Cancer cells express mutated proteins that are distinct from the proteins in non-cancerous cells, known as “tumor-specific antigens.” Over a century ago, scientists reasoned that our immune system (T cells) should be able to recognize these mutated proteins as “foreign” and eliminate cancer cells. While we find tumor-specific T cells within tumors, these T cells are not functional, allowing cancers to grow unimpeded. Our goal is to understand why tumor-specific T cells are dysfunctional and develop strategies to reprogram these tumor-specific T cells to fight cancer.
Using genetic cancer mouse models, we found that during tumor development, tumor-specific T cells become dysfunctional because the genes and pathways needed for normal T cell function are dysregulated. All cells in our body, including T cells, contain two layers of information encoding each cell’s characteristics. The first layer is the genome and consists of the DNA nucleotide sequence, the second layer is the epigenome and consists of chemical modifications to DNA or to the scaffold proteins associated with DNA. The genome and the epigenome together determine a T cell’s properties. Because functional and non-functional T cells in our model have identical genomes, tumor-induced loss of function must result from epigenomic changes. We propose to define the epigenome modifications that render tumor-specific T cells non-functional and test strategies to reverse this “code of dysfunction” so that we can reprogram tumor-specific T cells for human cancer therapy.
Funded by the Stuart Scott Memorial Cancer Research Fund, with Partial Funding in Year Two From The Ewing Sarcoma Fund
Ewing sarcoma is the second most common bone cancer in children and has a low rate of survival compared to other pediatric cancers. Genetically, Ewing sarcoma is characterized by a fusion protein known as EWS-FLI1 that is essential for the growth and survival of tumor cells. EWS-FLI1 operates by binding DNA and changing the expression levels of many genes and we believe that studying its mechanisms of action in detail may reveal new opportunities for therapy. We recently analyzed EWS-FLI1 mediated events at thousands of sites across the genome and identified genes that are highly responsive to the fusion protein. Among these genes we found VRK1, a kinase that is involved in coordinating cell proliferation and that represents an attractive therapeutic target. Our experiments show that EWS-FLI1 controls VRK1 expression directly and that Ewing sarcoma cells are highly sensitive to downregulation of VRK1. We now plan to characterize the function of VRK1 in Ewing sarcoma to learn about VRK1 dependent mechanisms in this tumor type and to test the potential of VRK1 and related pathways as therapeutic targets.
Cervical cancer is responsible for 15% of cancer-related deaths in women worldwide, with highest frequency occurring in resource-limited settings. In addition, incidence and mortality rates are disproportionately higher in African-American and Hispanic populations within the United States, compared with other ethnic/racial groups. Many patients die of cancer either because it spreads to other body organs (metastasis), or because the cancer grows again in the same organ (recurrence). In cervical cancer, 90% of recurrence cases occur within 3 years of diagnosis, and less than 5% of these patients survive beyond 5 years. It is therefore essential to find ways to predict the likelihood of tumor recurrence in order to improve the management and prognosis of cancer patients. We hypothesize that the biological events that lead to tumor recurrence are already at play, even at the time of treatment. In particular, we believe that several biological molecules (human, viral and bacterial) play role in this complex process. We therefore seek to identify and compare these factors in surgically removed cervical tumors and their adjacent normal tissues between 2 groups of women: those with tumor recurrence within 3 years of surgery, and those without recurrence despite longer follow-up. We hope to identify differences in the relative abundance of these biological molecules that will serve as sentinels (we call them biomarkers) to warn us of the likelihood of tumor recurrence. This work has the potential to lead to the development of diagnostic tools for predicting and preventing recurrence in and beyond cervical cancer.
The Jimmy-NCSU V Cancer Therapeutic Program allows young researchers the opportunity to work on multiple facets of cancer research in a set of diverse labs, each investigating different approaches for developing cancer therapeutics.
Enhancing cancer drugs We have discovered molecules that increase the effects of anticancer drugs by several orders of magnitude. Our goal is to reduce the working concentrations of all anti-cancer drugs in order to mitigate serious side effects. We will develop and screen our new molecules with both novel and existing chemotherapeutics against a variety of cancer cell lines in order to define the optimum combination treatment. Initial screens show effects against breast, renal and colon cancer cell lines.
Cell death and tumor formation The life and death of cells must be balanced. Normal cells accommodate this balance by invoking programmed cell death pathways, referred to as apoptosis. In cancer cells, these pathways are defective and normal cell death does not occur, leading to tumor formation. In addition, faulty apoptosis causes tumor cells to be resistant to chemo/radiation therapies. If we could make apoptosis occur properly, we slow down tumor formation and overcome this resistance.
The protein caspase-3 controls apoptosis. If caspase-3 fails to function, cell death does not happen correctly. We also know that the protein calbindin-D28K binds to caspase-3 and stops it functioning. If we can stop calbindin-D28K from interfering with caspase-3, apoptosis would occur normally and the risk of cancer developing would be reduced. Consequently calbindin-D28K is a powerful target for anticancer drug development.
USC Norris Comprehensive Cancer Center offers over 23 trials for patients with breast cancer at the USC Norris Cancer Hospital and at the Los Angeles County (LAC) USC Medical Center, making them accessible to all. Participation in cancer clinical trials is a key measure for delivery of quality cancer care. Adult participation in cancer clinical trials remains at 3% and participation among ethnic and racial minorities and medically underserved communities is even lower. The Clinical Investigation Support Office, led by Dr. Anthony El-Khoueiry is dedicated to increasing minority accruals to clinical trials and has enlisted support from Dr. Julie Lang, a breast surgeon to support patient education and enrollment efforts. We plan to leverage our strong tradition of minority accrual (minority patients represent 56% of accrual to interventional therapeutic trials at USC Norris) and further enhance access to clinical trials for minority patients.
The promise of cancer therapies that target the mutationally activated “drivers” of malignant behavior is that highly selective drugs can be developed that will be effective with minimal side effects. However, that promise has not been achieved because most cancers rapidly develop resistance to these targeted therapies. Recent experience with the leukemias and lymphomas that respond to the drug ibrutinib provide a sobering example of both the successes and disappointments of these targeted approaches. Whereas many patients with malignancies of B-cells (Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL) or Diffuse Large B-Cell Lymphoma (DLBCL)) show a beneficial response to treatment with ibrutinib, the responses are generally incomplete and often are not durable. The goal of the collaborative research proposal from UVA and VCU is to elucidate the important mechanisms of intrinsic and adaptive resistance to therapies for B-cell malignancies, and use this understanding to develop RATIONAL combinations of drugs that target both the driver of malignancy and the resistance mechanisms. The two groups have over the past few years taken complementary approaches to tackling this problem, and some of these discoveries are now entering clinical trial. The UVA and VCU groups will utilize materials from these clinical trials, as well as preclinical models and patient samples to develop tools to match patients with the most appropriate drug combinations, and to develop additional combinations of targeted therapies that will have deeper and more long-lasting benefits.
Funded in Collaboration with Stand Up To Cancer (SU2C)
Preclinical and clinical studies have informed the development of increasingly effective cancer therapies that can lead to dramatic clinical responses. However, in the majority of cases, patients subsequently develop therapeutic resistance. Although recent studies by our labs and by others have elucidated mechanisms of resistance, the complex series of genetic and epigenetic events that drive therapeutic resistance have not been well delineated, there are few therapeutic options to prevent resistance. We have chosen acute myeloid leukemia (AML) to investigate the dynamics of therapeutic response and resistance for several important reasons. First, there is abundant evidence that targeted therapies (tyrosine kinase inhibitors) can induce substantive clinical responses, including complete remissions, in patients with genotypically defined disease subsets. Moreover, combination chemotherapy can induce a high rate of complete response similar to that observed with molecularly targeted therapies. Second, our team proposes to perform genomic and transcriptional/epigenomic studies of serially obtained clinical isolates from patients before therapy, at the time of maximal response, and at therapeutic relapse. Our clinical sites have established a robust infrastructure to obtain clinical samples at the different time points. This sampling approach, coupled with state-of-the-art genomic, transcriptional, and functional studies, will address questions that are central to the fields of cancer biology, modeling, and cancer therapeutics, and – most importantly will allow us to test models of the evolution of drug resistance and novel therapeutic approaches that can then be rapidly translated to the clinical context.
Tumors consist not only of cancer cells, but also stromal and immune cells that constitute the tumor microenvironment (TME). Cancer cells can take on dramatically different properties based on the microenvironment. The clinical impact of the TME is only becoming appreciated in recent years. In many different cancer types, including breast cancer (BC), tumors with higher stromal fractions portend worse clinical outcomes. In contrast, tumors infiltrated by CD8 T cells have better clinical outcomes. Hence, tumors behave differently based on the collective behavior of the microenvironment. We will leverage biotechnology advances in sequencing single cells to better understand the important determinants of the coevolution between the adaptive immune response and the tumor. By tracking the spatial geometry of cells in tumor samples we hope to better understand the TME and ultimately determine which genetic factors can be best exploited for therapeutic intervention.
Funded in Collaboration With Stand Up To Cancer (SU2C)
The last two decades have seen the development of increasingly effective cancer therapies that target different aspects of tumors cells, including uncontrolled growth/survival, evasion of the immune system, hyper-activated signaling pathways and dysregulated gene expression programs. In a subset of cancers, including non-small cell lung cancer (NSCLC) with mutations in the epidermal growth factor receptor (EGFR), these therapies can lead to dramatic tumor regressions in a significant number of patients. However, in the majority of EGFR mutant lung cancer patients who respond to anti-cancer therapies, relapse usually occurs preventing long-term cures. We propose to investigate the reasons why cancer cells become resistant to treatment. We believe a tumor is made up of a number of different types of cells that can each respond differently to treatment. We hope to uncover and understand these differences by looking at genomic data taken from patients who are biopsied before treatment, during response to treatment, and when resistance emerges. We are also interested in understanding the role the immune system plays during cancer treatment. We’d like to understand if the tumor has developed ways to evade the immune system, and how we can promote the patient’s own immune system to fight back against the cancer. It is our hope that combining traditional drug treatment with newer immunotherapies will provide greater tumor regressions. Our goal is to create a deeper understanding of the make-up of a tumor in order to identify novel therapies to expand the survival of patients with NSCLC.
Funded in Collaboration With Stand Up To Cancer (SU2C)
The so called targeted therapies are effective in tumors that strictly depend on a given protein or cellular signaling (the target) for growth and survival. Hyperactivation of the PI3K pathway is frequent in breast cancers and its pharmacologic inhibition showed clinical responses. However, these molecules alone cannot elicit a durable inhibition of tumor growth because the tumor can adapt and compensate the inhibition of the pathway.
Thus, targeting these compensatory mechanisms in combination with the PI3K pathway would in principle lead to stronger and more durable antitumor activity.
In this proposal we aim to validate in the laboratory theoretical predictions of successful drug combinations. These predictions are obtained from mathematical models developed from what is currently known about the perturbations of the PI3K/AKT signaling network in response to different inhibitors of the pathway. In addition, we plan to test therapeutic combinations based on genomic analyses from tissue samples of breast cancer patients treated with PI3K inhibitors.
Taken together, our results should provide the rationale to test novel and more effective therapeutic options for patients with hyperactivation of the PI3K pathway.
