus, these B-RAF targeted therapies have only achieved limited durable survival benefit in melanoma patients. We are interested in exploring novel treatment strategies to eradicate B-RAF mutant melanoma tumor cells and increase the long-term survival of melanoma patients. In this regard, we have identified a novel protein, called GPNMB, which is expressed on the surface of melanoma tumor cells, which we believe is a viable therapeutic target to increase the long-term survival of melanoma patients treated with B-RAF inhibitors. There are four main reasons for this belief: (1) GPNMB has previously been shown to promote melanoma tumor growth. (2) GPNMB is highly expressed on the surface of melanoma cells, and (3) pharmacological inhibitors targeting the B-RAF/MEK/MAPK pathway further augment its cell surface expression levels. Given that GPNMB resides at the cell surface, a portion of the protein (called the extracellular domain) can be recognized by monoclonal antibodies that specifically bind GPNMB. (4) We have a long-standing collaboration with Celldex, a pharmaceutical company, which has generated a novel therapeutic compound that fuses an antibody targeting the extracellular domain of GPNMB to a cytotoxic compound, which immediately kills the tumor cell. This GPNMB antibody-drug-conjugate is called CDX-011. In this project, we will examine whether treatment of melanoma patients with B-RAF/MEK/MAPK inhibitors provides the patients with a window of opportunity to sensitize melanoma cells to the immediate cytolytic effects of CDX-011 as a result of increased GPNMB expression on the surface of tumor cells. In this manner, CDX-011 would immediately kill GPNMB-expressing melanoma tumors cells. Our research will determine whether combination therapies targeting the B-RAF/MEK/MAPK pathway along with CDX-011 will have a significant positive impact on the long-ter
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510577
Entities
People
- Peter Siegel
Organizations
- McGill University
- United States Army