Acral melanoma is a rare and understudied subtype of melanoma with few treatment options and poor outcomes. The current standard of care treatment for advanced disease is immunotherapies. However, many patients do not respond to this treatment. The protein, RAS, is a promising target for targeted inhibitor drugs in acral melanoma, as cancer cells frequently have increased activity of this protein. Additionally, acral melanoma tumors often have low levels of patient immune cells that can attack cancer cells. Our short-term goals are to understand the potential for RAS targeted inhibitor use in acral melanoma and identify the effects on interactions between cancer cells and surrounding immune cells.

We tested if RMC-7977, a recently developed RAS inhibitor currently in clinical trials, works in acral melanoma cell lines with mutations in the RAS gene. We found that RMC-7977 stops growth and causes death of cancer cells via pyroptosis, a form of cell death that recruits and activates immune cells that can clear tumors. Through this proposal, we aim to further understand how pyroptosis occurs in acral melanoma cells treated with RMC-7977. Additionally, we will study how RMC-7977 alters interactions between tumor cells and surrounding immune cells. We expect to show that RMC-7977 may be an effective therapeutic strategy for metastatic acral melanoma patients.

Acral lentiginous melanoma (ALM) is a rare kind of skin cancer that appears on the palms of the hands, soles of the feet, or under the nails, areas that may not be examined closely and can present with early signs that are hard to notice. As a result, ALM is often diagnosed at a later stage, when the cancer is thicker or has spread to nearby lymph nodes. This delay in diagnosis makes treatment more challenging and leads to worse outcomes compared to other types of melanoma. Past studies have suggested that ALM may be related to areas of repeated injury or slow wound healing. Many Veterans suffer from long-term nerve damage, known as peripheral neuropathy, or poor blood flow, called peripheral arterial disease (PAD).

These issues can lead to numbness, foot ulcers, and wounds that heal slowly, making the hands and feet more prone to ongoing injuries and poor healing that could lead to this melanoma. Despite this, researchers have not examined if peripheral neuropathy and PAD are directly related to the risk of developing ALM. To understand if they are, this study will look at data from 383 Veterans who have confirmed foot ALM and 383 similar Veterans who do not have it to examine if nerve damage or circulation issues raise the risk of developing ALM. We expect that Veterans with peripheral neuropathy and/or PAD will be more likely to develop foot ALM compared to those without these conditions. We will also investigate how these risks differ by age, sex, race, and ethnicity to identify groups that are at higher risk. By improving our understanding of whether nerve and blood vessel issues contribute to ALM, this research could help improve its screening and prevention efforts as well as possible therapeutic opportunities. 

Acral and mucosal melanomas(A&MM) are rare but aggressive types of melanoma, making up less than 5% of all cases. Unlike the more common type of melanoma, which develops on sun-exposed skin, A&MM arise in areas not typically exposed to the sun—such as the palms, soles, under the nails (acral melanoma), or in mucous membranes like the mouth, nose, and genitals (mucosal melanoma). These cancers follow a different genetic path and do not respond well to standard treatments, making them particularly difficult to treat. Research has shown that many A&MM tumors have mutations that activate a key cellular pathway known as the RAS signaling pathway, which drives cancer growth. However, there are currently no effective targeted treatments for these patients.

A new class of drugs, called RAS(ON) inhibitors, has been developed to block the activity of RAS, offering a potential breakthrough for patients with RAS-driven cancers. Early studies suggest that these drugs could be effective in slowing tumor growth. In my lab research, I tested a RAS(ON) inhibitor on tumor models derived from two patients—one with acral melanoma and one with mucosal melanoma. While the tumors initially shrank in response to the drug, which is a great win for this challenging cancer type, they later became resistant, meaning the treatment stopped working. This indicates that while RAS(ON) inhibitors hold great promise, we need to understand how resistance develops and find ways to prevent or overcome it. This study has two main goals. First, I will test RAS(ON) inhibitors on a larger set of patient-derived tumor models grown in mice to determine which types of A&MM are most likely to respond. Second, I will investigate how resistance to these drugs develops by analyzing genetic changes in tumors before and after they stop responding. By identifying the biological mechanisms that allow the cancer to escape treatment, I aim to discover combination therapies that can enhance the effectiveness of RAS(ON) inhibitors. The results of this research will provide valuable insights into how A&MM can be better treated, guiding the development of new, more effective therapies. Ultimately, this work aims to bring new hope to patients with these rare and challenging melanomas by advancing precision medicine approaches tailored to their unique cancer biology.