Dr. Roger Lo, professor of medicine, dermatology and molecular & medical pharmacology and investigator at the UCLA Health Jonsson Comprehensive Cancer Center, was awarded a $2 million grant from the National Institutes of Health to investigate innovative strategies to prevent drug resistance in melanoma treatment and improve the effectiveness of MAPK inhibitors, a common treatment for patients with melanomas that carry the BRAFV600 mutation.
The BRAFV600 mutation is found in about 50% of melanomas, and patients whose tumors harbor this mutation are often treated with MAPK inhibitors, which target the tumor's growth pathway. However, once resistance develops, treatment options become limited.
The five-year award supports Lo’s work into finding ways to prevent resistance to MAPK inhibitors by targeting the underlying genomic instability and immune evasion in tumors, two key factors that contribute to treatment failure in this aggressive form of skin cancer.
“Our goal is to stop the cancer from evolving a plethora of heterogeneous resistance mechanisms by targeting the very processes that allow the cancer cells to change parts of their genomes,” said Lo. “We’ve found that targeted therapy such as MAPK inhibitors can cause the cancer cells to undergo new rounds of genetic changes by enhancing genome instability, and we believe we can stabilize the melanoma genome while it is exposed to targeted therapy in order to pre-empt resistance evolution.”
In fact, therapy-induced genomic instability can also lead to a wide variety of genetic changes that lead to evasion of anti-tumor immunity. As a result, the team will also be exploring how tumors hide from immune cells, particularly by increasing levels of a protein called PD-L1 on the surface of cancer cells. This protein acts as a shield, preventing immune cells from recognizing and destroying the tumor.
To combat this, the researchers have developed a compound known as AK087, which degrades PD-L1 and makes melanoma cells more vulnerable to immune attacks in experimental models. Early tests in animal models show promising results, with AK087 boosting the effectiveness of both MAPK inhibitors and immune therapies.
By addressing both the genetic evolution of the tumor and its ability to hide from the immune system, the team aims to extend the effectiveness of current therapies and provide new options for patients with melanoma.
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