NRAS mutations are found in about 30% of melanoma, a dangerous type of skin cancer. Although recent advancements in melanoma treatments have helped many patients, those with NRAS-mutant melanoma still face challenges. Available treatments for these patients are often not effective, and their cancer can quickly become resistant to treatment. Recently, scientists have developed new drugs called pan-RAS inhibitors that can directly target the NRAS mutations responsible for tumor growth. These drugs have the potential to greatly improve treatment for people with NRAS-mutant melanoma, but we need to learn more about potential resistance to these new drugs. This knowledge will help us develop better treatments for this type of cancer. Studying drug resistance is difficult because tumor can be very different from one another. To overcome these challenges, our study uses advanced technology to observe how individual melanoma cells grow and change. Our approach allows us to monitor the rare cells that adapt to the new pan-RAS inhibitors, helping us understand why some cells become resistant. We will also compare the genes in these adapting cells to those in cells that do not adapt to determine what makes them different. By learning how NRAS-mutant melanoma cells adapt to new treatments, we can design better therapies for patients with this type of cancer. This will help us meet the needs of people with limited treatment options and improve their chances of recovery. Our research aims to move the body of knowledge forward, positively impacting cancer patients and cancer research.
Funded by the Constellation Brands Gold Network Distributors
Cancer often occurs because some pathways in our body’s cells become too active, and these pathways are the same ones normal cells use to function properly. Researchers made drugs to target these pathways and slow down cancer growth. However a major problem is that these drugs can also affect normal cells and cause harmful side effects. Our research focuses on a specific type of cancer called RAS-mutant, which represents more than a third of human tumors, including lung, colorectal, pancreatic, and skin cancers. RAS mutations cause the RAS pathway in cells to go into overdrive, and that leads to uncontrolled cell growth, causing cancer. Scientists have developed drugs to target the RAS pathway, like RAF and MEK inhibitors. However, these drugs have limitations because they can cause toxic effects in normal cells. The goal of our research is to find better ways to treat RAS-mutant cancers. We aim to understand why the drugs cause toxicities in normal cells by studying samples from patients and run experiments in the lab. We also found certain combinations of drugs that work better in cancer cells compared to normal cells. We will test these combinations in the lab and on animals to determine if they can effectively treat cancer without causing too many side effects. The ultimate goal of this research is to gather strong evidence to support quick clinical testing of these treatments in patients with RAS-mutant tumors, so we can develop better and safer treatments for people with these cancers.
This research is focused on better understanding and improving treatments for a specific kind of blood cancer, known as B-cell acute lymphoblastic leukemia, or B-ALL. Although the treatment for childhood B-ALL has been greatly improved, long-term survival for adult patients is still under 50%. Our research showed that about 13% of adult B-ALL patients have mutations in PAX5 gene, which is critical for B-cell development. Two B-ALL subtypes are defined by PAX5 mutations: PAX5alt and PAX5 P80R. Surprisingly, survival rates vary greatly between these two subtypes (30% vs. 65%), which suggests that different genetic characteristics are involved. The goal of our research is to better understand the biological changes and genetic markers linked to B-ALL from different PAX5 mutations. Based on our preliminary study, we believe that certain PAX5 mutations block normal B-cell development, thus creating cells that are more likely to develop into leukemia. Our objectives are to 1) Explore how PAX5 mutations influence the normal DNA patterns and gene activities in B cells, and 2) Investigate how these mutations drive leukemia development step by step. We anticipate that our work will shed light on how PAX5 mutations disrupt B-cell development, thereby initiating leukemia. Our results will provide a comprehensive insight into understanding PAX5 mutations in B-ALL. This will enhance our knowledge about the role of PAX5 mutations and the mechanisms in disease initiation and clinical outcomes. Understanding these mechanisms could pave the way for more effective, targeted therapies for this high-risk leukemia subtype in adult patients.
SMART-ER VA is a non-research health information service project to increase the awareness of colorectal cancer (CRC) prevention, early detection, and the uptake of colorectal cancer screening utilizing an evidence-based social media health awareness, education, and navigation intervention. Colorectal cancer remains the third leading cause of cancer death for men and women in the US. It is among the top cancers in Massey’s catchment. Twenty-Six rural southern localities in MCC’s catchment are reported as CRC “hotspots” with increased risk of CRC mortality. SMART-ER VA is designed to reach and capture the attention of those who use social media and live in targeted colorectal cancer Virginia hotspots, particularly those marginalized, disadvantaged, and geographically isolated, yet socially connected and engaged, yet not limited by geographical constructs, but have a sense of social identity, special interest, and shared norms and values, to address issues affecting their health and social needs. SMART-ER VA. is a non-research educational effort supporting the prevention and early detection of colorectal cancer utilizing social media platforms (Facebook and Instagram) and an evidence-based empowerment health education and prevention model for personal and social change.
Prostate cancer is a type of cancer that affects men, and it’s one of the most common types of cancer in the United States. Castration-resistant prostate cancer is a more advanced stage of the disease, which is harder to treat and can be life-threatening. Our research focuses on a protein called TRIM28, which is found at high levels in castration-resistant prostate cancer. We’ve discovered that TRIM28 promotes the growth of cancer cells by activating a specific oncogene. We believe that blocking TRIM28 could be a new way to treat castration-resistant prostate cancer, especially in patients who have lost an important tumor suppressor gene called RB1. Our goal is to develop new drugs that can block the activity of TRIM28, which could help to stop the growth of cancer cells and overcome cancer drug resistance. By better understanding the role of TRIM28 in castration-resistant prostate cancer, we hope to find new ways to treat this disease and improve the lives of patients.
Volunteer Grant funded by the V Foundation Wine Celebration in honor of Paul Dugoni and in memory of Lynn Dugoni
Cancer immune therapies that trigger the body’s own immune system to fight tumors have greatly improved cancer treatment over the last 10 years. Still, most patients do not benefit from this approach for reasons that remain unclear. The goal of our work is to determine what prevents the immune system from fighting cancer in order to design better immune therapies that can help more patients. Our studies focus on T cells, the immune cell type that plays the biggest role in killing tumor cells. T cells can kill cancer cells because cancer cells have mutations that T cells see as dangerous to the body. In theory, T cells that see different mutations should be able to work together to control tumors. However, our research has shown that T cells compete with each other to fight tumors and this greatly reduces the effectiveness of the T cell response. T cell competition may explain why some patients do not respond well to immune therapies. Our work is aimed at understanding why T cell competition occurs so that we can design immune therapies that promote T cooperation to better fight tumors. Our research will explore cancer vaccines as one potential treatment approach. We focus our studies on lung cancer, which causes the most cancer deaths each year, though we expect our results will be relevant to many cancer types. Findings from our work will allow development of more effective immune therapies for cancer patients that will decrease suffering from this terrible disease.
Funded with support from The Orr Family Foundation
Lung cancer is the most common source of cancer-related death in the U.S. and worldwide. Lung cancer is a heterogeneous disease, with multiple subtypes characterized by different genetic and molecular profiles, and different response to treatment. One subset of lung cancer is caused by the loss of a gene called LKB1, and approximately 50,000 people are diagnosed with this type of lung cancer in the U.S. each year. Currently, no available therapies elicit sustained clinical benefit for patients with LKB1-mutant lung cancer, and the current overall survival time for such patients from the time of diagnosis is less than one year. Thus, there is great unmet need to rapidly discover and translate clinical options to help these patients. Our recent work has discovered a mechanism of therapeutic resistance (an explanation why tumors do not respond to therapy) that is specific to LKB1-mutant lung tumors. We discovered that two available, clinically-tolerated drugs together can overcome this mechanism, and we are working toward clinical translation of this finding. However, we predict that this finding is only the tip of the iceberg, and that we are poised to discover additional promising therapy approaches as well. Therefore, it is now imperative to fully characterize the mechanisms of therapeutic resistance in this tumor type, as we will do in this project, to expand our understanding of how to treat patients with this disease. The hope is that this study will pave the way toward improved therapeutic options for patients with lung cancer.
Sarcoma tumors is a rare cancer that starts in our body’s connective tissues. These cancers spread quickly and less than 40% of people survive more than a year after it spreads. We need better treatments. One big issue is tumor hypoxia, or a lack of oxygen in the tumor. When tumors grow fast, they cannot get enough oxygen, which makes it hard for our bodies and treatments to fight off the cancer.
We have come up with a new method to get oxygen directly to the tumor using special materials called gas-entrapping materials (GeMs). These GeMs are made in a way similar to making whipped cream in a coffee shop. We plan to use GeMs to deliver oxygen to the tumor, which we believe could make treatments like immunotherapy work better and more safely.
Our research goal is to use a new series of GeMs to release oxygen into the tumor to help fight tumor hypoxia. Making GeMs is simple, cost-effective, and uses components considered safe. We think that using GeMs to increase oxygen could make immunotherapy more effective for spread-out sarcoma tumors.
We hope our research will show that these materials can be safely used with immunotherapy to help the body’s immune response fight the disease. This could mean a new way to get oxygen to tumors and could change how we treat sarcoma and other cancers that have spread to other parts of the body.
Anti-cancer monoclonal antibodies (mAbs) are a type of treatment for cancer that has helped many patients but they do not work for everyone. The overall goal of our research is to make mAbs better cancer treatments. MAbs stick to cancer cells and attract cells of the immune system known as Natural Killer cells (NK cells) that then kill the mAb-coated cancer cells. We have found that NK cells start to kill mAb-coated cancer cells, but stop killing cancer cells unless they get help from a different type of immune system cell known as T cells. This suggests one reason mAb might not work for some patients is a lack of help from T cells. We also found that a different type of antibody known as a bispecific antibody (bsAb) can increase the help T cells provide to NK cells. This suggests the combination of bsAb to mAb could be a better treatment for some cancers. In this project, we will conduct studies in both mouse models and in samples obtained from patients to evaluate the role of T cell help in anti-cancer mAb therapy and determine whether giving mAb and bsAb together is a better approach to cancer therapy. Our studies are focused on lymphoma, but the results could result in improved mAb therapy for a variety of cancers.
One of the biggest challenges to extending patient survival from recurrent ovarian cancer is to understand how these tumors can “hide” from detection by cells of the immune system. Immunotherapy involves treatments that use the body’s own immune system to help fight cancer. Despite successes in other cancer types, immunotherapy treatments for ovarian tumors have had limited success in promoting patient survival. Our work builds upon the idea that ovarian tumors upregulate immune “protective” molecules and that these provide a “shield” against immune cell attack. We have found that the activity of a protein (FAK) within ovarian tumor cells drives protection signals and that the combination of chemotherapy blocking FAK (weakening the shield) with immunotherapy resulted in tumor shrinkage. Mouse survival was associated with the gathering of immune cells within and nearby tumor sites in the process of tumor killing. In mice, we have also identified measurable markers that circulate in blood, the presence of which increased as tumors were being attacked by immune cells. In this proposal, we will treat mice with a novel combination of tumor- and immune-targeting therapies and will validate the timing and extent of marker changes in tissues and blood as the tumor shrinks. A clinical trial to test this novel treatment combination and marker evaluation is proposed. The benefit of measuring markers in blood is that this does not involve surgery and that this may provide the clinician with early insights of patient response.
