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
Osteosarcoma (OSA) is a bone cancer that mostly affects young people. Surgery and chemotherapy are the most common forms of treatment but can cause serious side-effects that make patients very ill. When a patient’s OSA has spread from the bone to the lungs it is much harder to treat. Recent research has shown that immune cells can be engineered to improve their ability to fight cancer. This approach has cured patients with certain blood cancers when all other previous therapies failed. However, this approach is less effective in “solid” cancers like OSA. We are pursuing a new approach where immune cells that naturally recognize mutated proteins in a patient’s tumor (TIL) are collected and grown to large numbers before returning them to the patient. This approach has achieved cures in several solid cancers, including those that have spread to other areas of the body including the lungs, but it is not always effective. In previous work, we found that disabling a gene called CISH allows TIL to kill cancer cells more effectively. We are currently testing this in a clinical trial in patients with gastrointestinal cancer. In the current proposal, our goal is to see if this approach can also be used to treat OSA. If successful, our approach may offer a curative option with far fewer side-effects compared to current therapies.
Renal medullary carcinoma (RMC) is a rare but deadly kidney cancer that mainly occurs in young individuals of African descent that carry a blood disorder called sickle cell trait. Most people carrying the sickle cell trait never develop any symptoms. Many do not even know that they have it. Approximately 1 in 14 African Americans have the sickle cell trait and are at risk for developing RMC at an average age of 28 years old. RMC is also an under-recognized global health challenge because the sickle cell trait is found in ~300 million individuals around the world, mainly in Africa. Almost every patient with RMC is diagnosed late, when the cancer has already spread to other organs. Less than 5% of these patients survive beyond 3 years. Furthermore, many patients with RMC are initially misdiagnosed and lose precious time while being treated with the wrong therapies. The chances of a cure considerably increase when RMC is diagnosed and treated early. With the help of our patient advocates, we have established the largest collection of blood and tissue samples from patients with RMC worldwide. Using these samples, we have found evidence that patients with RMC have antibodies against unique proteins found only in cancer. We have developed a novel technology that allows the detection of more than 400,000 of these antibodies using only a drop of blood, quickly (within 3 days) and affordably. Our proposal aims to investigate and develop this new approach for the early diagnosis of RMC.
Basal (BCC) and squamous cell (SCC) carcinomas are the most common form of skin cancer. If diagnosis is delayed, the tumors may require surgery that is more extensive. These tumors may be superficial, which are slow-growing, confined to the outer skin layers, and can usually be treated without surgery. Alternatively, they may be invasive, penetrating the deeper skin layers to destroy these tissues, often requiring surgery that can be costly and painful. While these skin cancers often may be diagnosed with the naked eye, it is difficult to tell whether they are superficial or invasive. Thus, there is a clear need for a new diagnostic approach that can inform patients and their physicians whether a particular lesion should be biopsied, and whether evaluation is urgent if the lesion is likely to be invasive. Currently there is no non-invasive (without biopsy) to accomplish this. Here, we propose to develop a new test based on micro-RNAs (miRNAs) that can be recovered simply on adhesive tape from suspicious skin lesions. We believe these miRNAs can be used to identify non-melanoma skin cancers and their subtypes as a new non-invasive way to decide whether (and how urgent) a biopsy needs to be performed. First, we will determine which miRNAs are most associated with superficial and invasive skin cancers by analyzing miRNAs in previously biopsied tissues. Second, we will validate this technique on a group of patients who come to clinic with a suspicious skin lesion.
Liver cancer is one of the deadliest cancers in the world and it is becoming more common in the United States due to liver disease or liver scarring. Patients with liver problems are at risk of developing liver cancer, and if the cancer is found at an early stage, it can be cured. Therefore, patients with liver problems should be screened regularly so that the cancer can be found early. Unfortunately, current screening techniques are not very sensitive and require trips to special imaging centers twice a year. Our work will create a new and better screening tool for early detection of liver cancer that can be used anywhere. By improving the quality and access to better imaging, screening will be more effective and can be done wherever patients need it most, without the need to travel to a hospital or specialized imaging center. We believe that by improving both the quality and access to screening, patients with liver cancer will be found at an earlier stage, allowing for better patient care. Further, easier access to this new screening tool will allow more people to access the healthcare they need.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Brain tumors are the leading cause of cancer related deaths and long term side effects in children. Treatments that are specifically directed to tumors, while sparing normal brain cells, are desperately required to increase the effectiveness of treatments and to reduce side effects. This project is focused on trying to find ways to inhibit specific mutations in a group of genes that are found across common childhood gliomas. Our hope is that our work will help us find ways to use medications that target these mutations specifically to allow precision medicine approaches.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Pediatric cancer patients have greatly benefited from advancements in CAR-T cell therapy, a cancer treatment in which a patient’s own T cells – a type of immune cell – are reprogrammed to recognize and kill cancer. CAR-T cell therapy has demonstrated remarkable clinical success and can even cure some patients; however, only 50% of those treated remain cured after 12 months. A major roadblock preventing this therapy from curing more patients is poor CAR-T cell survival. Patients with long-lived CAR-T cells are more likely to be cured than those with short-lived CAR-T cells. Therefore, there is an urgent need to develop strategies that help CAR-T cells stay in the fight against cancer.
My research project will test a new approach that helps CAR-T cells survive longer by tapping into the natural biology that helps T cells persist in the body. By forcing CAR-T cells to act more like naturally occurring long-lived T cells, we can boost their ability to survive and kill cancer. We will also determine the molecular “secret sauce” that allows some patients’ CAR-T cells to persist for longer compared to others. Collectively, this project will help advance more efficacious therapies for blood cancers and potentially other types of cancer in both children and adults, and reveal valuable information about CAR-T cell persistence that can be leveraged for future discoveries.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Children with aggressive brain tumors do poorly, and outcomes haven’t gotten much better for these terrible diseases in the past thirty years. A recent new treatment called chimeric antigen receptor (CAR) T cell therapy provides hope for these patients. CAR T cell therapy takes a patient’s own immune cells and reprograms them to find and kill cancer cells. We recently opened a unique Phase I clinical trial (NCT04510051) that uses CAR T cells to help children with hard-to-treat brain tumors.
We are excited that the first few patients treated on our trial had some shrinkage of their tumors. This gives us hope that CAR T treatment can help children with these diseases. Unfortunately, responses so far have been temporary, highlighting the clear and urgent need to improve these promising therapies. Our trial lets us sample cerebrospinal fluid repeatedly during treatment. This gives us a valuable chance to study in fine detail how CAR T cells talk to the patient’s immune system, and how that conversation changes over time. We know that if CAR T cells can teach the immune system to destroy tumor cells, treatment will work better. However, this does not happen very often in patients. Our study will help us figure out how to make CAR T cells that effectively promote an antitumor immune response, leading to better therapy for pediatric brain tumors with five years.
Funded by the Dick Vitale Pediatric Cancer Research Fund with support from Hockey Fights Cancer
Brain and spine tumors are the leading cause of cancer-related death in children, adolescents, and young adults. Outcomes for pediatric and young adult patients diagnosed with high-grade gliomas (HGG) remain dismal, with 5-year overall survival tragically <10%, despite intensive surgery, radiation, and/or chemotherapy. There is therefore a critical need to develop effective, well-tolerated therapies for children and young adults with HGGs. Recent scientific discoveries have provided valuable insight into the genomics of these aggressive diseases and identified genetic changes which can serve as targets for therapy. Research has helped develop less toxic medicines, usually oral drugs, which can directly target specific genetic alterations present in the tumor to slow or stop its growth and spare healthy organs. We propose an innovative multi-arm clinical trial offering a precision medicine approach to treat children and young adults newly diagnosed with HGGs. Detailed genetic sequencing using advanced technology will be performed on tumor tissue from all patients upfront, with return of results within 3-4 weeks. Patients will then be assigned to one of several unique molecularly-targeted treatment arms based on (and directly targeting) the genetic alterations identified in their tumor. We will also collect blood samples as well as cerebrospinal fluid and/or future tumor tissue throughout the study. Genomic and immune profiling analyses will be performed on these specimens over time that, in combination with imaging and patient-survey measures, can predict early response or recurrence to treatment (“liquid biopsy” tools) and improve the understanding of why some tumors become resistant to therapy.
Though survival for patients with advanced melanoma has improved over the last decade with the introduction of anti-PD-1 antibodies, half of patients treated with this therapy have disease that recurs. Both combination immunotherapies and single-agent anti-PD-1 antibodies are currently used to treat melanoma. However, combination therapies have higher responses but also higher toxicity rates. Currently, there are no definitive biomarkers that can predict which therapy choice is correct for metastatic melanoma patients.
This project is focused on understanding why patients are resistant to PD1-based therapies. We recently discovered that patients with more CD26 (a type of protein) foundin the tumor’s immune cells are more responsive to treatment. These collective findings beg the question: What is the role of CD26 in the immune response to melanoma?
To answer this question we will study CD26 melanoma immunity using melanoma patients’ blood and tumor samples. This data will allow CD26 to be used as a biomarker in prognosis for patients treated with PD-1-based therapies, and allow for future studies for clinicians to use CD26 as a predictive biomarker to help select the appropriate treatment for a patient, i.e., combination or single-agent immunotherapy.
The role of CD26 activity in melanoma immune response will be defined by this project. Findings from this research will be the basis for future clinical trials to target CD26 in order to enhance immunity against tumors that are unresponsive to PD-1-based therapy in order to create new hope for patients with PD-1-refractory melanoma.
Funded by the Stuart Scott Memorial Cancer Research Fund
Using immunotherapy to treat advanced cancer has improved the outlook of cancer treatment in many cancer types. However, most of the gastrointestinal cancers, including pancreatic adenocarcinoma, do not benefit from such advances in immunotherapy. Upon further research, we have learned that dense non-cancer cells that surround these cancers not only prevent the chemotherapy drugs from reaching the cancer cells, but also prevent the tumor-targeting immune cells that allow immunotherapy to be effective. Research from Washington University show that a molecule called IRAK4 can control such a process and make pancreatic cancer respond better to chemotherapy while allowing immunotherapy to be effective. Based on the promising data from the laboratory, we propose a clinic trial of CA-4948, a drug that inhibits IRAK4 and has shown to be safe by itself, to be added to standard chemotherapy drugs to ensure safety. Then an immunotherapy drug will be added to the combination. We plan to collect blood and tumor samples from the patients receiving the combination of CA-4948, chemotherapy, and immunotherapy, to understand how these drugs change the tumor and components of the immune system in patients. In addition, we plan to further test this combination in animal models to test additional mechanisms that can improve immunotherapy in pancreatic cancer.
