My research aims to understand why some melanomas stop responding to treatments over time and to identify new ways to make these therapies more effective. By studying how cancer cells adapt and survive under drug pressure, I hope to uncover the molecular “escape routes” that tumors use and to develop drug combinations capable of preventing or reversing resistance. The ultimate goal is to translate these findings into more durable and effective therapies for melanoma patients.

My current research focuses on understanding how individual patients’ tumors react to immune-centered therapies (immunotherapy). To capture the full picture of a tumor, I study thousands of single cells from samples taken before and during treatment. By tracking how these cells change over time, I work to predict who is likely to benefit from immunotherapy, who may need different or additional treatments, and when care should be adjusted. My goal is to turn these insights into clearer decisions in the clinic, helping patients receive the most effective, personalized care while avoiding unnecessary side effects.

Melanoma is the most lethal skin cancer, leading to an estimated 8,290 deaths and 100,640 new cases in 2024. Melanoma was traditionally very difficult to treat, which has changed in the past 15 years with the onset of immunotherapies. Despite their success, many patients do not respond to immunotherapy and are in need of secondary treatments. Different forms of cell death are able to improve the recognition of tumors by the immune system. A form of cell death called pyroptosis is when proteins in the cells, gasdermins, poke holes on the cell surface, causing various cellular components to leak out and stimulate the immune system. Pyroptosis improves immunotherapy in several cancers, thus we wondered if a particular form of pyroptosis driven by gasdermin D might improve the success of immunotherapy in melanoma. 

In the first aim of our project, we propose to study if causing pyroptosis through gasdermin D is able to effect tumor growth in cutaneous melanoma like model system. We will test if the immune system is needed for any tumor growth effects we observe after causing pyroptosis. Next, we will dissect the specific immune responses caused by gasdermin D driven pyroptosis, specifically testing the reliance of these immune responses on a specific population of immune stimulatory cells. Lastly, we will determine if specific factors released from pyroptotic cancer cells are driving the immune responses and tumor growth effects we observe. We ultimately expect to find that pyroptosis through gasdermin D slows tumor growth by engaging the immune system. 

For the second aim of this grant, we propose testing if pyroptosis induction through gasdermin D can improve the effect of immunotherapy in cutaneous melanoma tumor models. Specifically, we will investigate the best timing of pyroptosis induction to improve immunotherapy and lead to immune responses that can impact distant tumors that model metastases. We will also work with The Wistar Institute to screen thousands of anti-cancer drugs to discover which can cause pyroptosis through gasdermin D. We will then test to see if the drugs identified can slow the growth of primary and metastatic tumors through so called abscopal effects. With this aim we expect to leverage pyroptosis to improve immunotherapy in melanoma and discovery new treatments for melanoma. 

Immunotherapy has greatly improved survival for people with melanoma, but many patients also experience harmful side effects when the immune system attacks healthy tissues. Skin inflammation is among the most common problems, sometimes lowering quality of life or even discontinuing treatment.  

A growing body of research shows that neutrophils, a type of immune cell, play a central role in causing some of these toxicities. In our earlier studies in mice, we found that skin inflammation during immunotherapy was linked to neutrophils that express a molecule called VISTA. These findings suggest that VISTA-positive neutrophils may be especially important drivers of skin damage.  

We are now turning to human studies to determine whether the same process occurs in people. By examining skin samples from melanoma patients who developed immune-related side effects, we will test the role of VISTA-positive neutrophils in driving inflammation. Insights from this work may guide the development of safer and more potent immunotherapies that maintain strong anti-cancer activity while reducing harmful side effects.  

Immunotherapies including immune checkpoint blockade (ICB) have seen remarkable success in the clinic. Unfortunately, many patients with late-stage melanoma still exhibit only a partial response to therapy, where tumor lesions shrink temporarily but then continue to progress. If we could convert these partial responders to complete responders, we could make significant impacts on patient survival rates long-term. What causes these patients to differ from complete responders? If we think of the race between the growth and death of tumor cells, immunotherapy’s goal is to increase the death rate to overtake growth. In these partial responder patients, clearly the growth rate manages to catch up to and surpass the death rate and the race is eventually lost. We hypothesize that tumors can be divided into different types of regions that exhibit different levels of tumor cell death following ICB treatment. Some regions are “reactive” (RE) which exhibit enhanced levels of tumor cell death and others are “non-reactive” (NRE) which exhibit decreased levels of tumor cell death. The balance and interplay between these types of regions ultimately determines the outcome of therapy. How are these regions arranged in melanomas during ICB treatment? What causes these regions to develop? And if we look for these regions in patient samples, can we more accurately predict their treatment outcome. Our proposal will directly address these questions using advanced microscopy and spatial technologies. We will use mouse models of melanoma engineered to light up fluorescently when undergoing processes such as death, growth and quiescence. By imaging large pieces of these tumors, we will be able to precisely count the number of cells undergoing those processes and map their distribution in the spatial coordinates of the tumor. Once we have maps of the spatial distributions of tumor cell death, we will apply novel technologies to zoom in on the RE and NRE regions and ask, what types of cells are located there and how are they interacting? What kind of cell neighborhood leads to better or worse tumor cell elimination? 

We will then look at samples taken from patient tumors who underwent ICB therapy to examine if similar regions and features from our previous aims are found in these tissues. This will allow us to predict which region type (RE vs NRE) is more dominant as treatment progresses and thus the ultimate outcome of treatment on a per-patient basis. In other words, we can monitor the race between tumor death and growth in patients undergoing ICB and check our predictions against the known clinical outcome. We envision our work will reveal additional vulnerabilities to target in melanoma in combination with ICB to increase survival in patients. Additionally, the prognostic model we generate will provide an invaluable tool in the clinic for monitoring and predicting the outcome of ICB in patients, allowing for more precise and personalized cancer care. 

Melanoma is the most lethal skin cancer, and the success of current therapies remains limited. To better tailor melanoma treatments, we must understand the complexity of the tumor microenvironment (TME). Within the TME, many different types of cells interact with each other, including immune cells, tumor cells, and stromal cells. The stroma is composed of the structural components that support the tumor tissue. A key component of the stroma are cancer-associated fibroblasts (CAFs), which can control tumor growth, blood supply, protection from the immune system, or the ability to metastasize. However, these CAFs are complex and can display tumor-promoting or tumor-restraining functions. For example, inflammatory CAFs attract defective immune cells that can promote tumor growth, while myofibroblastic CAFs form barriers to tumor cell invasion and spread.

It remains unclear how these different types of CAFs develop from normal skin fibroblasts and how CAF identity and functionality is shaped.   Despite the growing importance of CAFs in tumor biology, our understanding of their ‘epigenetic’ regulation is extremely limited. Epigenetics is the study of the processes that control how and when genes are turned on or off and is critical for shaping cellular identity. Here, we will use cutting-edge high-resolution approaches to study the epigenetic features that control CAF identity. Using mouse models of melanoma that mimic the complexity of the TME, we will use spatially resolved approaches to ‘observe’ cellular interactions and behaviors within the tumor as the melanoma develops. We will focus on inflammatory CAFs, which we showed can lead to an impaired anti-tumor immune response and increased tumor growth in mice. Our proposed work could reveal the presence of CAFs that inhibit immune function and indicate approaches to dampen their pro-tumor features, as some epigenetic regulators can be effectively targeted with drugs. Thus, a deeper understanding of the tumor stroma can lead to novel therapeutic approaches for melanoma patients.

Analysis of large families with more disease than expected has been shown to be a powerful way to identify cancer predisposition genes. We have used this approach in Utah to identify the major cancer genes BRCA1, BRCA2, as well as CDKN2A (identified in Utah and Texas cutaneous malignant melanoma (CMM) pedigrees). We have used the Utah high-risk pedigree approach more recently to identify genes for many cancers, including GOLM1 for CMM, as well as genes for other cancers (colon cancer, breast cancer, prostate and bladder cancer) and other disorders (e.g. Chiari malformations, osteoporosis, and Alzheimer’s). We propose to efficiently use this same approach here for an available resource of melanoma cases who died from their melanoma (lethal melanoma) and who belong to high-risk Utah melanoma pedigrees. In our Genetic Epidemiology Biorepository, we have 904 stored germline DNA samples from melanoma cases who are members of extended Utah pedigrees with a significant excess of melanoma (high-risk pedigrees). Among these sampled Utah cases there are 55 who have a linked Utah death certificate showing that melanoma was a contributing cause of death (lethal melanoma). Three of the pedigrees include 3 related affected sampled melanoma cases; the other 14 pedigrees include 2 related affected sampled melanoma cases.

We will perform whole genome sequencing (WGS) on these samples. We will apply a unique approach that includes analysis of the genetic sequence data to identify the rare genetic variants that are shared among these related Lethal melanoma cases; this will identify a set of strong candidate predisposition genes/variants for lethal melanoma. We will validate our candidates by testing for association with melanoma risk in publicly available data for independent populations of melanoma cases and controls (e.g. UKBiobank, VHA MVP, AllofUs). We will identify our top 10 candidate variants. We will assay the best candidates in the set of additional previously sampled and melanoma affected relatives of the affected cousin carriers (from our Biorepository) to confirm segregation in pedigrees. Identification of additional genes and variants responsible for lethal melanoma will improve identification of those people at most risk, will expand our understanding of the causes of lethal melanoma, and will allow the application of powerful screening and prevention strategies for this deadly cancer. 

Skin cancer is one of the most common types of cancer, with melanoma being the deadliest form. In the United States, approximately 104,960 new cases of melanoma are expected in 2025, and about 8,500 people are projected to die from the disease. Melanomas often result from genetic mutations in genes controlling cell growth. A key pathway involved in this is the MAPK pathway (Mitogen-Activated Protein Kinase pathway), which transmits growth signals from the cell surface to the nucleus. When mutated, this pathway becomes overactive, leading to uncontrolled cell growth and melanoma. The BRAF (V600E) mutation is one of the most common causes, leading to constant activation of MAPK and uncontrolled cell division. Treating advanced melanoma, especially when it spreads to other parts of the body (metastatic melanoma), was historically difficult. Over the past decade, targeted therapies have changed this. BRAF inhibitors were developed to block the BRAF (V600E) mutation and paradoxically hyperactivate the MAPK pathway in normal cells, preserving healthy tissue function. This effect makes the combination of BRAF inhibitors and MEK inhibitors (which block another part of the MAPK pathway) more tolerable, improving patient survival and quality of life. However, some patients eventually develop resistance, causing cancer progression. Ongoing research (including our) focuses on finding ways to overcome it. Also, around 20% of melanoma cases carry mutations in the NRAS gene, which also overactivates the MAPK pathway. However, unlike BRAF-mutant melanoma, there are no approved targeted therapies for NRAS-mutant melanoma, and BRAF inhibitors are ineffective. To address this, a new class- pan-RAF inhibitors were developed to block RAF proteins in all contexts. However, these inhibitors shut down the MAPK pathway in both cancer and healthy cells, causing significant side effects. Combining pan-RAF inhibitors with MEK inhibitors improves their cancer-fighting ability but still causes unwanted suppression of normal cell function. As a result, treatment options for NRAS-mutant melanoma remain limited and urgently needed. 

Here, we propose a novel approach to melanoma treatment by developing and characterizing a new class of RAF inhibitors targeting all classes of melanomas. Like BRAF inhibitor, but with a distinct mechanism, this class of RAF inhibitor selectively increase MAPK pathway activity in healthy cells while blocking the pathway in all melanoma cells we tested. This approach allows us to combine these RAF inhibitors with MEK inhibitors (and other MAPK inhibitors) to enhance cancer cell potency without affecting normal cells. Using this cutting-edge approach, we will provide new insight into the molecular mechanism of action underlying this novel class of RAF inhibitor. This project has the potential to advance novel drug combinations into human clinical trials, offering new hope for patients with BRAF-mutant, NRAS-mutant, and treatment-resistant melanoma. 

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. 

While immunotherapy has greatly improved the survival for patients with melanoma of the sun-exposed skin, especially for those with advanced disease, at least half of the patients receiving this form of treatment still do not benefit. In addition, patients with forms of melanoma that are not caused by sun exposure, such as melanoma on the palms, soles, or under the nails, melanoma of the eyes, and melanoma of our mucosal membranes of for instance nose, mouse, or throat, respond poorly to current immunotherapies. Especially for the latter, an important reason for treatment failure is that the patient’s immune systems only weakly respond to these forms of melanoma. This happens presumably since these melanoma lack the wide-spread DNA damage that is caused by ultraviolet light and that would allow immune cells, especially so-called T cells, to “see”, infiltrate, and destroy the cancer cells. An important recent insight has been that in many forms of cancer, the majority of infiltrating T cells do not recognize the cancer but are so-called bystander T cells. Many of these bystander T cells were activated during past or ongoing common viral infections, circulate in the bloodstream, and are unspecifically recruited to the tumors, where they however do not unfold any activity since they don’t “see” the virus. It would be highly desirable to direct the activity of these bystander cells against the cancer cells, especially in poorly immunogenic forms of melanoma, which could lead to the destruction of these cancers. Our lab is working on a novel antibody-based therapy that aims to deliver small protein fragment of viruses(‘peptides’) to the surface of cancer cells in order to ‘trick’ antiviral bystander T cells into attacking the cancer cells as if they were infected by viruses.

We have already found in a mouse model of head and neck cancer that this form of immunotherapy is highly effective even in tumors that do not respond at all to conventional immunotherapies. Here we propose to develop these so-called antibody peptideepitope conjugates (APECs) for the treatment of those melanoma that fail to respond to current immunotherapies. APECs consist of antibodies that bind to the cancer cell surface and that are loaded with viral peptides. These peptides need to be released from the antibody by cancer cell-expressed enzymes called proteases. A critical aspect of designing APECs for a particular form of cancer is therefore to examine which proteases this cancer expresses. The first part of this project seeks to characterize the proteases active in melanoma, and especially in those forms of melanoma that are not caused by sun exposure and pose the greatest challenge to treatment. In the second part of the project, we will build APECs based on an improved design that will be easier to manufacture for future clinical use and test their therapeutic potential in a mouse model of melanoma, guided by knowledge of the proteases active in this melanoma model.