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
Pancreatic cancer is deadly. The only treatment that can cure it is surgery to fully remove the tumor, but that is only an option when the cancer is caught early, which is rare. Radiation to shrink the tumor before surgery has been tried, but with little benefit. By studying both patient and mouse models, we discovered that while radiation can kill cancer cells and stimulate some good immune cells, it also can make the environment harsh, help cancer cells escape, and bring in some bad immune cells. It can also scar the tumor, making surgery harder. In lab studies, we found a molecule called STAT3 that enables radiation’s negative effects. When we blocked STAT3 in mice, we harvested the radiation’s good effects while blocking its bad ones. In this proposal, we are testing a pill for patients to take with radiation that blocks STAT3. This is the first time it is combined with radiation to treat pancreatic cancer in humans. In liver cancer, this drug was so effective that the FDA has prioritized it for trials. In our proposed trial, we will collect blood and tissue from pancreatic cancer patients before and after the pill and radiation and study how this combination affects the tumor and the patients’ immune system. We hope to develop a test that predicts patient response to the STAT3 blocker with radiation combo and to identify other ways the cancer cells escape.
Funded with support from Sarah Ferguson, The Duchess of York
While there are an increasing number of treatments for breast cancer, a sizeable number of patients develop resistance to these agents and experience disease recurrence. These numerous therapies have been enabled by our deepening understanding of the biology of breast cancer at the molecular and cellular levels, which continues to advance as a result of powerful technologies. To date most treatments have focused on targeting the molecular drivers present within tumor cells, it is increasingly apparent that the effective treatment of aggressive tumors, will necessitate strategies that harness the patient’s immune system to detect and eradicate tumor cells. Such immunotherapies have been highly effective in other tumor types, but their use has lagged breast cancer as this tumor type is thought to be immune cold. Here we perform detailed studies of breast tumor samples from patients enrolled clinical trials evaluating the efficacy of novel targeted and immunotherapeutic strategies in both early-stage and advanced breast cancers with the goal of uncovering the molecular hallmarks of tumors that respond to these agents, as well as those that do not. These studies harness powerful new technologies to study tumor tissue in its native context, while preserving spatial relationship between tumor cells and surrounding immune and stromal cells. This approach will uncover molecular interactions that can be exploited to overcome resistance and to optimize therapies across different subgroups of disease.
Most people who die from skin cancer died because their cancer has spread to the brain. Recent progress in treating patients whose cancer has spread to other organs has not kept pace for patients in whom skin cancer spread to the brain. At least part of the reason for this is likely because the environment in the brain is so different from other parts of the body. To address this urgent need for better treatments developed specifically for patients with skin cancer who then develop brain tumors, we looked for genes that might help cancer cells that spread from the skin to adapt so they can do well in the brain. We have identified a molecule that explain how it might help skin cancer cells to adapt to the brain. Already, we have encouraging evidence of how this molecule allows tumor cells to survive and grow inside the brain. Equally exciting is that there are already ways to block this gene function by taking a pill or injection, which will allow us to test if we can prevent or reverse the spread of skin cancer to the brain in our models, and eventually in patients. However, we first need to better understand exactly how important this process is in helping skin cancer cells to adapt to the brain microenvironment, and gather more information about how this gene seems to help skin cancer cells to invade the brain and adapt to a new environment.
Immune therapy has introduced a new way to treat cancer. One type of immune therapy is called PD1 immune checkpoint inhibition (ICI). PD1 ICI has enabled some people with melanoma and other cancers to live longer. These people have specific features on their tumors that are called biomarkers. People without these biomarkers do not respond as well to PD1 ICI therapy.
Our lab recently showed that a combination of two drugs can completely clear tumors in mice. One drug is a type of immune therapy called CTLA4 ICI; the other is an oral cancer drug called a PARP inhibitor. We developed two clinical trials to test this combination in people. In the first clinical trial, we showed that people who lived longer had a new biomarker called VSTM5. In the second clinical trial, we will confirm that this biomarker predicts who will live longer when given this drug combination.
In this project, we will study why the VSTM5 biomarker predicts a response to the CTLA4 ICI therapy. We will use these results to select people who are likely to respond to CTLA4 ICI therapy. Our goal is to help more people get immune therapies that help them. We also want to help develop new types of treatments for ovarian and other cancers.
Funded by the V Foundation Wine Celebration in honor of Mike “Coach K” and Mickie Krzyzewski
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.
Funded by the V Foundation Wine Celebration in honor of Laura Cortez
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 with support from the Glover and Frazier families
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.
