Scientific Objective and Rationale: About 7,000 patients will die from melanoma in the U.S. this year. Although patients with early stage melanoma are treated with surgery, many subsequently succumb to metastatic disease. It is therefore critical that we design new therapies to treat and prevent spread. How melanoma spreads to lymph nodes (LNs) and other organs is not known. Melanoma is believed to travel via lymphatic channels that connect the primary tumor to LNs that filter body fluid and immune cells from the area of skin containing the melanoma. We studied how efficiently the radioactive “dye” used in LN biopsies for melanoma surgery traveled from the injection site at the primary melanoma tumor to LNs and discovered the “dye” traveled faster in patients with LN tumors. Interestingly, the “dye” travels not only by passive flow but also with help from immune cells known as macrophages that can swallow the “dye” and carry it to LNs. Thus, we suspect that these macrophages that migrate from the primary tumor may help melanoma develop secondary tumors in LNs. Since more macrophages have been observed in aggressive melanoma skin and LN tumors, we propose that macrophages play a critical role in creating and supporting LN tumors. Based on these data, our hypothesis is that macrophages from the primary melanoma travel to LNs and alter cells there to suppress the immune response to cancer. Using a mouse model of melanoma, we will test the hypothesis that macrophages from the primary tumor support LN metastases by altering the expression of genes of immune cells in the LN.

Scholar’s Career Goals in Melanoma Research: I have a passion for basic research and have pursued dedicated research time at every step in my training. From each of these laboratory experiences, I have become more productive, more thorough, and more successful. I joined a thriving research community at University of Alabama at Birmingham that provides an excellent environment for me to achieve my objective of building a high-impact melanoma research program, with assistance and direction from my Career Guide. I am dedicated to building my own lab focused on how melanoma metastasizes to identify new treatments for patients that prolong quantity and quality of life. When combined with my previous experience, the talent of my intramural multidisciplinary mentoring team and my Career Guide and the knowledge acquired from the proposed training in immunology, bioinformatics, and grant writing, will position me to transition successfully into a leader in melanoma research.

Ultimate Applicability of Research: The knowledge gained from this research will improve our understanding of lymphatic spread and inform drug development to target tumor-promoting macrophages. The projected time to achieve a clinically relevant outcome is within 7 years from the initiation of this project. From my experience in developing a patent-pending chemotherapeutic film, I believe that an intratumoral injectable agent can be designed from the results and tested in a phase 1 clinical trial within 3 years of completion of this award. This research will lead to betterment of cancer patients by focusing on developing a treatment for patients with melanoma at risk for metastasis without current evidence of stage IV (distant metastatic) disease. By informing the design of an intratumoral agent that can modify the ability of tumor-derived macrophages to modulate the immune microenvironment of tumor-draining LNs, this research can prevent and/or decrease metastasis in patients. Preventing and decreasing LN metastasis will lead to improved survival and decreased morbidity from patients, as regional LN dissections may be avoided as well.

Benefit of Research to Active-Duty Service Members, Veterans, and Their Families: Studies have demonstrated that U.S. military personnel are uniquely at increased risk for melanoma due to occupational sun exposure, Service in tropical environments, lack of sun protection, and a demographic population that encompasses two groups (Caucasians and men over 50 years of age) known to have increased incidence of skin cancer. Active-Duty Service Members often are also taking medications, such as doxycycline for malaria prevention, that act as photosensitizers or serve as pilots frequently at working in higher altitudes, both of which place them at increased risk for UV radiation. Furthermore, Active-Duty Service Members, especially those in remote areas, are unlikely to be able to undergo quarterly surveillance for high-risk melanoma; these delays permit high-risk melanoma the time to progress to stage IV (distant metastatic disease). Therefore, this project focuses on improving therapeutic prevention by discouraging microscopic melanoma cells from spreading to LNs preventing progression of disease. The knowledge gained from this research provides the opportunity to translate these findings rapidly into therapeutic applications that can be injected into the primary melanoma prior to undergoing surgery to remove it. By preventing the development of micrometastatic disease to draining LNs, we can decrease the morbidity of treatment and prolong patient survival to benefit the care of Veterans, Active-Duty Service Members, and their families.