The advent of molecular biology and molecular profiling in clinical medicine has transformed our understanding of childhood leukemia. As a result, we are now empowered to shift away from the classification of hematologic malignancy based on microscopic appearance towards a new paradigm of diagnosis and treatment focused on specific molecular mechanisms of pathogenesis, or alterations detected in both leukemia cells and cells representing an individual’s heritable constitution. The heritable, constitutional or germ-line contribution to the development of childhood leukemia is a phenomenon increasingly recognized in childhood cancer. Studies to date have revealed the constitutional basis for cancers in subtypes of leukemia, however there is a clear missing heritability fraction given a high frequency of families without an identifiable genetic etiology. Given a lack of awareness and an incomplete germline evaluation, pediatric oncologists are unable to take avail of complete information pertaining to a child’s predisposition to developing leukemia when planning therapeutics and guiding. Knowledge of germ line alterations may direct patient care, and enable genetic counseling for patients and their families. My research focuses on identifying the heritable underpinnings of childhood leukemia.
Funded by the Dick Vitale Gala in honor of Leah Still
Neuroblastoma, an embryonal tumor that arises in the peripheral sympathetic nervous system (PSNS), accounts for ~10% of cancer-related deaths in childhood. About half of all patients, especially those over 18 months of age with amplified copies of the MYCN oncogene, present with evidence of widespread metastasis at diagnosis and have a very high risk of treatment failure and death despite receiving greatly intensified chemotherapy. Attempts to improve the treatment of metastatic neuroblastoma have been slowed by the lack of a full understanding of the multistep cellular and molecular pathogenesis of this complex tumor. Recently, I developed the first zebrafish model of neuroblastoma metastasis by overexpressing two oncogenes, human MYCN, which is amplified in 20% of neuroblastoma cases, and mutationally activated SHP2, which is the second most frequently mutated gene in high-risk neuroblastoma. This transgenic model affords unique opportunities to study the molecular basis of neuroblastoma metastasis in vivo, and to identify novel genes and pathways that cooperate with MYCN and activated SHP2 to promote this usually fatal stage of disease development. This research approach is expected to reveal novel molecular targets that can be exploited therapeutically. To achieve this goal, I propose to establish reliable in vivo zebrafish models of the aberrant genes and pathways that contribute to neuroblastoma metastasis. In the near future, these models will be used to screen for effective small molecule inhibitors that block specific steps in metastasis with only minimal toxicity to normal tissues, and thus would be assigned high priority as candidate therapeutic agents.
Funded by the Dick Vitale Gala in memory of Dillon Simmons
Cancer is a disease genetic in origin and a major cancer causing gene is MYC. Many human cancers, including pediatric sarcomas such as osteosarcoma, rhabdomyosarcoma, Ewing’s, and synovial sarcoma, are driven by MYC. It has been argued a major leap towards finding a cure for these cancers will be the development of therapies that target MYC. Unfortunately, MYC has been notoriously challenging to target therapeutically. We have recently found a new regulator of MYC called PVT1. We demonstrated PVT1 helps sustain MYC at elevated levels in adult cancer cells, and when PVT1 is removed MYC returns to levels seen in non-cancer cells. This reduction in MYC drastically reduces the cancerous potential of these cells. Thus, the purpose of this work is to investigate this phenomenon in pediatric sarcomas. We have preliminary demonstrating this interaction indeed occurs in pediatric osteosarcoma cancer cells and removing PVT1 leads to reduced MYC levels; which we previously demonstrated leads to diminishes growth and viability of cancer cells. Accordingly, this work will investigate if this phenomenon occurs in many pediatric sarcomas and develop a therapeutic approach to inhibit PVT1 in pediatric cancer patient tumors, leading to loss of MYC and regression of tumors. This would be a breakthrough for the treatment of pediatric sarcoma as this disease has seen little to no advances in targeted therapy over the last several decades. If an effective therapeutic is developed, a clinical trial using this therapeutic approach will be carried out in pediatric sarcoma patients in the future.
Cells within a tumor must acquire nutrients from their environment and convert these nutrients into the cellular components necessary to support continued growth. This set of processes is broadly referred to as tumor metabolism. We are interested in understanding how tumor metabolism is distinct from the metabolism of normal tissues with the hope of identifying those genes or pathways upon which cancer cells are particularly dependent for survival. Recently, we have become fascinated by how tumors utilize one key metabolite, the amino acid serine. We found that the production of serine is activated in several cancer types, including breast cancer of the basal type, a particularly difficult to treat form of breast cancer. Cancer cells use this serine for various purposes, including the production of DNA. In this proposal we will evaluate the anti-cancer effect of inhibiting utilization of serine in a mouse model of basal breast cancer that recapitulates many aspects of the human disease. Furthermore, we will use a novel technology permitting editing of the cancer genome to determine whether perturbing serine utilization uncovers additional dependencies which can be the target of future anti-cancer therapies.
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.
