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.
Funded by the Marks family in honor of the Hoff family
Multiple myeloma is a type of cancer that affects the blood and bone marrow. Although there are many treatments, it almost always comes back. Scientists are looking for new treatments. Studies have shown, perhaps surprisingly, that the body’s ability to control a cancer is affected by the microbiome. The microbiome is the collection of bacteria that live in the gut. We hypothesize that myeloma, and how the immune system fights it, might respond to signals from the gut microbiome.
We are planning a new clinical trial to see if a fermented food product that may protect the microbiome will help nurture the microbiomes of patients getting bone marrow transplants. We will use samples collected from the trial participants to determine the effect of the fermented food on the microbiome and the metabolites that get into the patients’ bodies. Then we will study what happens to the immune system of patients in the trial. Finally, we will give myeloma to mice in the laboratory, while treating them humanely, and ask if antibiotics affect how the cancer behaves.
This study is important because it could help us understand how the microbiome affects MM and how to prevent cancer from coming back after treatment. The findings may also be helpful for developing new treatments for other types of cancer. Ultimately, we hope this will make people feel better and live longer.
Funded by the Constellation Brands Gold Network Distributors
Bladder cancer is a lethal disease with limited treatments. While we know that we can turn on patients’ own immune system to fight this cancer, using treatments called immunotherapies, most patients do not respond. We have been working on developing better immunotherapies that turn on a new kind of “killer” immune cell that can attack bladder tumors but has not been targeted before. With the support of the V Foundation, we will study samples from bladder cancer patients who received immunotherapy in a clinical trial. We will perform a deep dive into their tumors to see what other kind of cells and genetic changes make up the “neighborhood” that talks to these killer immune cells. We hope that this will provide key direction for a near-term clinical trial for bladder cancer patients who may benefit from a novel treatment targeting these killer cells. This will benefit bladder cancer patients in need by helping them live longer while also relieving the suffering from this disease.
Today oncologists have in their arsenal highly active and precise systemic therapies but often times cannot predict which patients would benefit the most. A major contributor to this knowledge gap is the cancer’s ability to resist therapies. Here, we will focus on malignant melanoma, an aggressive type of skin cancer, where two major precision-oncology therapies were first developed. One targets the so-called ‘MAPK cancer pathway’ that sustains the growth of many cancer types, not just melanoma. The other consists of immune checkpoint blockade (ICB) therapy, which unleashes the body’s cancer-killing immune cells and has been approved in >30 cancer types. In patients with melanoma, >70% and >40% of patients respond initially to MAPK targeted and ICB therapies, respectively. However, after initial responses, ~20-40% of patients experience relapse due to their melanomas developing resistance to therapies. In this study, we dissect how melanomas evolve resistance so that we can prevent resistance. In response to therapies, melanoma and other cancers diversify their genetic makeup, creating new species, and this diversity increases their chance of survival or ‘fitness’ through Darwinian natural selection. We will identify ways in which melanomas diversify in response to these two pillars of modern-day cancer treatment in order to construct new therapies to prevent cancers from coming back. Preventing resistance will spare patients from the emotional and physical tolls of clinical relapses and surgical and radiation therapies to control resistant tumors. Ultimately, preventing resistance will improve the patients’ quality and quantity of life and reduce financial tolls.
Colorectal cancer (CRC) is a common and deadly cancer that often arises from abnormal pre-cancerous growth of polyps in the colon. Colonic polyps can be detected and removed during colonoscopy, therefore reducing the risk of cancer development. While most CRC cases occur randomly, about 25% of CRC cases have a familial component, including hereditary syndromes like Lynch Syndrome and Familial Adenomatous Polyposis (FAP).
Individuals with FAP have a very high susceptibility to developing CRC, requiring frequent diagnostic testing. However, for FAP patients, the number of colon polyps is often too high to be removed through colonoscopy. In these situations, patients may require surgery to remove their colon, which is costly, has risks, and changes bowel movement habits. Therefore, finding new ways to slow down the development of polyps and CRC would greatly benefit FAP patients.
Using mouse models of FAP and an intervention study in FAP patients, our study aims to develop a new approach to prevent CRC in FAP, called chemoprevention, by exploring the potential of a new substance to reduce the development and/or progression of colon adenomas. We have observed that beta-hydroxybutyrate (BHB), which is a natural substance that our bodies produce while in a starving state or when on a ketogenic diet, can slow down colon tumor growth. As there is currently no standard chemoprevention treatment for FAP, our study aims to address this critical need for effective approaches to reduce CRC risk and improve the lives of those with genetic conditions that lead to colon cancer.
