Funded in partnership with Miami Dolphins Foundation
Cancer immunotherapy has been one of the great advances in the treatment of cancer in the past decade. In B-cell cancers, hijacking T-cells by insbertion of a synthetic receptor (CAR-T cells) enables these cells to recognize and kill lymphoma through a specific marker (CD19). However, despite CAR-T leading to high rates of remission, only about 40% of patients are cured. Some major causes for why CAR-T does not work in patients is too great a burden of tumor cells and the cancer learning to hide the target the CAR-T needs to be effective. Therefore, there is great interest in combining CAR-T with other cancer therapies to improve efficacy. We have a clinical trial combining 2 drugs, mosunetuzumab and polatuzumab, targeting other lymphoma markers (CD20 and CD79b), together with CAR-T in patients with aggressive B-cell lymphomas. Using this approach, we hope to improve outcomes by addressing the main reasons for CAR-T failure. In this grant, we will track a patient’s response to treatment by monitoring a patient’s blood for small tumor fragments, to allow us to determine when extra therapy is needed in addition to CAR-T. We will precisely measure the amount of target markers on lymphoma cells to assess its importance for success of this therapy. Lastly, as CAR-T therapy has a high risk of infection, we will monitor recovery of the immune system to learn how adding extra therapies may affect a patient’s risk.
Funded in partnership with Miami Dolphins Foundation
Pancreatic cancer is a really bad disease that’s hard to treat. Even though treatments like immunotherapy have helped with other cancers, they haven’t worked well for pancreatic cancer. Some people get pancreatic cancer because of a problem gene passed down in their family, like BRCA. We tried treating these people with a mix of immunotherapy drugs, and it worked amazingly well for a few. Their cancer completely went away, and they stayed cancer-free for over 5 years. Now, we’re trying to figure out why it worked for some and not others. We are doing some lab experiments in mice with pancreatic cancer and it seems like something in the cancer cells called STING might be the main reason why this treatment is working. We want to study more tumors from people with pancreatic cancer and the BRCA gene problem to confirm this. Also, we plan to do more tests on mice to see if we can make STING work better in those that don’t respond to treatment at first. If these tests work, it could help create a new treatment for pancreatic cancer in the future.
Funded in partnership with Miami Dolphins Foundation
Blood cell cancers often bear mutations in STAT3. This protein is normally beneficial but, when overactive, becomes a cancer ‘driver’. More than 150 relevant mutations have been identified but only 7 have been studied in any detail. Thus, it remains unknown how mutations alter STAT3 activity to drive blood cancers. In fact, the same can be said of most oncogenes. The capacity to identify mutations far exceeds the capacity to appraise them. Our research will directly address this problem. To that end, we have devised an experimental platform that enables us to study all known STAT3 mutations at once. This platform is scalable, new mutations can be easily added, and readily adaptable to other cancer drivers. It is also designed to be implement in mice, allowing us test drugs in vivo, across all mutants at once. Using this platform, we will advance basic understanding of STAT3 and inform treatment options for associated blood cancers.
Diffuse large B-cell lymphoma (DLBCL) is a common and aggressive type of malignant B-cell tumor. Despite progress in lymphoma treatment, up to 40% of patients will ultimately succumb to their disease. Chimeric antigen receptor (CAR) T-cells (CAR-T) are immune cells from patients where a patient’s own white blood cells are isolated and engineered to target and kill tumor cells. CAR-T cell therapies demonstrated an entirely new paradigm for cancer therapy and produced unprecedented initial responses in patients of relapsed or refractory DLBCL. However, our group and others recently observed that over half of patients on CAR-T therapy eventually had disease relapse and fatal progression due to development of resistance. Thus, there is an urgent need to improve the efficacy of response and delay or prevent CAR-T therapy resistance. To tackle this major obstacle, my group has developed sophisticated models and expertise to develop a novel strategy to target the tumor in a more precise, personalized manner to overcome chemo-, targeted- and CAR-T therapy resistance. Ultimately, we will rationally design and test the improved and safe combinations of CART with the newly discovered inhibitor for DLBCL therapy. The outcomes of this study have broad applicability 1) improve the current standard of care by overcoming refractory and relapsed DLBCL current therapy resistance, 2) enhance the CAR-T therapy efficacy, and 3), we anticipate, can be readily translated to improve quality of life and/or length of life and has immediate impact on DLBCL patient care.
North Carolina (NC) has the largest American Indian (AI) population east of the Mississippi River. Yet, we do not know much about the health and health care of AIs in NC. We do know cancer is their number one cause of death. We need to better understand cancer and cancer-related needs in this group to reduce the burden of cancer. Three NC cancer centers joined together in 2021 to learn more about how to help AIs with cancer. We will study how cancer of the liver and stomach affects American Indians in NC. And we want to find and create resources for our AI community. First, we will use the NC Cancer Registry and health insurance files to learn more about how and where AIs in NC get cancer care and any potential disparities. We will then have a community event to test for and treat the top cause of stomach cancer. Lastly, we will educate about liver and stomach cancer to help prevent them. This work will help AIs in NC by showing what the greatest needs are and the opportunities for better care. The long-term goal is to improve cancer outcomes in all AIs.
Head and neck cancer is deadly because there are no effective drugs. Cisplatin is a commonly used drug for cancer treatment. However, patients with head and neck cancer usually develop resistance to this drug, which eventually leads to death. Although cisplatin can effectively kill most cancer cells, it is less effective in killing a specific type of cancer cells called cancer stem cells, which are responsible for the regrowth of the cancer after cancer therapy. Accordingly, inventing a new drug that can effectively kill cancer stem cells will improve patient survival. However, no drugs are available for killing cancer stem cells. Identifying key players maintaining cancer stem cell growth will help develop more effective drugs. Recently, we found a protein named FOSL1 is required to maintain cancer stem cell growth in head and neck cancer. However, the reason why FOSL1 keeps cancer stem cells growing is not fully understood. We also found a drug that can block FOSL1 function to prevent cancer stem cell growth. However, the efficiency is low. To increase the treatment effect, we developed a more potent compound based on this drug that can more effectively kill cancer stem cells 100 times in head and neck cancer. Our goals are: 1) using this compound to explore why FOSL1 can maintain cancer stem cell growth; 2) determine whether this compound can overwhelm cisplatin resistance using animal models. The knowledge obtained in this study will lead to developing more effective drugs to improve head and neck cancer patient survival.
Cancer is a leading cause of sickness and death around the world, with limited treatment options available for people whose disease has progressed or spread. While new treatments have improved how long people can live with cancer, lifespan for those whose disease has spread has seen far less improvement. One reason for this is the cancer’s ability to become resistant, or “immune,” to treatment. A new method of treating cancer, called precision oncology, uses molecular testing to not only understand how and why a tumor grows, but also how it can begin to become resistant to treatments that may have once worked.
One challenge, however, is that access to this molecular testing is not always available to all groups of people. This unequal access, based on race and other factors, can have a measurable impact on cancer patients’ lives — in a recent study, black patients were 38% less likely to receive this type of testing compared to white patients. Through our research, we hope to change this to create a more equal approach to cancer treatment regardless of race or other factors. To do this, we will create a high quality molecular testing program in the DC region, with particular attention to communities in need of more equal access to these treatment approaches. By including all racial groups more equally in this research, we will also be able to better answer future research questions in a way that does not exclude any groups of people.
In patients with hormone positive breast cancer that has spread to other parts of the body eventually the cancer can stop responding to hormone blocking pills and their cancer starts to grow again. In this project we will develop vaccines that eliminate breast cancer cells that no longer respond to hormone blocking pills. This will cause the remaining breast cancer cells start responding again to hormone blockers. The result of these vaccines would be that those patients with hormone positive breast cancer will have a much longer time where that the hormone blocking medication would work. The immune response would also help to kill more of the breast cancer cells. This should mean that patients will live much longer with hormone positive breast cancer that has spread. This research will be tested first in mice and then in patients with hormone positive breast cancer that has spread to other parts of the body.
We are testing a drug, tucatinib with a form of focused radiation called stereotactic radiosurgery for a type of breast cancer (HER2-positive) that affects 20-25% of breast cancer cases when it spreads to the brain.
This study will help find out if the combination of tucatinib and radiation is safe and if patients can tolerate it well without too many side effects.
About 40 patients with this type of breast cancer that has spread to the brain will be part of the study. First, they will receive the drug tucatinib along with the focused radiation treatment. After that, they will continue taking tucatinib along with two other medicines called capecitabine and trastuzumab. These three medicines are already used as the standard treatment and have been effective for patients like these. Patients will receive this combination until their tumor grows back or if there are serious side effects.
This study will also help find out the correct dose of tucatinib to use. Additionally, the study will answer how well the treatment works and how it affects brain function.
Funded in partnership with WWE in honor of Connor’s Cure
Diffuse midline glioma (DMG) is a devastating and aggressive type of brain tumor that primarily affects children and young adults. Despite advancements in medical research, DMG remains a medical challenge with limited treatment options and a poor outcomes. Considering these difficulties, there is an urgent unmet need to develop new and innovative therapies for DMG. One promising avenue for discovery is the exploration of targeted agents that disrupt key signaling pathways involved in tumor progression without affecting the healthy normal cells in the brain. Our previous work has identified a potential new therapeutic target that could be leveraged in this way to specifically combat this tumor. New drugs that selectively inhibit this aberrant signaling pathway show great potential for slowing down the growth of DMG cells, thus creating a new opportunity for intervention. In these proposed studies, we will explore precisely how this intracellular signaling pathway controls cancer progression. Further, we will test in the lab whether treatment with new drugs designed to inhibit this pathway can halt DMG tumor growth. We hope that our studies inform the use of new targeted drugs to treat this devastating childhood cancer and thereby drive advancement of patient care and redefine the treatment of DMG.
