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. 

Diabetes is chronic metabolic disorder of insulin resistance or deficiency. Diabetes has previously been linked to certain cancers: colorectal, liver, pancreatic, and endometrial; however, their association to melanoma remains unclear. Racial minorities make up about half of people with diabetes in the US and are more likely to have worse cancer outcomes. Additionally, racial minorities have worse melanoma outcomes in general. Given these prior findings, we aim to determine if there is a relationship between having diabetes and melanoma in racial minorities compared to Non-Hispanic White individuals. Our goal is to address a gap in knowledge in the literature while also contributing to future guidelines and recommendations for skin cancer screening.

Melanoma cases are increasing each year and can be difficult to diagnose. Pathologists look at special markers in skin samples under the microscope to help determine whether a growth is harmless or cancerous, but current methods rely on subjective judgment and can sometimes lead to disagreement even among experts. A promising marker called PRAME has been found to be more common in melanoma than in benign growths, but it is not yet measured in a way precise enough to fully leverage its diagnostic potential. This study aims to improve how PRAME is analyzed by using advanced digital tools. We will examine skin tissue samples and create detailed images of PRAME in melanocytes (the cells involved in melanoma). By calculating a new measurement called the PRAME index, we will be able to precisely determine the percentage of melanocytes that display the PRAME marker. This will provide a more precise and objective way to assess PRAME. By refining PRAME testing, our study aims to identify patterns that could lead to better diagnosis and treatment and lay the groundwork for using PRAME in targeted cancer therapies. We will also explore the use of artificial intelligence to predict PRAME index from routine pathology images. This could make PRAME analysis faster, more accessible, and more consistent, helping pathologists make better-informed decisions. By combining cutting-edge tools in laboratory science, digital pathology, and artificial intelligence, this research represents a major step toward making early detection and treatment of melanoma more reliable and accessible to patients everywhere. 

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. 

Melanoma, an aggressive skin cancer, can spread cancer cells to nearby lymph nodes. When removing a melanoma, surgeons will often also remove one or more lymph nodes from the basin, or collection, of lymph nodes nearest to the cancer. This is called a sentinel lymph node (SLN) biopsy, and helps determine if cancer has spread to lymph nodes. Previously, if cancer cells were seen in the SLN (SLN+), all other lymph nodes in that nodal basin would be removed through a completion lymph node dissection (CLND). While this procedure helped reduce the risk that melanoma would come back, it also put patients at risk for lymphedema, which can lead to severe swelling in the arm or leg. Over the past five years, there has been a dramatic shift in treatment for patients with SLN+ melanoma towards surveillance with frequent ultrasounds and examinations instead of additional surgery. Medical therapies such as immunotherapy have also significantly patients’ likelihood of surviving melanoma-free, which has increased the number of melanoma survivors who need high-quality survivorship care and melanoma surveillance. Our goal in this study is to closely study the outcomes of SLN+ melanoma patients at our institution who are undergoing nodal surveillance, so that we can better understand challenges that they face as melanoma survivors. We will conduct patient surveys to collect detailed information about their melanoma care, including patient-reported quality of life measures. We also want to understand how social determinants of health (SDoH), which are characteristics about the places in which people grow up and live that can influence their health outcomes, might affect patients’ experiences with melanoma survivorship. Findings from this study will help us to be able to identify melanoma survivors whose social needs may put them at higher risk for worse outcomes, so that we can design interventions to address these needs and improve the care of all SLN+ melanoma survivors.

Melanoma is the most aggressive form of skin cancer. One of the most common and devastating complications of melanoma is the spread of cancer to the brain, which is called melanoma brain metastasis. The survival of patients with melanoma brain metastasis used to be very short. However, new treatments have been developed that can control melanoma brain metastases, including stereotactic radiosurgery, immune therapy, and targeted therapy. Despite these advances, many patients eventually develop resistance to these treatments. In this project, we will focus on the impact of tumor metabolism on metastatic progression of melanoma. Cancer cells have the capacity to modify their metabolism to adapt to different environments in order to metastasize and grow in organs beyond where they originated. We believe that these different metabolic pathways (such as pathways involved in glucose and lipid production and oxidative stress) can be potentially targeted to develop novel therapeutics and to also improve the response of melanoma tumors to current immune and targeted therapies. In the current project, we will use melanoma cell lines in which expression of major genes involved in these pathways have been silenced. We will then inject these cells into the brain of mice (intracranial injection) and will study how inhibiting each of these pathways affects the growth and immune characteristics of melanoma brain tumors in mice. By targeting each individual pathway, we will be able to gain a better understanding of the role they play in development and growth of brain metastasis and use that information towards building new therapies. These studies will provide critical insights into potential therapeutic targets, ultimately offering hope for more effective treatments in patients with melanoma brain metastasis.

Melanoma is the fifth most common cancer in the U.S. Melanoma is an important public health concern and has a rising number of new cases and deaths per year. Prevention through sunscreens or barrier protection is limited, and no other preventive agents for melanoma have been approved for use. It is vital to develop a more effective prevention method. Atypical/dysplastic nevi (A/DN) are moles that appear abnormal and exhibit irregularity under the microscope. A/DN can develop into melanoma, and an increased number of A/DN is associated with increased risk of developing melanoma. A/DN are a good study target for melanoma prevention. Anti-PD1 therapy is a type of immunotherapy that can be used to treat Stage IIB-IIIC melanoma after surgical removal to reduce the risk of recurrence. This therapy works by removing the brakes from the immune system to allow it to target cancer cells. AntiPD1 therapy may also be useful in preventing melanoma, especially in patients who are at high risk or have multiple A/DN. This research will study the effects of anti-PD1 therapy on A/DN to understand its impact on precursor lesions of melanoma. 30 patients with non-metastatic, Stage IIB-IIIC melanoma receiving treatment with anti-PD1 and with 4 or more A/DN will be included. We will study how anti-PD1 affects A/DN after 3 months of treatment by assessing the changes in appearance of A/DN on the skin and under the microscope, as well as the changes at the molecular, immune, and gene expression level. We hypothesize that A/DN will appear smaller and less pigmented, will regress under the microscope, and will have increased immune cells and decreased expression of genes associated with melanoma. Patients will undergo photographs of the back, magnified dermatoscopic images of select nevi, as well as tape stripping and biopsy of select nevi. This study will help us better understand anti-PD1 as a potential prevention method, and will provide a basis for future melanoma prevention research.

Pediatric melanomas are a rare and deadly form of skin cancer. Melanomas in adults have better studied than the pediatric variant due to the rarity of melanomas arising in children. Most of the information available about pediatric melanomas are from smaller studies, and the medical literature is sparse on information about factors that are associated with more aggressive disease. Disease staging is an important predictor for how long a patient is expected to live. Patients with localized disease generally have better outcomes than those with advanced disease that have spread to the brain, lungs, liver, among other organs. In adults, staging criteria are well defined, and factors such as tumor size, how deep a tumor invades into the tissue, and how a tumor looks under the microscope, have been helpful in identifying whether a melanoma will behave aggressively and spread to distant tissues. In children, these factors are well less defined given the rarity of the disease, and current studies suggest that pediatric melanomas may behavior differently than those that arise in adults. Our study aims to use a national database of pediatric melanoma patients to address these uncertainties in the medical literature. We performed a preliminary analysis that demonstrates that different subtypes of pediatric melanomas behave differently. We demonstrate that epithelioid/spindle cell and melanoma arising from a previous mole are more aggressive than other subtypes. We additionally found that nodular melanoma and epithelioid/spindle cell subtypes have higher rates of having metastatic disease. In our study, we aim to identify high-risk features that increase the probability of a child developing metastatic melanoma. We additionally want to create a risk calculator to help clinicians quantify this risk to help them decide as to whether a child with melanoma requires further studies, such as lymph node evaluation or clinical imaging to assess whether advanced disease is present.

Melanoma can be classified according to TCGA into 4 genetic subtypes: BRAF, NRAS, NF1 mutants or triple wild type. A lot of research focused on BRAF and NRAS mutant melanoma and limited research was focused on understanding NF1 mutant melanoma despite having worse prognosis compared to all other melanoma subtypes. Our preliminary results from analyzing 33 melanoma cell lines that were isolated from patients, identified EGFR to be upregulated in NF1 mutant melanoma. Moreover, testing independent patients for their EGFR expression by histochemical analysis  showed similar results. This is a novel finding as EGFR is target in other cancer types like colorectal and lung cancer but not in melanoma. Our proposal aims at understanding the mechanism by which NF1 loss leads to EGFR activation and test if EGFR inhibition will prove a successful approach to be used as a treatment for NF1 mutant melanoma. This can lead to a fast transition to clinical use as EGFR inhibitors are already available and are used to treat other cancer types.