There are certain genes called “oncogenes” that when over expressed in cells can result in several deadly forms of cancers. Cancer patients with high oncogene levels show poor survival and have no defined cure. Therefore, there is an urgent clinical need for new therapies to treat these cancers. We are developing ways to selectively target oncogene-high cancer cells, while leaving normal cells unaffected.
DNA replication is important for cell survival. Our results suggest that oncogene-high cancers face many problems during DNA replication. These observations suggest that these cancers can be more dependent on pathways that allow them to fix the problems during DNA replication. Therefore, inhibiting these pathways will selectively kill oncogene-high cancer cells. In this grant, we will: (i) identify how oncogene-high cancers deal with problems in DNA replication and manage to survive; and (ii) identify why cancer cells with high oncogene levels do not respond to traditional cancer therapies. Our results can help find new ways to treat this high-risk group of patients who have little to no cure.
The role of the immune system is to survey the body in search of dangerous “non-self” elements and to eliminate them without damaging the host. Cancer is a disease which develops when host cells genetically change and begin growing in an uncontained fashion. It was therefore thought for many years that the immune system was incapable of recognizing or eliminating cancer cells due to their emergence from, and similarity to, “self” elements. The remarkable discovery that blocking signals (“immune checkpoints”) that restrain the ability of immune cells to recognize and destroy foreign elements can enable the immune system to treat cancer has fundamentally changed our approach to the treatment of these patients. Even in the setting of immune checkpoint inhibitors, however, immune cells lose functionality within tumors as part of a stepwise process known collectively as T-cell “exhaustion.” Reversing T-cell exhaustion is essential to make immunotherapy a viable treatment for all patients.
Our laboratory recently discovered that the metabolism of T-cells – the way that cells take up, break down, and utilize nutrients – becomes dysfunctional within tumors and, and moreover that this metabolic switch is required for T-cells to become fully exhausted. In work supported by the V foundation, we will understand how tumors exploit this metabolic dysfunction by creating metabolically inhospitable environments in which T-cells lose their capacity to control tumor growth. By identifying and reversing these environmental barriers, we hope to reverse or prevent T-cell exhaustion and make immunotherapy a viable strategy for every patient.
Invasive ovarian cancer is one of the deadliest types of cancer in the world, as less than 30% of these patients remain alive after 5 years. Treatment options are limited for these women, as they usually do not respond well to a new type of therapy that uses the patient’s own immune system to fight cancer. This is despite the fact that ovarian cancer does often have high numbers of T cells – an immune cell that has an ability to kill cancer cells. Therefore, identifying ways to improve the T cell’s ability to kill ovarian cancer cells will likely improve the outcome of these women. To this end, we have discovered a mutation in a molecule found in ovarian cancer cells that is associated with an improved outcome. Importantly, we have found the mutated version of this molecule is linked with increased T cell activity in ovarian cancer. Therefore, our study is designed to understand the connection between this molecule and immune cell activity. Our work will explain a new way that T cells in ovarian cancer can be stimulated to kill cancer cells and will improve our understanding of how immune activity is orchestrated in this disease. We expect that the completion of this work will drive the development of drugs that can target this molecule in cancer cells to improve responsiveness to ‘immune therapies’ and to significantly improve the outcome of women with ovarian cancer.
Pancreatic cancer remains a devastating diagnosis that is incurable in most patients, killing ~50,000 Americans per year. Treatment options including newer immunotherapy approaches are notoriously ineffective. These grim numbers motivate the search for a new strategy called “interception” that might prevent pancreatic cancer altogether. Interception seeks to target the earliest events in the progression of normal pancreas cells into invasive cancer. While this progression spans over a decade, no interception options currently exist.
We have identified a compelling target for interception. This protein is responsible for maintaining the normal identity of pancreas cells, and its activity diminishes as cells progress to cancer. Furthermore, studies comparing thousands of individuals with or without pancreatic cancer have found that this protein impacts risk of developing pancreatic cancer. Lastly, our team has developed potent drugs that can modulate the activity of this protein.
Our goal in this proposal is to pioneer an interception strategy by pharmacologically boosting activity of this protein to prevent progression of normal pancreas cells into cancer. We will characterize the mechanisms and impacts of these new drugs in mouse models of pancreatic cancer as well as in human specimens. Our studies will lay groundwork for clinical trials of interception to prevent pancreatic cancer altogether. Pancreatic cancer interception can also help address issues of psychological trauma associated with diagnosis and unequal access to treatment. Like taking aspirin to prevent heart disease before it happens, we envision these new drugs will be transformative in the fight to end pancreatic cancer.
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.
Liver cancer is among the top four causes of cancer death. Historically, liver cancer is driven by HCV. Now, liver cancer is the fastest-growing cause of cancer death in the United States. This is due to the increase of nonalcoholic fatty liver disease (NAFLD), affecting around 25% of the global population. Emerging evidence defines over-nutrition environment and circadian misalignment as risk factors for NAFLD and liver cancer. So far, there is no FDA-approved drug to target the progression of NAFLD to liver cancer. Therapeutic approaches for liver cancer are also limited. Therefore, it is important to understand the mechanisms behind NAFLD-related liver cancer and identify new therapeutic targets.
We reported that a lipid-lowering drug decreased liver fat more when given in the afternoon than when given in the morning. This work is an example of chrono-pharmacology, where giving drugs at specific times of the day can maximize efficacy. My recent work revealed eating time as a key pacemaker for rhythmic metabolic processes in the liver. We can find a potential preventive approach for metabolic disorders and cancer patients by exploring this relationship between the internal clock and eating time. Chrono-nutrition is adjusting diet schedules to maximize results for treatment. The future project will identify how circadian rhythm affects liver cancer cells. These studies aim to find new targets of circadian physiology and reveal insights into liver cancer prevention and treatment.
Funded by the Stuart Scott Memorial Cancer Research Fund
Liver cancer is a leading cause of cancer-related deaths. Its incidence continues to increase, posing a significant threat to public health. A leading risk factor is the chronic exposure to liver stress, which, in turn, enhances the uncontrolled division of cancer cells and tumor growth. Proteins are the functional units within cells. They are made from the instructions stored in DNA and carried by messenger RNA (mRNA) through a process known as translation. Notably, the information stored in DNA is not static and can be modified to alter the outcome of translation to promote cancer growth. Two of these modifications are called ‘RNA oxidation’ and ‘RNA acetylation’, which are induced in liver cells in response to cellular stress, and their levels correlate with tumor growth. Thus, this study will investigate how the interplay between RNA modifications and translation promotes liver cancer. The results obtained in this study will allow for future clinical efforts to fight liver cancer.
Funded in partnership with Miami Dolphins Foundation
Liver cancer is deadly. Hepatocellular Carcinoma, or HCC, is the most common type of liver cancer. There are significant racial differences (disparities) in how long people with HCC survive. Black people with liver cancer do not live as long as White people. Also, Black patients are less likely to receive treatment. Previous studies have been unable to explain why these differences exist. We started a research study to learn about various factors that might contribute to these disparities. When we approach patients to participate, many say that they are too overwhelmed. Some patients do not understand what is happening when they are first diagnosed. In this study, we will ask patients and caregivers what needs we might be able to help with. We will also ask healthcare staff and patient advocates to identify what needs patients have. Together with patients, caregivers, advocates and medical staff, we will create a program that helps high-risk patients to navigate the health care system and provides extra support to the patients who need it most. This study is unique because we will train lay people to work as navigators, rather than nurses. By building a relationship between the patient and navigator, we will be better able to meet our patients’ needs. We expect this program to increase the number of patients that come to their appointments and get cancer treatment. This program may increase patients’ willingness to participate in research studies, which could dramatically improve our ability to understand and eliminate disparities in survival.
Funded in partnership with Miami Dolphins Foundation
Like computers, the cells that make up our bodies also have specialized ‘software’ that runs their specific functions. When cells in the blood become cancerous -known as leukemia-, they hijack this biological software. By doing this, the leukemia cells can grow very fast and quickly multiply. Despite the many different types of leukemia that exist, they all share certain defects in their biological software. We call these shared defects a ‘biological common denominator’ across all of them. As part of this biological common denominator of leukemia we have identified the abnormal loss of PDZD2. Although PDZD2 is a gene capable of stopping the growth of other types of cancers it has never been studied in leukemia. Normally, PDZD2 is present in healthy blood cells. However, when blood cells become malignant, they lose PDZD2. We will explore how loss of PDZD2 helps turn healthy blood cells into leukemia. Importantly, we will determine if treatment of cells with a synthetic version of PDZD2 can help stop the growth of leukemia cells. Our long-term goal is to develop a novel way to treat patients with leukemia. We expect that this synthetic PDZD2 will kill the leukemia cells while having no effect on healthy blood cells.
The Epidermal Growth Factor Receptor (EGFR) gene mutations can be detected in about 15% of patients with lung cancers. In female lung cancer patients who have never smoked cigarettes, as many as 50% of patients have this EGFR mutation. These mutations in the EGFR gene can be different from patient to patient, but all lead to the generation of an active protein that drives cells to survive, proliferate, and become cancerous. Currently, we have efficacious drugs for some of the EGFR mutations, but many other mutations do not have an approved drug. To address this unmet need, I am leading a clinical and translational research program including multiple clinical trials aiming to bring new approvals to treat those atypical EGFR mutations lung cancers. We will collect clinical information and bio-samples (both blood and tissue) to understand why some tumors respond to a certain drug, whereas other tumors not, to characterize the landscape of resistance mechanisms for each group of EGFR mutations. We will test a number of novel drug-drug combinations to overcome resistance and provide more potential options for EGFR mutation lung cancer patients. In this program, we will take a team approach to engage investigators with different expertise, use leading-edge technologies, including computational biochemical approaches and single-cell transcriptomics analysis, and ultimately nominate future therapeutic options for patients.
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