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.
Pancreatic cancer kills just about every patient that has it. Patients are first seen with advanced disease and rarely respond to current treatments. More advanced therapies are needed to save lives. Recent studies suggest that pancreatic cancer cells are especially reliant on cellular recycling processes for growth. Mouse models of pancreatic cancer show that blocking these recycling processes can decrease the growth of tumors. These results have led to the launch of several clinical trials. However, initial results from these clinical trials show that pancreatic cancer cells stop responding. The tumors become resistant to blocking recycling pathways. We have made pancreatic cancer cells resistant to these therapies in the lab. We will use these cells to uncover better therapies to prevent resistance and increase patient survival.
Previously, research showed that these recycling processes promote tumor growth. But, in some contexts these same recycling processes can block pancreatic tumor growth. Researchers still don’t know how or when this switch happens. This dual role could contribute to the therapeutic resistance seen in patients. To study this phenomenon, I will use mini-pancreatic organs, called organoids, that can be grown in the lab. For the first time, we will be able to study the mechanisms that regulate the dual roles of cellular recycling in pancreatic cancer. Together these studies will allow us to target the tumor promoting functions of the recycling pathways while preserving the tumor blocking functions. This will prevent resistance and increase patient survival.
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.
Therapies that recruit and reactivate a patient’s own immune system against cancer have shown a great deal of promise. However, not all patients benefit from these therapies. Thus, developing strategies to boost immune-based treatments is critical. One approach is to develop drugs that improve the function of immune cells. This can be done by targeting transcription factors, which are proteins that help regulate the expression of other proteins. However, transcription factors are very difficult to drug because they often do not have suitable binding sites for chemical compounds. Nevertheless, we recently developed compounds that target a transcription factor known to be important in certain immune cells. Our major goal is to see if targeting this transcription factor can boost the immune response against tumors in mice. We will also try to understand how these compounds reprogram immune cells. This is important because several companies are developing similar drugs, but how these drugs work is not fully understood. The experiments in this proposal will shed light on how this class of drugs work. This will be useful for evaluating how they are used in patients to improve patient outcomes like increased survival.
Funded by the Stuart Scott Memorial Cancer Research Fund and the V Foundation Wine Celebration for Julie Maples, in honor of Antrese Rose Allegro
Breast cancer is one of the most diagnosed cancers in women and it is the top cause of cancer death in Black and Hispanic women. While great advances have been made in the detection and treatment of breast cancers, certain forms of breast cancer remain difficult to treat. Some patients develop resistance to current therapies leading to relapse, metastases, and ultimately death.
We are proposing to use our own immune cells to treat difficult cases of breast cancer. Our approach is to modify T cells with synthetic receptors to specifically recognize and kill breast cancer cells without harming normal tissues and organs.
We are using the T cells ability to patrol our body and modifying them to recognize specific molecular signals, such as the amount of a protein (HER2) present on the surface of cancer cells, to execute potent killing responses. If successful, our approach will lay the foundation for clinical studies, potentially will have major impact on our ability to treat effectively and safely some of the most difficult forms of breast cancer and will provide new approaches to other challenging solid cancers.
Immunotherapy is a new method of cancer treatment that boosts the immune system to help kill cancer cells. Patients with head and neck cancer that has returned or spread to other parts of the body have few treatment options, and immunotherapy has been a breakthrough to improved survival. However, this therapy works in less than 20% of patients. We believe that this immune system treatment does not work in some patients because their immune system is desensitized to the cancer, and the cancer is able to hide from the immune system. In this study we propose that splicing, which are gene rearrangements, can (1) help identify which patients will benefit from this treatment, and (2) find new ways to make this treatment effective for more patients. First, we will look at splicing as a marker to help predict which patients will respond to immunotherapy. Next, we will use a mouse model of oral cancer to understand how splicing is related to a suppressed immune system to understand why some patients do not respond to treatment. Lastly, we will combine immunotherapy with new drugs that can increase splicing rearrangements to see if this combination will improve response to treatment. Ultimately, we believe that study of these gene rearrangements will lead to new treatments that could help cure more patients with head and neck cancer.
The overall goal of “Enhancing Lung Cancer Screening For Eligible Patients (ELFE) through human- centered intervention” is to increase the completion rates of lung cancer screening (LCS) among eligible patients. LCS is important because it can facilitate the detection of lung cancer at the earliest and most treatable stage before the cancer has spread. The goal of ELFE is two-fold: 1) interviewing patients who have completed lung cancer screening to better understand factors that served as barriers to or facilitators of LCS participation and 2) develop a clinical intervention incorporating the lessons discovered through the interviews. We will explore the use of a Pre-Visit Planner in which a licensed medical assistant will engage with patients alone or coupled with a web portal to identify patients who are eligible for LCS. ELFE is a collaboration that includes the UC Davis Comprehensive Cancer Center, UC Davis Health, and Amazon Web Services to bring innovative research and tools to patients. Using a patient-centered intervention such as what we are proposing potentially could impact clinical practice thus, reducing the mortality associated with lung cancer.
Funded by the Scott Hamilton CARES Foundation in partnership with the Dick Vitale Pediatric Cancer Research Fund
Brain tumors are the leading cause of childhood cancer mortality. Two types of these brain tumors, both with mutations in different parts of the histone 3 protein, are both aggressive and deadly. Although these tumors are so awful for the child that has one in their brain, when the tumor is removed with surgery, it is very hard to grow in a dish. For this reason, many scientists take these patient tumor cells and grow them in a mouse. Yet, we and others have seen that although this way of growing the tumors is better than nothing as it allows us to research the tumor cells, the tumor changes a lot in the mouse brain. For this reason, we have generated new models, using transplantation to a cortical organoid. A cortical organoid is a three-dimensional model of the developing human brain made from stem cells. Our work shows this system mimics more aspects of the original tumor, and also provides an opportunity to see how the tumor cells interact with the human brain. We will further optimize this system to study these pediatric brain tumor and we will now begin to ask, which cell types actually cause the tumor to recur after surgery? Which cell types are most invasive, and thus most dangers? Finally, we will also try to identify the cause of these tumors so that we can either prevent them from emerging in children in the first place, or detect them early to prevent tumor progression.
Lung cancer is the leading cancer killer in both men and women in the U.S. Early detection is the most effective way to fight against this deadly disease. In recent years, an imaging method known as low-dose CT (LDCT) scan has been studied in people at higher risk of getting lung cancer. LDCT scans can help find nodules in the lungs that may be cancer. However, majority of those nodules are actually benign, yet exposing many of those patients to a needle biopsy or other invasive procedures. Hence, there is an urgent and unmet need for an accurate and non-invasive approach to distinguish those nodules that are malignant from those that are not. In this proposal, we will develop and validate a novel method to integrate a blood test and the LDCT imaging for the early detection of lung cancer. Specifically, from blood we extract cell-free DNA, from which we develop an ultra-sensitive assay to profiles the epigenome of cell-free DNA, therefore to detect even a trace amount of tumor DNA. Using advanced machine learning algorithms on the integrated genomics and imaging data, we aim to significantly improve the accuracy of the cancer detection. For those patients with nodules identified from LDCT, we will integrate the two sources of information to determine whether the nodules are malignant or benign.
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