Improving Therapy for Melanoma Brain Metastases
Abstract
Topic Area: This proposal will address the Topic Area of Melanoma and Other Skin Cancers with a focus upon the gaps in cancer treatment that may affect the general population but have a particularly profound effect upon Military Health. Objective and Rationale: Melanoma is the most serious type of skin cancer and accounts for the vast majority (>70%) of skin cancer deaths in the United States. Among all tumor types, melanoma has a high chance of spreading into the brain. Brain involvement is clinically evident in ~30% of melanoma patients (as high as 75% at autopsy), and the brain is often the major site of disease progression, even when disease at other, non-brain sites is well controlled by drugs such as targeted therapy and immunotherapy. Melanoma brain metastases are a devastating complication of advanced melanoma that seriously impacts patients, caregivers, and their families. Symptoms are frequently severe and can include pain, headaches, cognitive issues, and motor disorders. Few patients ever recover from melanoma brain metastases, and the majority will unfortunately die. At this time, we lack effective therapies that can either prevent brain metastasis development or treat established melanoma brain metastases. A growing body of evidence suggests that melanoma cells growing within the brain are shaped by the brain environment, and this in turn increases their resistance to commonly used anti-melanoma drugs. It is our belief that the normal cells of the brain help drive these responses, making them an active player in melanoma brain metastasis progression. In this proposal, we will address two key questions. First, how does the brain environment alter the behavior of melanoma cells and how do these changes impact upon drug responses? Second, can we identify drugs that disrupt the communication between brain and melanoma cells and develop this as a strategy to prevent and treat melanoma brain metastases? We will use the latest technology to identify how the brain microenvironment alters the behavior of melanoma cells at the single cell level and will then use innovative proteomic approaches to decipher how melanoma cells talk to brain cells and in turn how the brain cells talk to the melanoma cells. Research Applicability: This work is expected to have a huge impact upon individuals with advanced melanoma (as well as those with other cancers that metastasize to the brain, such as breast and lung cancer), giving fundamental new insights into how drug sensitivity in the brain can be restored. We expect real clinical impact to be achieved within the time frame of the grant (e.g., over the 2-year funding period), with the development of a rationale for a new brain metastases-directed clinical trial expected by completion of the project. My group works closely with the Department of Neurooncology at the Moffitt Cancer Center, and we already have a track record of translating our findings from the bench to the bedside. Military Personnel Relevance: A recent analysis from the Naval Health Research Center showed melanoma incidence to be higher among active duty military personnel than the general population. Melanoma incidence is also particularly high among Veterans who served in high sun exposure locations such as Vietnam, Afghanistan, and Iraq.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810268
Entities
People
- Keiran Smalley
Organizations
- H. Lee Moffitt Cancer Center & Research Institute
- United States Army