Melanoma Drug Addiction and Its Therapeutic Implications
Abstract
Multiple studies show that a vast majority of Soldiers are facing a high risk of skin cancer caused by unprotected exposure to the sun, of which melanoma is the most aggressive. Therefore, increasing efforts to find better and innovative treatments for people, including those who serve our nation, with melanoma are needed. We know that approximately 40%-60% of melanomas contain an activating mutation in the BRAF protein kinase. Therefore, the emergence of drugs that target BRAF and downstream MEK has changed the clinical arena for treatment against melanoma. However, most patients treated with these drugs eventually relapse within several months. Our recent findings suggest that melanomas that have become resistant to BRAF and MEK inhibition become dependent on the presence of the drugs for survival, a phenomenon we term "drug addiction." We have recently identified that removal of drugs leads to strong induction of the MAPK pathway, causing stress and eventual cell death. Our studies have provided rationale to test the novel concept of drug addiction to BRAF and MEK inhibition therapy, via intermittent drug dosing, in clinical trials. Further understanding of the biological processes associated with drug addiction will provide diagnostic tools to predict which patients may benefit from drug holiday or intermittent therapy. To achieve our goals to guide iterative efforts to advance melanoma patient therapy, we will address three important aims. First, we will uncover signaling routes that mediate drug addiction, focusing on the subsequent targets of MAPK hyperactivation. Second, we will identify therapeutic agents and strategies to enhance drug holiday therapy. Finally, we will validate drug addiction molecular markers and strategies in mouse models and tumor samples. We expect that these investigations will enable rapid translation by matching patients to agents augmenting drug holiday treatment in melanoma. My PhD training has given me opportunities to engage in highly translational melanoma research, including the research proposed for this award. Under the mentorship of Dr. Roger Lo, I will continue to have outstanding scientific guidance and all the necessary resources and facilities to develop, refine, and successfully accomplish my research projects. The relationships extended from the Lo Lab, from strong collaborative efforts, have opened opportunities to interact with and learn from other renowned scientists within the broader scientific community. This has played a huge role in furthering my career and intellectual development as a cancer researcher. The Horizon Award will help facilitate my career transition from a predoctoral trainee to a postdoctoral scholar and independent researcher. This will ultimately serve to achieve my career goals, which is to formulate novel strategies for better therapeutic opportunities for cancer patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610290
Entities
People
- Aayoung Hong
Organizations
- United States Army
- University of California, Los Angeles