Funded in Collaboration With Stand Up To Cancer (SU2C)
Pancreatic ductal adenocarcinoma (PDAC) is a frequent cause of cancer death in the United States; it currently is the fourth most common cause of cancer death and is expected to become the second most common cause of cancer death within the next five years. Unlike virtually all other major cancers, pancreas cancer is both increasing in incidence and has shown essentially no improvement in five year survival over the past two decades. The exceptional lethality of pancreas cancer is multifactorial, resulting from an intrinsically aggressive biology, lack of effective means of early detection, and poor responsiveness to systemic chemotherapy. Clearly novel approaches to this disease are needed.
Although there have been anecdotal reports of responses to immune-based therapies in pancreas cancer, activation of cellular immunity using checkpoint inhibitors, vaccine strategies and transfer of genetically modified T cells has not been shown to be generally effective. We have assembled a team of physicians, cancer immunobiologists, computational biophysicists, and engineers to better understand the unique immunological microenvironment of pancreatic cancer, develop the technologies needed to take advantage of therapeutic vulnerabilities, and to form a multi-institutional clinical consortium to readily implement these strategies to help change the course of this deadly disease.
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)
The study encompasses multiple directions. First, genome of cancer cells acquires mutations at a higher rate compared to benign cells. Some of these novel mutations affect proteins synthesized within the cell, and these modified proteins (tumor neoantigens) may interact with immune system. We identify these novel neoantigens and study their interaction with immune cells in the tumor microenvironment. The other direction is quantification of non-coding RNAs, in particular, some repeat RNAs, expressed by cancer cells. We focus on the mechanisms of expression of these RNAs, their immunogenic properties and their interaction with tumor microenvironment. Understanding these topics would open the door towards unleashing immune response against pancreatic tumors.
Funded in Collaboration With Stand Up To Cancer (SU2C)
Decades of cancer research and therapeutic development have made it clear that achieving durable control of invasive solid tumors requires therapeutic combinations of a large number of drugs that target different elements within cancer cells. In aggressive cancers where cure is achievable (e.g., subtypes of leukemia and lymphoma), as many as 4-6+ drugs may be needed when administered as curative treatment to patients. This is because simpler drug combinations become ineffective due to the development of drug resistance by the tumor.
The guiding hypothesis of this project is that network-based models of cancer cell signaling together with evolutionary analyses and therapeutic data can identify a set of element within cancer cells that might eventually be exploited through therapeutic combinations to achieve a more durable control of cancer, even in the presence of tumor drug resistance. Specifically, we propose a theoretical framework that integrates so-called discrete dynamic network models and control theory with genomic evolutionary approaches. These models will be informed, tested, and iterated using experimental approaches applied to relevant cancer model systems. Based on its exemplary clinical need, we will focus on BRAF-mutant melanoma (skin cancer) and PIK3CA-mutant, estrogen receptor positive (ER+) breast cancer as initial tumor types in which to test and develop our approach. The final result will be a theoretical and experimentally validated approach that can in principle be generalized across many other therapeutic strategies.
Funded in Collaboration with Stand Up To Cancer (SU2C)
Pancreatic ductal adenocarcinoma (PDAC) is a frequent cause of cancer death in the United States; it currently is the fourth most common cause of cancer death and is expected to become the second most common cause of cancer death within the next five years. Unlike virtually all other major cancers, pancreas cancer is both increasing in incidence and has shown essentially no improvement in five year survival over the past two decades. The exceptional lethality of pancreas cancer is multifactorial, resulting from an intrinsically aggressive biology, lack of effective means of early detection, and poor responsiveness to systemic chemotherapy. Clearly novel approaches to this disease are needed.
Although there have been anecdotal reports of responses to immune-based therapies in pancreas cancer, activation of cellular immunity using checkpoint inhibitors, vaccine strategies and transfer of genetically modified T cells has not been shown to be generally effective. We have assembled a team of physicians, cancer immunobiologists, computational biophysicists, and engineers to better understand the unique immunological microenvironment of pancreatic cancer, develop the technologies needed to take advantage of therapeutic vulnerabilities, and to form a multi-institutional clinical consortium to readily implement these strategies to help change the course of this deadly disease.
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.
Despite decades of research, breast cancer still represents second most deadly malignancy for women in the United States. Furthermore, current therapeutic options can cause disfigurement and malaise, potentially reducing quality of life. Therapies that lead to durable remission with minimal side effects are urgently needed. We propose that an integrated approach to cancer research that considers both tumor heterogeneity and associated cells in the tumor microenvironment may reveal novel therapeutic approaches. A population of cancer cells, termed cancer stem cells, has been proposed to be resistant to therapies and lead to relapse. Very little work has examined the sensitivity of breast cancer stem cells to different methods of immune-mediated killing or their ability to suppress local immune responses. We first intend to ensure that the breast cancer stem cell population we plan to study is likely to be the chemoresistant population of cells in patients with breast cancer. We will then measure the sensitivity of these cells to different mechanisms of immune-mediated killing along with their ability to protect neighboring cells from attack by immune cells. We will identify how these breast cancer stem cells interact with the immune system in order to identify potential weaknesses that can be targeted clinically to sensitize breast cancer stem cells and their neighboring cancer cells to immunotherapy approaches.
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.
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.
Funded in Collaboration With Stand Up To Cancer (SU2C)
Clinical oncology has entered an era of personalized molecular diagnosis and targeted therapy. This means treatments are tailored to each patient based her tumor’s histopathological and genetic characteristics. Such personalized treatment often involves a combination of multiple active agents to treat one tumor. In estrogen receptor positive (ER+) breast cancers, the three most promising classes of treatments are hormonal therapy, PI3K pathway inhibitors and cell cycle inhibitors.
Although patients derive benefit from such treatment, for most of the advanced ER+ breast cancers, the tumors respond initially but then stop responding, which is called “resistance” to therapy. Unfortunately, this resistance results in death in most cases of advanced breast cancer. Treating these cases requires developing novel therapeutic strategies to overcome the resistance based on an understanding of the mechanisms of resistance.
In this project, we leverage the leading edge technology of high-throughput whole-genome screening to discover mechanisms of resistance to each of three classes of drugs and all of their combinations. We also characterize the identified genes and their function in a variety of breast cancer cell types and mouse models. The knowledge of resistance to treatment obtained through this project will guide our effort to design more effective combinational therapeutics to overcome resistance. Ultimately, this work will be translated to benefit most of the patients with ER+ breast cancers.
