V Scholar Archives - Page 38 of 59

Branden Moriarity, Ph.D.

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.

Richard Possemato, Ph.D.

Funded by Hooters of America, LLC

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.

Andrea Schietinger, Ph.D.

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.

Miguel Rivera, M.D.

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.

Akinyemi Ojesina, M.D., Ph.D.

Funded by The Stuart Scott Memorial

Cancer Research Fund

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.

Grant Challen, Ph.D.

Hematopoietic stem cells (HSCs) are responsible for the lifelong regeneration of the blood and bone marrow. During the lifetime of an individual, genetic mutations can occur in HSCs that slightly alter their properties, potentially leading to diseases of excessive or deficient production of blood cells. When myeloid cells are chronically affected, these conditions fall into two main categories called myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS). These disorders are the most common blood cancers in adults with ~20,000 new cases diagnosed each year in the United States. While these diseases themselves present significant problems such as excessive bleeding and more susceptibility to infections, in a significant number of these patients the disease transforms to a leukemia that is much more difficult to treat and rapidly proves fatal (typically about five months). It is important to identify the genetic processes associated with progression of MDS and MPN to leukemia to improve treatment of these patients. I believe we have identified a new pathway that facilitates this process by identifying a gene that is genetically mutated specifically in the leukemia phase of the disease, but not the preceding MPN phase. The goals of this work are to develop new models to understand these processes, and to identify factors to improve the treatment outcomes of such patients. As there are no effective therapies for these patients that progress to leukemia, any findings that improve the diagnosis and treatment of these patients would represent a significant advance in this field.

Rebecca Chin, Ph.D.

Albert Wyrick V Scholar

Triple negative breast cancer (TNBC) is aggressive and has a poor prognosis. Currently, chemotherapy is the only treatment option. Therefore there is unmet need to identify novel therapeutic targets for TNBC. Acquired resistance to targeted therapy, a newer treatment type with drugs targeting specific molecules necessary for tumor growth, poses another major clinical problem. We have recently identified a major mechanism that TNBC cells utilize to promote tumor growth. This proposal aims at deciphering this mechanism in cancer growth and drug resistance, as well as discovering novel therapeutic targets for TNBC.

Akt1, Akt2 and Akt3 are a “family” of proteins with both overlapping and unique functions. Akt plays critical roles in tumor growth, and a number of drugs targeting Akt are being tested in clinical trials. Our recent findings indicate that Akt3 has an increased expression in ~30% of TNBC. Importantly, Akt3, but not Akt1/2, is critical for regulating TNBC growth. Moreover, Akt3 is implicated in drug resistance to Akt inhibitors. We propose that Akt3 regulates tumor growth and resistance by activating specific downstream targets and upregulating receptors on cell surface. To identify novel Akt3 targets, we will use a discovery-based proteomics approach. For drug resistance study, we will analyze Akt3 signaling in tumor samples, and test if certain receptor inhibitors effectively eliminate resistant cells. In the short term, our results will provide rational combination treatment strategy to combat drug resistant breast tumors. In the long term, we anticipate developing effective therapeutics targeting Akt3 or its substrates to treat TNBC.

Felix Feng, M.D.

Prostate cancer is the second leading cause of cancer-related death in American men, resulting in 29,480 fatalities last year. Death from prostate cancer most frequently occurs following the development of resistance to first- or second-line androgen deprivation therapy (ADT). As such, there is a critical need to discover early drivers of ADT resistance to help guide selection of patients for earlier intensification of therapy.

The majority of cancer biomarker research has focused, to date, on protein-coding genes, which are pieces of DNA that are converted to RNA and then converted to protein. Our team instead focuses on investigating long noncoding RNAs (lncRNAs), which are pieces of DNA that are converted to RNA but are not further converted to protein. These lncRNAs, which function as RNAs instead of proteins, represent an underexplored, but crucial, area of cancer biology. Our team recently identified over 45,000 novel lncRNAs, and determined that several lncRNAs, including one named SChLAP1, were better indicators of disease progression than conventional protein-coding genes.

Based on our initial findings, we hypothesize that lncRNAs serve as important mediators of treatment resistance in prostate cancer. The goals of this application are: 1) to investigate the mechanism by which our top candidate lncRNA, SChLAP1, promotes ADT resistance and 2) to determine if SChLAP1 and other lncRNAs can serve as predictive biomarkers to guide therapy selection in patients with aggressive prostate cancer, using tumor samples from a phase III clinical trial.

Anthony Letai, M.D., Ph.D.

Every cancer is unique pointing to the need for personalized medicine. In oncology, a fundamental challenge is to assign the right treatment to every patient due to cancers’ biological complexity and the lack of effective predictive biomarkers. At the Letai lab we developed a functional predictive assay called Dynamic BH3 Profiling to rapidly test different treatments prior to giving them to the patient. It has already been successfully proved as an excellent predictor in different types of cancer, including melanoma. We aim to combine sophisticated genomic analyses with this novel test to improve melanoma treatment, improving patients’ clinical outcome, clinical trials and drug development.