Facilitate the transition of projects from the laboratory to the clinic. Translational researchers seek to apply basic knowledge of cancer and bring the benefits of the new basic-level understandings to patients more quickly and efficiently. These grants are $600,000, three-year commitments
Funded by the Dick Vitale Pediatric Cancer Research Fund with support from the Marc and Peg Hafer Family
Acute myeloid leukemia (AML) remains one of the most difficult leukemias to treat. Pediatric patients with AML have relied on standard toxic chemotherapy and bone marrow transplantation for the past few decades for treatment without any advancement in the development of targeted therapeutics for this disease. The development and clinical investigation of a new class of orally available drugs, called Menin inhibitors, has shown great promise in patients with specific, hard-to-treat subtypes of AML. However, we have recently described acquired resistance to Menin inhibitors through genetic mutation in the Menin gene during treatment. After characterizing and understanding the mutations in Menin, we now aim to try to overcome and possibly prevent resistance with the next generation of Menin inhibitors or with combinations with other drugs that show promise in treating AML. The experiments proposed here will guide the clinical implementation of Menin inhibitors into the standard of care in children with either newly diagnosed or refractory AML. We hope/expect that these approaches will, over time, supplant the need for chemotherapy much as has been the case for targeted therapy in APML, which previously required bone marrow transplantation, but is now cured with two oral therapies that have minimal toxicities.
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.
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.
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.
Acute Myeloid Leukemia (AML) is a blood cancer that arises from cells that normally fight infections in the body. However, these cells can become fast-growing and hard to kill, which causes their over-production. Eventually, healthy cells in the blood stop working because the diseased cells take over. Patients with AML are often treated with a novel drug called Venetoclax, which kills the majority of AML cells. However, residual cancer cells that did not die eventually re-populate the body leading to the patient’s death. In this research proposal, we identified the protein BAX as a key effector of cancer cell killing by Venetoclax. We also made several scientific observations about Venetoclax and BAX that are critical to understanding why this drug works for some cancer cells and not others. A scientific goal of this V Foundation Award is to provide the scientific reasoning for why Venetoclax does not always work in AML patients. At the same time, a therapeutic goal is to examine the new drugs that directly activate BAX, which restores its ability to kill AML cells. Our scientific goal is to work together and to provide a deeper knowledge of cancer therapies with the aim of cancer cures.
