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.
Lung cancer is the leading cause of cancer death in the US and worldwide with 15-18% cure rate. Thus, prevention is a critical strategy to decrease lung cancer deaths. Tobacco smoking causes the large majority of lung cancer and smoking cessation is the best intervention in smokers; however, the risk of lung cancer in former smokers remains high. The administration of drugs or natural products to prevent cancer is called chemoprevention. Unfortunately, currently, no drug, natural product or vitamin has been shown to decrease lung cancer incidence in humans.
The prostacyclin analog, iloprost, prevents lung cancer in mice exposed to tobacco smoke, as well as other chemicals. Therefore, we performed an early phase clinical trial of iloprost in humans. Iloprost improved airway changes that lead to lung cancer in humans, but only in former, not current, smokers. 59% of former smokers given iloprost improved airway dysplasia compared to 29% given placebo. Our goal is to be able to identify those former smokers who will benefit from iloprost so as to treat the right patients with the right drug. We have developed a patient-derived epithelial progenitor cell culture that can lead to such a test, as it recapitulates the morphologic improvement in dysplasia. Preliminary data suggest that gene expression differs between iloprost responders and non-responders at baseline. If we can develop a biomarker to discriminate responders from non-responders, future clinical trials can be accelerated and if positive, iloprost chemoprevention can be targeted to the correct subset of former smokers.
Acute myeloid leukemia (AML) is a devastating cancer of the bone marrow resulting in progressive accumulation of leukemia cells and rapidly leads to bone marrow failure and death if not timely treated. In 2016, 20,000 new cases of AML and 10,000 disease-related deaths occurred in the United States alone. The median age at diagnosis is 67 years and the incidence of the disease increases with aging of the population. Estimated survival for AML patients diagnosed in the last 5 years in US is only 26.6%. Since 1969 only 5 drugs has been approved for treatment of AML. Therefore there is a clear unmet need for new and more active drugs. The current view is that AML treatment resistance or disease reoccurrence is due to the inability of current chemotherapy and/or molecular targeting drugs to eliminate the leukemia stem cells (LSC). These primitive malignant cells are capable of initiating and maintaining leukemia and are most resistant to current treatments. Here we propose to target and eliminate LSC by harnessing the immune system with newly synthesized bispecific antibodies and engineered T-cell cells aimed at IL1RAP, a protein that is preferentially expressed in LSC. Both these products are already in our hands and have a strong antileukemia activity and the ability to reduce LSC burden. Leveraging the infrastructure for drug development (including manufacturing facilities) already present at our Institution, we propose to complete preclinical, pharmacokinetic and pharmacodynamic studies and prepare for toxicology studies in order to move these products rapidly into the clinic.
Pancreatic cancer is highly lethal. Successful treatment may be possible if the cancer is identified early, but most pancreatic cancers are not caught until they have spread. Some pancreatic cancers start off as cysts, or fluid-filled sacs. Not all pancreatic cysts are cancerous though. It is easy to see pancreatic cysts using imaging tools like MRI, and to collect fluid from them using a biopsy procedure. However, we currently don’t have any good tests to determine which cysts are likely to become cancerous. We think the necessary information may lie in proteins contained in the pancreatic cyst fluid. Our project aims to create a test that will analyze the fluid to identify which cysts are cancerous and which are benign. By finding cancerous pancreatic cysts at an early stage, before they spread, we expect to be able to improve survival for patients. Our project will also help patients with benign cysts to avoid risky and expensive surgery. We also expect to learn more about the ways these special proteins play a role in the development of cancers in other bodily organs.
