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 Hockey Fights Cancer™ Powered by the V Foundation
Meningiomas are the most common intracranial tumor in adults. While most meningiomas can be successfully treated with surgery, there are a significant proportion of cases that require the addition of radiation therapy to delay tumor recurrence. However, our current methods of selecting which patients should be escalated for radiation after surgery remain relatively imprecise, especially for intermediate-grade meningiomas that can behave in a highly variable manner. Molecular profiling, specifically DNA methylation of meningiomas has proven to be an effective and efficient method of providing additional information on these tumors that can be used to better predict whether they will or will not recur after surgery. However, whether a similar set of molecular signatures exist to predict whether a meningioma of any given patient will respond to radiotherapy after surgery remain to be determined. This V Foundation grant will enable us to 1) develop a clinically important predictor using specific molecular signatures of any given patient’s meningioma to tell us whether their tumor will respond to radiation, 2) test this predictor through a novel, real-time, molecular-pathology informed clinical trial, and 3) determine if the same signatures that can prediction response to radiotherapy in the tumor tissue can be used to non-invasively provide the same information through a simple blood test. Results from this study have the potential to dramatically improve the way we treat patients with meningiomas and will represent a significant shift forward in the field of neuro-oncology.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Clinical outcomes in children diagnosed with high grade glioma and diffuse intrinsic pontine glioma remain very poor. Even with surgical resection, chemotherapy and radiation, most of the tumors eventually relapse. This is primarily because some cancer cells develop resistant to the therapies that doctors prescribe. For the past 50 years, the identities of these therapy-resistant cancer cells remain unknown. Difficulties of obtaining relapsed tumor tissues and limited availability of animal models are the major reasons why we still don’t have new treatment. With the strong support of patients and families, we have developed a panel of animal models by directly implanting brain tumor cells into the brains of immunodeficient mice. We can now use these models to mimic what happens in children but treating the animals with the similar drugs/radiations. These models are very helpful. Indeed, our preliminary study in a small number of models have identified a set of cells expression CD57 as candidate root cells as they were found before drug treatment, remain present after very extensive clinical treatment, and can even survive the most harmful environment with no oxygen and no nutrient. This exciting finding has promoted us to perform a detailed analysis using more animal models to confirm the extraordinary capacity of the CD57+ cells in resisting therapy induced cell king, to understand how they can survive current treatment, and to find new drugs and strategies to selectively kill these seed cells. Our ultimate goal is to find new cure for children with highly malignant gliomas.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Children with muscle cancer commonly develop resistance to therapy. This is a major problem and most kids will die from resistant disease. Our group has developed a new combination of drugs to kill muscle cancers and is now being tested in kids and young adults. Yet, drug resistance to this same combination has been reported in other cancers and may develop in our patients. Our work will uncover how resistance develops and identify a new drug that can restore sensitivity to chemotherapy. This work is important because the new drugs we identify could be used to treat kids in the future.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Acute Lymphoblastic Leukemia (ALL) is a common cancer in kids. There are two types, B-ALL and T-ALL, depending on the type of white blood cells affected. Most kids get better with current treatments, but sometimes the cancer comes back and we can’t help them anymore. That’s why we need new treatments for T-ALL.
We know that certain drugs used in the hospital affect how leukemia metabolism works. So, we wondered if changing the diet could also help. In our lab, we tried different diets on mice with leukemia. Surprisingly, we found that removing just one component of the food (an amino acid), made a big difference. Leukemic mice eating food without this amino acid lived much longer. Now we want to understand why this dietary approach helps and if we can use it in combination with other treatments. We will study mice with leukemia and samples from real patients to see how this amino acid affects cancer. We also want to find out if combining this diet with current treatments works even better.
If our research is successful, we can try it on real patients. We want to see if reducing this amino acid in the diet can make treatments safer and help more kids survive, especially those whose cancer has come back. This research is important because it could give us new ways to treat leukemia and help more kids get better. It might even help with other types of cancer too.
Funded by the Constellation Brands Gold Network Distributors in honor of the Dick Vitale Pediatric Cancer Research Fund
Ewing sarcoma is a cancer that is most often diagnosed in teenage children and young adults. There is a need for new therapies for this disease. The goal of our work is to develop new therapies for Ewing sarcoma focused on a drug target called EWS-FLI1. Multiple studies have shown that EWS-FLI1 is a promising drug target for this disease. In a clinical trial called SARC037, we are currently testing a combination therapy that we have shown targets EWS-FLI1. The goal of the current study is to try to understand why some patients in this trial respond to the therapy and others do not. To accomplish this, we will study ways that EWS-FLI1 resists targeting. We will identify molecular differences in tissue collected from patients who had an excellent response to the therapy compared to those who did not respond. In addition, we will test these differences in the laboratory to see how they impact sensitivity to the therapy used in SARC037. The results will guide future clinical studies that seek to target EWS-FLI1. In addition, they will provide insight into how EWS-FLI1 contributes to drug resistance to more traditional chemotherapy.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Brain tumors are the leading cause of cancer-related death in children. While recent advances in neuro-oncology have helped us understand the biology of what is causing brain tumors to develop and grow, many children with brain tumors will still have a dismal prognosis. These tumors can be refractory to upfront treatment, such as radiation or chemotherapy, and there is need for better options. CAR T-cell therapy is a new type of treatment that uses the patient’s own immune cells and modifies them in the lab to recognize and kill cancer cells. CAR T-cell therapies are highly specific to the cancer cells. In our clinical study, we are evaluating the safety and anti-cancer activity of CAR T cells for pediatric patients with brain tumors.
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.
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