Scientists have recently made tremendous progress in treating cancers by activating the immune system to attack the tumor. However, these therapies are not effective against cancers with less DNA damage due to insufficient anti-tumor immune responses. The immune system is capable of attacking these tumors, but suppressive immune subtypes such as regulatory T cells (Tregs) are coopted by the tumor to protect itself. Tregs are associated with poor survival in many cancers, and show enrichment for particular T cell receptors (TCR). The TCR senses targets by binding to their peptide-MHC ligands, which display a cross-section of peptides expressed by a particular cell. Despite their important role in protecting tumors, the identity and specificity of tumor-resident Tregs is poorly studied. We are working to profile what T cells are enriched in low mutation rate cancers. We can then use approaches we have developed to find what these T cells as seeing in the tumor. This information will help us understand of one of the most important tumor-protective cell types, and may open the door to new cancer immunotherapies.
About 12% of U.S. women will develop invasive breast cancer over the course of her lifetime. Despite advances in early diagnosis and treatment of the disease, breast cancer remains the most commonly diagnosed non-cutaneous malignancy and the second leading cause of cancer death in American women. Acquisition of resistance to current therapies is a major challenge in everyday clinical practice, which significantly reduces the disease-free survival and overall survival in breast cancer patients. Thus, it is important to develop new therapeutic approaches for circumvention of resistance and also to identify predictive biomarkers for more effective treatment decisions. Our previous work found a protein called EZH2 as a very promising therapeutic target in metastatic breast cancer that becomes refractory to hormone therapy. Several highly selective inhibitors of EZH2 are currently being tested in phase I/II clinical trials in patients with B-cell lymphoma. In this study, we will evaluate the efficacy of these EZH2-targeting drugs in metastatic, endocrine resistant breast cancer. We further demonstrated that DNA methylation of one of EZH2-regulated target genes, called GREB1, is highly associated with EZH2 activity in advanced breast cancer. So we will test whether methylation of GREB1 can be used to identify patients who will respond to EZH2 inhibitors. Results from this clinical study provide a novel targeted therapy for advanced breast cancer and a biomarker for choosing the right treatment. Our work will pave the way for the development of personalized medicine as an alternative approach to fighting metastatic, endocrine therapy resistant breast cancer.
Great strides have been made toward finding cures for cancer, which is expected to strike 1.6 million Americans this year. Although many cancer patients still die from their disease, the overall cancer death rate is declining due to improved detection methods and novel therapies. The exciting development of immune therapy has shown that activating a patient’s own immune system to attack and kill cancer cells can lead to cancer cures and improved life spans for patients with many forms of cancer. However, there are still many patients whose tumors are resistant to immune therapy. We recently found that tumor associated macrophages, immune cells that are found in great numbers in tumors, cause resistance to immune therapy. We identified new drugs that break this resistance to immune therapy; these drugs led to cures in animals with cancer. We will test these drugs in patients with head and neck squamous cell carcinoma, monitoring for changes in biomarkers of immune suppression and tumor progression. We will also identify new immune therapy drug combinations that can improve cancer care. These studies will contribute to the development of novel, effective immune therapies for cancer patients.
Funded in partnership with WWE in honor of Connor’s Cure
Medulloblastoma is the most common malignant brain tumor in children. Medulloblastoma is really made up of four diseases, of which two types: Group 3 and Group 4 account for the majority of cases. The main tumor ‘lump’ in the brain is called the ‘primary tumor’. The primary tumor can spread (metastasize) to cover other regions of the surface of the brain and spinal cord. Most children who die from medulloblastoma die because the tumor has spread (metastasized) and not due to the primary tumor. The most damaging therapies (radiation) for children with Group 3 and Group 4 medulloblastoma are necessary to treat the metastases.
For the most part, medulloblastoma only spreads to the surface of the brain and spinal cord, and not to other organs. According to the textbooks this occurs when cells drop off the primary tumor, float around in the spinal fluid, and then reattach to the brain or spinal cord and start growing again. There really is no evidence or experiments to support this mechanism, just historical speculation. We have now shown that in fact, medulloblastoma spreads through the blood stream—the cells enter the blood stream, and then home back to the brain and spinal cord where they grow and kill the child.
This new understanding of the metastatic process for medulloblastoma offers fresh opportunities to non-invasively diagnose medulloblastoma in the blood, to prevent the metastatic cascade, prevent the progression of metastases, and decrease the toxicity of therapy for children with medulloblastoma.
Cancer is caused by genetic changes (errors), making every cancer unique. Nevertheless, cancers share features that allow them to be grouped into categories or “subtypes.” A tumor’s subtype strongly influences its behavior, including growth rate, likelihood of responding to one therapy versus another, and probability of relapse. Knowing each tumor’s subtype could thus help determine which therapy is best for a give a patient, a concept known as “Precision Medicine.” Currently, subtype can only be determined by in-depth sequencing of tumor tissue, and thus it is not routinely determined in clinical practice.
The goal of this proposal is to develop a rapid, non-invasive, and inexpensive way to determine tumor subtype from a blood test. This is called “liquid biopsy,” and it is playing an increasingly important role in cancer care. Because liquid biopsies are non-invasive (i.e. they do not require surgery or other procedures), samples can be obtained repeatedly over a course of therapy, allowing better clinical decisions to be made.
Colorectal cancer (CRC) is the second-leading cause of cancer death in the United States, where it has a disproportionately lethal effect on African-Americans. Recently, a consensus panel concluded that the disease has four major subtypes based on patterns of gene expression (which genes are “on” or “off” in the tumors). In this proposal, we will use these definitions to perform subtyping from liquid biopsies. In the future, the approaches we will develop here will be applicable to all cancers, not just those affecting the colon and rectum.
Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women. The primary cause of death is metastasis, or spread of the cancer via the blood stream to other organs, which is incurable and associated with an average life expectancy of only 3 years. Although breast cancer death rates have declined due to screening and more effective treatments, more accurately identifying metastatic risk in order to prevent overtreatment remains a major clinical challenge. Therefore, the most important problems in breast cancer include reducing overtreatment by identifying more accurate prognostic markers and preventing spread of cancer cells in those at risk. Our program has focused on addressing these problems by studying breast cancer cell dissemination at single cell resolution using innovative experimental methods, with a focus on translating these discoveries into the clinic through multidisciplinary collaboration. In aim 1, we will confirm the association of 2 specific breast cancer tests that may more accurately identify who is at risk for recurrence, one of which identifies microscopic structures (which we call “TMEM”) that seed tumor cells into the blood and other organs. In aim 2, we will test a new drug which blocks TMEM function to see if it can block seeding of tumor cells into the blood. The project is therefore studies an entirely new approach to cancer diagnostics and treatment. The basic science studies that led to this work have been described in an award winning video entitled “Spying on Breast Cancer Metastasis” (https://www.youtube.com/watch?v=q_JDp-VePAs)
The administration of a subset of human immune cells cultured in the laboratory and known as T lymphocytes that have been engineered to express a chimeric molecule that recognizes tumor cells has shown remarkable antitumor effects in patients with blood tumors. Although there is much promise in these therapies, there is still a need for improvement in safety and efficacy. This project is important to patients because it examines a considerable challenge with these therapies, e.g. their toxicities. The way toxicities are being addressed in this project is unique and holds the promise of alleviating many severe side effects experienced by patients. Additionally, controlling toxicities will be extremely important to the success of treating patients with solid tumors when normal tissues may be targeted. So, there are many advantages to the “safety switch” approach that we propose in this application to alleviate side effects.
Over the past decade, harnessing the power of a patient’s own immune system for the treatment of cancer has been a major medical breakthrough. By using drugs to block inhibitory signals on immune cells, these medicines help “release the brakes” allowing them to kill cancer cells. Given the tremendous success of this approach, our lab has worked to identify another class of drugs that help “wake up” the immune system to help it fight off cancer. We have performed extensive studies on a protein called CD40, which is naturally used by the immune system to fight off infections. By activating CD40, cells of the immune system are better able to recognize and kill cancer cells. We modified a class of drugs, called antibodies, to help stimulate CD40 on immune cells. By doing this, we generated a drug which was twenty-five times more potent than the currently available form. This enhancement led to better immune system activation and treatment of cancer. We are now aiming to test this improved immune therapy in patients with cancer, hoping to provide another class of drugs that help the immune system attack and kill cancer cells.
Funded by the Stuart Scott Memorial Cancer Research Fund
American men of African descent (AAM) are known to experience greater incidence of and mortality from prostate cancer (PCa) than their Caucasian (EAM) counterparts. The determinants of this high rate of PCa in men of African descent remain unresolved. The genomic and epigenomic contribution to PCa disparity has been well established with the identification of significant racial differences in DNA methylation level and expression of various genes. In the last decade a number of biomarker-driven predictive tools have been developed for clinical use to aid in PCa treatment decisions. These biomarkers show promise as predictors of aggressive and lethal PCa with potential clinical utility. However, these predictive tools were developed mostly from EAM specimens. There is a lack of data on the relevance of these biomarkers on observed increased aggressiveness and lethal PCa among AAM. We and others have provided evidence suggesting that AAM with aggressive phenotypes have significantly different methylation level and expression of many PCa biomarkers compared to EAM, suggesting that these may be ideal prognostic biomarkers for AAM. Therefore, comparative evaluation of biomarkers for aggressive PCa in AAM is imperative, and carries the inherent potential to elucidate the pathogenesis of aggressive and lethal PCa in this at-risk population. The focus of this proposal is to unravel the epigenetic and genomic predictors of aggressive and lethal PCa in AAM. The implications of our proposed study have immense clinical relevance in this era of personalized medicine for the at-risk population of AAM.
Brain cancer is now the leading cause of cancer‐related death in children, due to the significant improvements in outcomes for children with more common cancers such as leukemia. This research proposal advances a novel immunotherapy treatment for medulloblastoma (MB), the most common malignant brain tumor in children. We have pioneered a treatment platform for pediatric brain tumors called adoptive cellular immunotherapy, which involves expanding tumor‐reactive ‘killer T cells’ to large numbers outside of a patient and delivering these potent immune cells back to children with resistant brain tumors. This approach is currently undergoing evaluation in first‐in‐human clinical trials at our center. This project will advance this platform into a next generation approach that uses genomic technology to identify patient‐specific antigens expressed in medulloblastoma tumors and specifically isolate and expand T cells recognizing these unique tumor targets (called neoantigens). If the objectives of this study are met, we will be able to significantly enhance the specificity and potency of an already promising platform and rapidly translate our findings into innovative clinical trials for children battling brain cancer.
