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.

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 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.

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, 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.