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
Few words inspire more fear than “pancreatic cancer,” which is the third leading cause of cancer death in the United States. Treatments have changed little over recent years despite the fact that researchers have learned a great deal about the genetic mutations that give rise to pancreatic cancer. One challenge is that there are different “subtypes” of pancreatic cancer, thereby making a one-size fits all approach difficult. Tailored therapeutic approaches are desperately needed. While studying pancreatic cancer subtypes, our lab identified that drugs which block a protein called cyclin-dependent kinase 7 (CDK7) could selectively kill the most lethal subtype of pancreatic cancer at extremely low doses. This subtype, referred to simply as basal, makes up ~25% of pancreatic tumors and has the worst overall survival. Further, because the drug works at such low doses, we may be able to treat patients at doses that do not cause significant toxicity. Here, we propose to study a drug that inhibits CDK7, in patients with early-stage pancreatic cancer following chemotherapy and before surgery. Concurrently, we will test new pancreatic cancer treatment strategies and drug combinations in mouse models of pancreatic cancer. We will validate and search for new blood markers of treatment response and drug resistance. Finally, we will identify pathways that allow cancer cells to survive CDK7 inhibition and determine whether other drugs can be added to enhance this therapy. The ultimate goal of our research is to provide a new targeted treatment option and hope to pancreatic cancer patients.
Radiation therapy is used to treat cancer and is very effective, but radiation can cause side effects in some patients. Scientists have shown that if radiation is delivered to a tumor very, very quickly (termed Ultra-high dose rate or FLASH radiation therapy), the tumor will still die, but the patient will have fewer side effects. This phenomenon is called the “FLASH effect”. However, this new type of radiation is very challenging to deliver and to be certain it was delivered correctly, because it is given so fast (less than a second). We need to make special machines and tools before this treatment can be used optimally for patients. The main goals of this study are to develop these new tools and to conduct a clinical trial to test the safety and feasibility of this new type of radiation. The first trial we will run will test this treatment in patients with lymphomas that involve the skin. Finally, building on the experience using this new (UHDR) radiation for lymphoma treatment, we will prepare and design a clinical trial for testing this treatment in breast cancer, a very common cancer. The overall goal of this project is to reduce the treatment related side effects of radiation, while maintaining or improving cure rates.
Funded by the V Foundation Sonoma Epicurean in honor of Leslie Sbrocco
CAR-T cell therapy is a type of therapy where a cancer patient’s immune cells, called T cells, are removed from the patient, altered in the laboratory to make them recognize cancer cells, and then given back to the patient. These CAR-T cell therapies have been unbelievably successful for liquid cancers like leukemias and lymphomas, however they have not yet been very successful for patients with solid tumors. Recently, a clinical trial of a certain kind of CAR-T cells for patients with stomach and pancreas cancers showed that CAR-T cells can fight these cancer cells in the body, but the patients only had short responses and their tumors came back. CAR-T cells need to be good serial killers of cancer cells, however they can often get tired in battle and stop working well. We want to apply our knowledge of gene engineering to make new and better versions of these CAR-T cells that do not tire quickly and can therefore fight cancer for longer. We do this by making different kinds of alterations in the genes of the CAR-T cells that give them more endurance, changing them from sprinters to long-distance runners. We can also make entirely new CARs (the part of the CAR-T cell that recognizes the tumor cells) that can bind the tumor cells with slightly different strengths, which we know can also make the cells less exhausted in battle. If successful, we will push these CAR-T cells to new heights, achieving longer remissions for patients battling gastrointestinal cancers.
Funded by the Dick Vitale Pediatric Cancer Research Fund
The bone cancers Ewing sarcoma and osteosarcoma are some of the most common solid tumors occurring in children and young adults. When these tumors spread outside the bone where they start (metastatic disease) or they come back after initially going away (relapse), they are very aggressive and nearly impossible to cure. New treatments are urgently needed. CAR T cells are a type of therapy that uses a patient’s immune system to attack their cancer by recognizing a target on its surface. This target must be minimally expressed on normal cells to prevent toxicity. We have identified a target B7-H3 as being highly expressed on Ewing sarcoma and osteosarcoma and will now run a clinical trial testing antiB7-H3 CAR T cells in those diseases. We will also re-engineer these CAR T cells to be more effective in potential future trials.
Funded by the Dick Vitale Pediatric Cancer Research Fund
T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma (T-ALL/LBL) are types of blood cancer that are very hard to treat. Patients with these leukemias need to get strong chemotherapy that can have bad side effects. Because of this, we need to find new treatments that are less toxic. CAR T-cell therapy is a new type of treatment that uses the patient’s own white blood cells and allows them to detect and kill cancer cells. These therapies can focus on only killing the cancer cells and not normal tissues and have few side effects. We have invented a way to treat this type of leukemias and have shown that it works well in models in the laboratory. We want to find out if our CAR T-cells are safe and effective in patients with childhood T-ALL/LBL. To help us reach our goal, we have formed a group of experts, including a) Lab experts – who design CAR T-cells, b) Clinical experts -who know how to treat leukemias c) Immunology experts – who can tell us how the CAR T-cells work and d) Pathology experts – who can study how the leukemias respond to the treatment. Our hospital has what is needed to start the clinical trial that we are planning. We want to find a cure for T-ALL/LBL that has few side effects and help save the lives of children with this type of leukemia.
Funded by the Dick Vitale Pediatric Cancer Research Fund
Osteosarcoma is the most common bone cancer of children. When this cancer recurs in the lungs, we have no effective therapies for these patients, and they continue to be treated with the same drugs that have been used for the past 40 years. This work seeks to develop new treatment options for patients with recurrent osteosarcoma. We will use dogs, a natural model of this cancer, to test a new drug combination which uses the immune system to stop osteosarcoma growth. We will also use advanced monitoring techniques to determine which patients benefit from this new treatment. Testing these drugs in dogs will inform how best to use these new therapies for human patients with osteosarcoma. Importantly, it uses drugs which are also readily able to be used in human patients, thus having the potential for rapid movement to the clinic.
Lung cancer kills the most cancer patients in the world. Most of these patients are diagnosed late in their disease, and there is no cure. Having a chest CAT scan (CT scan) every year helps detect lung cancer early and reduces the chance of dying. When lung cancer is detected early, the patient has a higher chance to survive. Patients who are diagnosed with small lumps in their lungs, called lung nodules, have a higher chance of getting lung cancer. Having lung nodules can also require unnecessary, uncomfortable, and sometimes painful medical procedures that are not helpful for the patient. The purpose of our research is to help detect lung cancer earlier for patients with lung nodules, which could give them a better chance to beat cancer and survive. To do this, we propose to combine new medical test tests, from a blood draw and computer measurements from CAT scans. We will use simple blood draws to measure DNA materials in the blood that can help detect if lung cancer is present. We will also use computers to analyze hundreds of measurements from lung nodules in CAT scans that can tell us if the nodule is cancer. We will then combine the blood draw and computer measures from CAT scans using advanced math to detect lung cancer early more accurately without hurting the patient. Our goal is to improve early lung cancer detection so that it can be cured and help save patient lives.
The cells in the human body are constantly subjected to stress, which is linked to changes in cellular metabolism. Our research team, and others, have made connections between these cell conditions and cancer. Our central question is: Can we make a simple blood test that provides an accurate measure of ongoing cell stress and metabolic changes to gauge an individual’s risk of cancer? This test may provide more than just a snapshot measure of cancer risk. For example, the test could be used to measure how lifestyle changes modify cancer risk across the lifespan. To answer our question, we developed expertise that enables rapid measurement of signals in certain blood cells attributed to changes in cell stress and metabolism. Our study will determine if these signals can be used to quantify cancer risk. We will obtain blood samples from individuals without cancer, from individuals who have a condition known to increase their risk of cancer, and from individuals diagnosed with cancer. We will isolate certain cells from these samples and then measure the candidate signals in the cells. We anticipate our studies to reveal that the signals we are measuring will be the lowest in healthy individuals, will increase in individuals with the precancer condition, and will be highest in people diagnosed with cancer. These findings would powerfully validate our technology and suggest that individuals may benefit from our test for the early detection, and even prevention, of cancer.
The study will detect cancer of the prostate in African-American men. African American men develop prostate cancer at a young age. The cancer spreads rapidly making it difficult to treat. Our method will detect substances produced by prostate cancer. The test will examine blood collected from men who have concerns with their prostate. The study will develop the test and make it available in the clinic. The test will help African American men in the community who do not have access to medical care. Early finding of prostate cancer will provide enough time for cure and will help reduce cancer related suffering and death.
Lung cancer is the leading cause of cancer death in both the US and the world. There is an effective screening tool called low dose computed tomography (CT) scans of the lungs, which can find lung cancers earlier while curative surgery is still an option. These screening CT scans are recommended once to year for heavy current and former smokers, but only a tiny fraction of those who should be getting lung screening are receiving it, in part because of the high false positive rate with screening CT scans. When lung screening identifies an abnormal area (called a nodule) within the lung, the chances are much greater that it will turn out to be benign rather than cancer. However, to prove the nodule is benign a battery of tests and procedures are often ordered, leading to cost, inconvenience, possible complications, and worry. Our project aims to cut the obstacle of false positive results on lung cancer screening in half by developing a blood test that can be drawn in a doctor’s office after a patient is found to have a lung nodule on a screening CT scan and can help predict whether the nodule is benign or cancerous. The test is built upon a cutting-edge technology called multiplexed mass spectrometry-based plasma proteomics, which can detect the signature spectrum of hundreds of proteins within a patient’s blood plasma using just a small sample. Our test will look at the pattern of proteins to see if the pattern matches those seen in cancer patients. Our long-term goal is to develop an accessible test that will promote increased lung cancer screening uptake and lead to more lives saved.
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