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.
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.
SMART-ER VA is a non-research health information service project to increase the awareness of colorectal cancer (CRC) prevention, early detection, and the uptake of colorectal cancer screening utilizing an evidence-based social media health awareness, education, and navigation intervention. Colorectal cancer remains the third leading cause of cancer death for men and women in the US. It is among the top cancers in Massey’s catchment. Twenty-Six rural southern localities in MCC’s catchment are reported as CRC “hotspots” with increased risk of CRC mortality. SMART-ER VA is designed to reach and capture the attention of those who use social media and live in targeted colorectal cancer Virginia hotspots, particularly those marginalized, disadvantaged, and geographically isolated, yet socially connected and engaged, yet not limited by geographical constructs, but have a sense of social identity, special interest, and shared norms and values, to address issues affecting their health and social needs. SMART-ER VA. is a non-research educational effort supporting the prevention and early detection of colorectal cancer utilizing social media platforms (Facebook and Instagram) and an evidence-based empowerment health education and prevention model for personal and social change.
Cervical cancer can be prevented with regular exams that detect precancerous lesions. However, these lesions are common and their progression to cancer is uncertain, resulting in unnecessary invasive procedures such as biopsies and their associated consequences of pain, bleeding, and scarring. Black women are disproportionately affected by these lesions and respective consequences. Black women also have different vaginal microbiomes (VMB) than their white counterparts. The VMB, comprising microorganisms in the vagina, has been linked to these lesions and could be a target for improved screening.
Our preliminary data suggests that the VMB’s protective effect may be influenced by race. To understand whether racially distinct pathways contribute to precancerous lesions and what factors influence them, we will recruit 90 Black and 90 white women with abnormal cervical cancer screenings. We will analyze VMB profiles, HPV viral load, and stress levels at two timepoints. Our goals are to determine if racial differences exist in HPV and VMB dynamics and assess the role of stress in disparities of lesion regression. We will also explore how HPV and VMB changes mediate the stress-regression relationship differently based on race.
This research will improve our understanding of the impact of VMB, HPV, and stress on lesion regression and racial disparities. By uncovering these factors, we can develop targeted interventions to improve the health outcomes of all women.
Lung cancer is the leading cause of death from cancer in the United States. When lung cancer is found before it spreads to other parts of the body, it can be treated and people can live longer.
There is a screening test for people who are at high risk for lung cancer. People who are over 50 and have smoked may be able to get screened. However, less than 6% of Americans in this group have been screened for lung cancer. People may not be screened because they do not know about lung screening or are worried about being screened. This project will create educational materials to help people understand if they are eligible for lung cancer screening, explain the benefits and risks and help them talk to their doctor. Education will be made available by video, in print and by website. We will test the materials using a survey. The survey will help us learn how people like the materials and if they learned about lung cancer screening.
Endometrial cancer (EC) is the most common cancer of the female reproductive tract inthe US. There has been an increase in the amount of this cancer and more women aredying of this than in the past. Black women are twice as likely to die from EC than whitewomen. There are many possible reasons for this, one of which might be that Blackwomen have different stressors than white women and this can change the way theimmune system works with chemotherapy to fight cancer. Our center is leading a one- of-a-kind research study dedicated to Black women with EC to better understand if anew immunotherapy treatment works as well in Black women as it does in whitewomen. We hope to look for markers that can help us predict if someone will respond tothe new treatment or not. These biomarkers can be used to help women decide if atreatment is right for them and are likely to be different between Black and whitewomen. We plan to look at three types of biomarkers: allostatic load (a measure of theimpact of stress on the body), microbiome (different bacteria make up in our bodies),and cytokines (markers of how our immune system is working). We hope to find out ifany of these biomarkers can help us predict which patients will respond to therapy andhelp improve outcomes for Black women.
Chimeric antigen receptor (CAR) T-cells are immune cells from patients that are engineered to target and kill cancers (not normal tissue). This is a new and exciting way to treat cancer. CARs have been wildly successful in treating children with leukemia that does not respond to any other therapy, saving many lives. I ran one of the first clinical trials to show this. Sadly, many patients experience severe or life-threatening side effects. The only drug that helps is currently on national shortage. This means some patients needing this lifesaving therapy may not get it. Even if that drug was available, CAR therapy still needs to be safer. We developed a chimeric inhibitory receptor (CIR) that we believe does just that. When it is combined with a CAR it dramatically decreases the production of the side effect causing proteins called cytokines. Importantly, it still kills tumors. Funding from this grant will allow us to make more versions of the CIR that can put the brakes on CARs in different ways. We will test the best ones in mice that have leukemia to confirm they still work. Results from these experiments will allow us to start a clinical trial of CIR-containing CAR T-cells for patients with leukemia or lymphoma here at the University of Virginia using our new CAR T-cell manufacturing facility. This unique approach to improving safety will have a dramatic impact on Virginians as well as all others with cancer who need life-saving CAR T-cell therapy.
V Scholar Plus Award – extended funding for exceptional V Scholars
Acute Myeloid Leukemia (AML) is the most common acute leukemia in adults. The majority of patients diagnosed are over the age of sixty and individuals in this age range experience poor response to treatment and worse clinical outcomes compared to younger patients. Despite advances in the field, clinical outcomes for AML patients over the age of sixty remain poor. To improve upon current treatment options for AML patients over the age of sixty, it is essential to better understand the mechanisms that drive the disease in these patients. The project proposed utilized data generated from AML patients older than 60 to identify RBM47 as a potential biomarker and driver of the disease. We will utilize data from another set of patients to confirm the association between the level of RBM47 in AML cells and clinical outcomes in these patients. Furthermore, in order to identify how RBM47 may contribute to the disease, we will determine what aspect(s) of AML biology RBM47 may regulate. Collectively, these findings will contribute to a body of knowledge for a long-term goal of identifying potential targetable mechanisms of disease that could be used to develop new and more effective treatments for AML patients over the age of sixty.
Prostate cancer afflicts one in seven men and is their second leading cause of death, justifying development of more effective therapies. Prostate cancer depends on testosterone binding to and activating the androgen receptor (AR), which in turn promotes the growth of prostate cancer. Current therapies for prostate cancer are aimed at reducing AR activity, either by blocking the production of testosterone or through agents which compete with testosterone for binding to the AR. Our approach is depleting cancer cells of the AR protein by promoting its degradation. We will accomplish this by manipulating the pathways (either genetically or with drugs) which control protein degradation. Our preliminary data show that we can promote degradation of the AR in cells in test tubes. In this proposal we will test if we can promote AR degradation in mouse models of prostate cancer.
The goals of “precision medicine” in cancer are (1) to identify the molecules that drive the cancer and (2) develop “smart drugs” that block these drivers. These “smart drugs” should stop the cancer but not be toxic. Many “smart drugs” have been developed, but the cancer cells adapt and find escape routes. We get many hopeful “responses” to therapy but disappointingly few “cures.” Our research identifies escape routes that cancer cells use to evade death, and then uses additional drugs to block the escape from treatment.
Our approach is already showing success in treating a blood cancer called Mantle Cell Lymphoma. One of our combinations is causing complete responses in over half the patients we treat. Unfortunately, many cases show resistance to our drugs, even though the patients had never previously seen them. We are researching the ways that cancer cells become resistant to these powerful drug combinations. Our goal is to achieve deeper responses to therapy and turn the frequent “responses” into genuine “cures.”
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