The CALM-AF10 chromosomal abnormality is seen in aggressive pediatric and adult acute leukemias that have a poor prognosis. Our lab has discovered that CALM-AF10 interacts with CRM1, a protein that helps transport other proteins from the nucleus to the cytoplasm. This interaction is required to activate HOXA genes, which play a critical role in both CALM-AF10 and other leukemias. This discovery suggests that CRM1 may be important in other leukemias as well, as is significant because a new class of drugs that inhibit interaction with CRM1 (SINEs-Selective Inhibitors of Nuclear Export) has recently been developed. These drugs are effective in a number of human tumor types, and are currently in clinical trials for adult leukemias. Our studies indicate that SINEs may block cancer cells through an unappreciated and novel mechanism-inhibiting CRM1 involvement in activating HOXA genes. In this proposal, we will examine the molecular mechanisms by which CRM1 activates HOXA genes. We will then identify additional CRM1 target genes that are involved in causing leukemias. Studying this previously unrecognized role for CRM1 will enhance our understanding of how SINEs work, and provide preclinical support for their use in pediatric leukemia clinical trials. Since HOXA genes are involved in many hematopoietic malignancies (including MLL-fusion leukemias that are seen in 80% of infant leukemias), these studies may have broad implications for leukemogenesis.
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.
Neuroblastoma is the most common extracranial solid tumor of childhood. Amplification of the MYCN proto-oncogene occurs commonly in high-risk neuroblastoma and marks a particularly aggressive and lethal form of the disease. We and others have described an array of highly targeted inhibitors to block kinases both upstream and downstream of MYCN in neuroblastoma. Among these targeted inhibitors, we have recently described a novel conformation disrupting inhibitor of Aurora Kinase A which potently induces MYCN degradation through an allosteric change in Aurora Kinase A. Because these inhibitors target distinct members of the MYCN pathway, we hypothesize that they will have nonoverlapping toxicities and that combinations of MYCN targeted therapies will more potently block MYCN. In Aim 1 of this proposal we will rigorously test combinations of MYCN targeted therapies for pre-clinical efficacy with the goal of rapidly translating combinations into patients with neuroblastoma. In Aim 2 of this proposal we will develop our novel conformation disrupting Aurora Kinase inhibitor to “dial out” toxic Aurora Kinase A activity and finesse more potent MYCN degradation in neuroblastoma to optimize therapeutic efficacy. Successful completion of this proposal will result in direct and rapid translation of therapeutic combinations of MYCN targeted therapies into children with neuroblastoma and provide new clinical grade drug candidates for conformation disrupting Aurora Kinase A inhibitors.
Pancreatic cancer is a lethal disease. 95% of patients die within 5 years of diagnosis, despite our best current treatments including surgery, chemotherapy, and radiation. By 2020, pancreatic cancer is projected to become the second leading cause of cancer death in the United States. Novel strategies to combat this deadly disease are urgently needed.
T-cells are highly specialized cells of the immune system designed to protect the human body from infections and cancer. In the past decade, we have discovered that T-cells recognize proteins that only cancers make, identifying cancers as foreign, triggering T-cells to kill cancers. Cancers however are equipped with strategies to escape T-cells. Our group has recently identified a drug paricalcitol that eliminates barriers that tumors have developed to block T-cell attack. Our preliminary findings demonstrate that this drug increases T-cell numbers within tumors by greater than 10 fold. These results are promising as it allows us to further boost T-cells with other drugs, and increase the ability of T-cells to kill tumors.
Our proposed research will delve deep into understanding the specific proteins on tumors that T-cell recognize, the specifics of how tumors create barriers to block T-cells, and combining paricalcitol with other drugs that boost T-cells in a clinical trial. Our proposals allow us to gain a deeper understanding of the biology of T-cells in pancreatic tumors so that we may develop better treatments to improve outcomes in patients.
Triple Negative Breast Cancer (TNBC) accounts for 15-25% of breast cancers. TNBC is well known for its aggressive clinical behavior and early peak of recurrence. Due to the lack of good therapeutic targets, TNBC represents the specific subtype of breast cancer with worst prognosis. Therefore, there remains the urgent question to be addressed: Can we identity important biological features that serve as high value targets for the development of novel treatment modalities for TNBC? This line of research carries significant social and economic importance. Hypoxia is a characteristic of solid tumor, which contributes to radiation and chemotherapy resistance. One important feature of tumor cells is that they sense the oxygen tension and rewire their signaling pathway to survive under harsh living conditions. EglN2 prolyl hydroxylase serves as an important oxygen sensor. In this proposal, we presented some preliminary data in the TNBC cell lines that getting rid of EglN2 could decrease TNBC tumor growth and invasion. We propose to obtain primary tumors from TNBC patients, implant them into mice and treat them with siRNA nanoparticles that deplete EglN2, which will be used to test the efficacy of targeting EglN2 in a patient relevant system. In addition, we will study mechanistically how EglN2 protein stability is regulated by FBW7 E3 ligase complex. Furthermore, we will implement a novel screening for EglN2 specific inhibitors, which will motivate testing the effect of these potential inhibitors on TNBC tumorigenesis. Successful completion of proposed research will open new therapeutic avenues in treating TNBC.
One of the most exciting frontiers in cancer treatment is the field of immunotherapy where beneficial effects have been observed in a broad range of cancers. The major goal of our project is to identify the determinants of immunotherapy success in patients with head and neck cancers. We are performing a novel clinical trial with an immunotherapy-targeted agent that allows the patient’s own immune system to control their cancer. Using samples from this trial, our goal is to understand why some patients do or do not respond to immunotherapy. We have assembled a multi-disciplinary team that will use genetic and immunologic tests on patient samples to clarify which patients may actually benefit from this powerful approach. These data will allow us to define a precision approach to immunotherapy and in addition will provide an improved biologic understanding of the mechanism of immunotherapeutic modalities.
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