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. 

Melanoma is a disease that places an incredible physical, financial, and emotional burden upon our society. Treatment options for melanoma have been focused on targeting our immune system. Melanoma cells can evade and utilize our immune systems by interacting with various immune cells. This research proposal focuses on understanding and improving the mechanisms by which the immune system can recognize and eliminate melanoma cells. Using various laboratory studies, we plan to assess the function of immune suppressor cells that melanoma recruits to block our body’s ability to fight cancer cells. By understanding more about these cell processes, we can work to identify treatment targets that are more effective at eliminating melanoma cells. As a result of this research, melanoma cancer patients may be able to experience fewer symptoms and have a prolonged life. 

Melanoma is a deadly form of skin cancer, and while new immunotherapy treatments have significantly improved survival, not all patients respond the same way. Doctors currently lack reliable tools to predict who will benefit from neoadjuvant immune checkpoint blockade (ICB), a treatment given before surgery to shrink tumors and improve long-term outcomes. This study aims to develop better biomarkers—biological indicators that can help predict treatment response—so that doctors can personalize therapy for each patient. 

We will study over 70 patients with Stage III melanoma, analyzing their tumors before and after treatment to identify key immune features that may predict who will respond well. Specifically, we will measure tertiary lymphoid structures (TLS)—specialized immune cell clusters within tumors—as well as CXCL13, a protein that helps immune cells communicate, and tumor-infiltrating lymphocytes (TILs), which are immune cells attacking the cancer. We will also assess PD-L1, a protein linked to immune evasion by cancer cells. 

By combining advanced lab techniques with machine learning, we aim to develop a predictive model that can help doctors classify patients into different risk groups and tailor their treatments accordingly. Our goal is to make immunotherapy more precise and effective, ensuring that patients receive the right treatment while minimizing unnecessary side effects. This research could revolutionize melanoma treatment by providing clinicians with better tools to guide therapy decisions, ultimately improving patient survival and quality of life. 

Sinonasal mucosal melanoma (SNMM) is a rare high-grade malignancy involving the sinonasal tract, primarily including the nasal cavity, turbinates, nasopharynx, and paranasal sinuses. The 5-year survival rate is less than 30% due to its advanced clinical presentation and frequent late-stage diagnosis, which is even worse in SNMM patient with distant metastatic disease. This underscores the critical need for investigating molecular profiles and identifying potential therapeutic strategies for metastatic SNMM. In this study, we used sequencing techniques to investigate distinct molecular profiles of metastatic SNMM and explores potential therapeutic strategies for metastatic SNMM patients. First, overall survival analysis revealed that SNMM patients with metastasis exhibited significantly poorer overall survival compared to non-metastatic patients (median survival: 18.8 vs 38.7 months). Our preliminary NGS data further identified missense mutations in SLX4 gene as being exclusively detected in metastatic SNMM. These mutations were associated with significantly shorter survival (median: 9.9 vs. 34.2 months). Notably, all three patients with SLX4 mutations died 2.4, 9.9 and 28.1 months, respectively. In addition, a comparative analysis of genomic alterations of clinically relevant genomic alterations (CRGAs) that are defined as genomic alterations (GAs) linked to available or investigational targeted therapies between metastatic and non-metastatic SNMM revealed that CDK4 gains/amplifications targeted by a selective CDK4/6 inhibitor, such as Palbociclib, were commonly seen in metastatic cases. Collectively, these exploratory findings suggest SLX4 mutation as a potential prognostic marker and CDK4 inhibitors as promising therapeutic options for metastatic SNMM. 

Patients with mucosal melanoma are likely to have poor outcomes with current standard-of-care treatment options. The reasons are multifactorial but include difficulty obtaining wide surgical resection margins given anatomically challenging sites of disease (e.g., near the base of the skull or in the anogenital area) and suboptimal response rates to immunotherapy. This project aims to improve outcomes for mucosal melanoma patients by combining radiation therapy with immunotherapy in the pre-operative setting, while creating a new, multimodality biomarker platform to predict for the likelihood of response. We anticipate that adding pre-operative radiation therapy will help improve immunotherapy response rates by directly killing melanoma cells while also improving the immune system’s ability to recognize and eradicate these cells. Such an improved treatment response may also help a surgeon remove the tumor completely with negative margins while maintaining maximal organ functionality and patient quality of life. In addition, we expect that our longitudinal blood-, tissue- and advanced imaging-based biomarker platform will create a framework to help personalize treatment recommendations for future patients to maximize the likelihood of treatment response and long-term disease control.

Mucosal melanoma (MM) is a rare form of melanoma with poor survival outcomes. Data on treatment for MM is limited to results from studies on cutaneous melanoma or from small cohorts of MM patients. The Veterans Affairs population is one of the largest U.S. healthcare networks and includes individuals traditionally under-represented in clinical trials (older age and diverse ethnic and racial backgrounds). Using data from the Veterans Affairs will allow us to examine one of the largest cohorts of MM patients.

Immune checkpoint inhibitors (ICIs), specifically anti-programmed death-1 (PD-1) therapies (nivolumab and pembrolizumab) and anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) (ipilimumab), have emerged as promising therapeutic candidates for treatment of MM, but studies have thus far yielded mixed results. A large-scale outcomes study in patients treated with immunotherapy may provide us with additional information to guide therapy choice based on real-world data.

Survival among MM patients varies by anatomical location, possibly due to anatomical surgical constraints, different lymphovascular supplies, different stages at diagnosis, different tumor mutational burdens, and different immune system characteristics by site. We will examine whether site of primary tumor predicts improved survival with ICI treatment.

Medical Student Award – Nicole Trepanowski

Career Development Award – Colt Egelston, PhD