CAR T cell therapy is an exciting new cancer therapy where immune cells from a patient, called T cells, are reprogrammed outside the body to seek out and kill tumor cells. While this approach has been highly effective for some types of cancer such as lymphoma and leukemia, it has not yet been effective for solid tumors such as ovarian cancer and pancreatic cancer. One reason for this failure is that many tumor cells have found ways to hide from the engineered immune cells and avoid being killed. We call the genes that enable tumors to hide “immune evasion genes.” Our lab has identified one of the key immune evasion genes, called NKG2A-HLA-E. We believe that blocking this gene could make tumor cells more visible to CAR T cells and greatly increase their cancer killing abilities. This would result in more effective therapies for patients that could lead to longer survival. Additionally, our lab has also developed new ways to identify all the evasion genes used by tumors to hide from CAR T cells. This exciting new approach could reveal several additional genes that tumors use to escape CAR T cells, and we identify these genes and attempt to block them to determine if this also improves the ability of CAR T cells to kill tumors. This work could help to identify the ways tumors escape from the immune system and could provide researchers and clinicians with the information required to build more effective cancer therapies using the immune system.
Funded with support from Hockey Fights Cancer powered by the V Foundation presented by AstraZeneca
Lung cancer is the deadliest cancer in the United States and lung adenocarcinoma is the most common type of lung cancer. While genetic mutations contribute to the development of cancer, cancer cells also activate gene programs over time that allow the cancer cells to become more aggressive and harder to treat. Advanced lung cancer cells evade current treatments such as chemotherapy or therapies that target the immune system. In our work, we have found that late-stage lung cancer cells expressed a unique transcription factor that activates gene programs which permit cancer cells to spread throughout the body. Of note is that these cancer cells also release molecules which we believe signal myeloid cells to enter the tumor. In doing so, the myeloid cells cause the immune system’s T-cells to be less effective and reduce how well current treatment strategies work. We seek to understand how late-stage cancer cells facilitate disease progression and how they limit response to current therapies. We have generated new mouse models which will allow us to investigate the gene programs that are active in these advanced cancer cells and to determine how these cells become resistant to therapy. Overall, our goal is to identify new options for targeting late-stage cancer cells which could be combined with, or used in place of, current treatment strategies so that we can increase how long patients with lung cancer live and improve their quality of life.
Abeloff V Scholar* Funded with support from Hockey Fights Cancer in honor of Lana Manson
In just over the past 10 years, new drugs that improve our own immune system’s ability to clear tumor cells have become an incredibly powerful class of cancer treatments. These therapies known as immune checkpoint inhibitors or ICIs work broadly against many different tumors, providing hope for many patients to better fight off their cancer. However, each patient is unique, and ICIs can work better for some patients than others. There are many reasons for these differences, including a person’s genetics, their type of cancer, and their environment. Recently, studies including our own have shown that microbes in our bodies also affect how well ICIs stop the growth of tumors. In our lab, we aim to understand how these microbes function during cancer treatment. We focus on how microbes make molecules that stimulate our immune system, which work with ICIs to fully activate tumor-fighting cells. In our work sponsored by The V Foundation, we will find new enzymes to make these active molecules. Using these enzymes, we will build better probiotics and test whether they can help to clear ICI-resistant tumors. Together, these studies will advance our long-term goals to understand how gut microbes affect cancer treatment and to generate new bio-based therapies that improve outcomes for cancer patients.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Asparaginase is an important drug for the treatment of childhood leukemias. However, some leukemias become resistant to asparaginase, and this makes them very difficult to treat successfully. We discovered that by blocking a protein called GSK3α, we can make drug-resistant leukemia cells sensitive to asparaginase again. Although this finding is promising in the lab, there are currently no drugs known to block GSK3α that can be used to treat patients.
This proposal is focused on overcoming this problem by testing two different but related ideas. First, we will test the hypothesis that some existing drugs, which have already been developed for other purposes, also possess the ability to block GSK3α. Because these drugs are already approved for use in patients, we would be able to quickly start testing these in patients with leukemia. Second, we have engineered several new compounds that are specifically designed to target GSK3α. Fortunately, these have shown early promise in the lab, and we are ready to evaluate whether these newly engineered compounds fit the criteria as candidates for new drug development. If this line of research is successful, we expect it will lead to two different treatment strategies combining asparaginase with a drug that blocks GSK3α.
With support from the V Foundation for Cancer Research, we are optimistic that our work has the potential to lead to the development of potent new treatment strategies for some of the most difficult-to-treat forms of childhood leukemia.
In patients with hormone positive breast cancer that has spread to other parts of the body eventually the cancer can stop responding to hormone blocking pills and their cancer starts to grow again. In this project we will develop vaccines that eliminate breast cancer cells that no longer respond to hormone blocking pills. This will cause the remaining breast cancer cells start responding again to hormone blockers. The result of these vaccines would be that those patients with hormone positive breast cancer will have a much longer time where that the hormone blocking medication would work. The immune response would also help to kill more of the breast cancer cells. This should mean that patients will live much longer with hormone positive breast cancer that has spread. This research will be tested first in mice and then in patients with hormone positive breast cancer that has spread to other parts of the body.
We are testing a drug, tucatinib with a form of focused radiation called stereotactic radiosurgery for a type of breast cancer (HER2-positive) that affects 20-25% of breast cancer cases when it spreads to the brain.
This study will help find out if the combination of tucatinib and radiation is safe and if patients can tolerate it well without too many side effects.
About 40 patients with this type of breast cancer that has spread to the brain will be part of the study. First, they will receive the drug tucatinib along with the focused radiation treatment. After that, they will continue taking tucatinib along with two other medicines called capecitabine and trastuzumab. These three medicines are already used as the standard treatment and have been effective for patients like these. Patients will receive this combination until their tumor grows back or if there are serious side effects.
This study will also help find out the correct dose of tucatinib to use. Additionally, the study will answer how well the treatment works and how it affects brain function.
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.
