V Scholar Archives - Page 40 of 62

Muhammed Murtaza, M.D., Ph.D.

Rectal cancer affects 40,000 individuals in the US every year. The primary treatment is surgical resection when possible but a growing number of patients receive pre-operative chemo-radiation therapy before surgery to improve outcomes. In up to 30% of these patients, the tissue removed from the rectum after chemo-radiation is found to have no evidence of the original tumor. However, at present, the only accurate way to find out if the tumor responded completely to pre-operative chemo-radiation is to go through with surgery. There are no established biomarkers that can identify patients with complete response before surgery so that they may be potentially saved from a morbid operation. In previous work, we have shown that cancer mutations can be detected in blood plasma from advanced cancer patients. We have also shown that changes in the circulating levels of these mutations correlate with tumor burden. In this project, we are evaluating detection of cancer mutations in plasma from patients with rectal cancer as a potential biomarker. Our goal is to identify patients with rectal cancer whose tumors have completely receded after completing chemo-radiation before they under go surgery. These results will set the stage for prospective follow-up studies to enable biomarker-guided non-operative management of localized rectal cancers.

Nikhil Wagle, M.D.

Abeloff V Scholar*

In spite of tremendous advances in the treatment of estrogen receptor-positive (ER+) breast cancer using therapies directed against the estrogen receptor (ER), patients frequently develop resistance to these therapies. These resistant tumors remain the most common cause of breast cancer death, yet mechanisms by which this resistance develops are poorly understood. Much more work is required to fully understand all of the clinically relevant resistance mechanisms in breast cancer patients treated with ER-directed therapies. Moreover, there is an urgent need to develop new therapies for patients who no longer respond to these therapies. The goal of this project is to improve our understanding of resistant ER+ breast cancer by using cutting-edge genomic technology to directly characterize tumor samples from patients who have developed resistant breast cancer, as well as systematic pre-clinical approaches in breast cancer cell lines. First, we will use next-generation sequencing technology to comprehensively characterize the genomic and molecular alterations from breast tumor samples obtained from 50 patients who have developed resistance to the drug fulvestrant, an FDA-approved therapy that directly targets the estrogen receptor. At the same time, we will conduct a systematic pre-clinical study in breast cancer cell lines to identify genes that might contribute to resistance to fulvestrant. Once completed, this work should help us understand how ER+ breast cancers develop resistance to ER-targeted therapies, as well as identify new targets and therapeutic strategies in resistant breast cancer.

Paul Northcott, Ph.D.

Funded by Vs. Cancer

Brain cancer is the leading cause of cancer-related death in children. Current therapies for medulloblastoma, the most common type of aggressive childhood brain cancer, cure 60-80% of patients from their disease, however, these treatments are non-specific, highly toxic, and impose devastating consequences on the developing child. Novel, rationally designed therapies informed by studying medulloblastoma in the laboratory and identifying the causes of this childhood cancer are desperately needed to improve patient outcome and quality of life for survivors and their families.

Studies outlined in this application aim to gain a better understanding of the genes responsible for a large subset of medulloblastoma patients whom are typically associated with an exceedingly poor clinical outcome. There are currently no effective therapies designed to specifically treat these high-risk patients and as such they are treated with standard protocols that carry with them considerable side-effects, effectively stealing any possibility of a normal ‘life after cancer’ for kids fortunate enough to survive.

Discoveries made using state-of-the-art technologies during my recent Post-Doctoral Fellowship revealed important new insight into the genes involved in these high-risk medulloblastoma patients. The most compelling evidence from my analyses implicated a new gene – KBTBD4 – a gene not previously implicated in childhood brain cancer, nor in any other cancer type. The experiments outlined in this application will directly evaluate the role of this novel, frequently altered gene (most commonly affected gene in high-risk patients) in medulloblastoma and establish its potential as a future target of therapeutic intervention in high-risk patients.

Dan Raz, M.D.

Lung cancer is the most common cause of cancer death in the US and worldwide. Because it has a five-year survival rate of only 18 percent, new therapeutic approaches are urgently needed. We propose to develop novel therapies by targeting the Wnt signaling pathway, which is involved in normal cell growth, but is also implicated in lung cancer development, progression and metastasis. Historically, Wnt signaling has been challenging to target directly, but epigenetic changes that chemically modify DNA or DNA packaging proteins, known as histones, can turn Wnt signaling on or off. In over 80% of lung cancers, the WIF1 protein that normally turns Wnt signaling off, is not produced. We showed that a drug which alters specific modifications to histone 3 restores the production of WIF1, shuts down Wnt expression and induces lung cancer cell death. To advance our observations from bench to bedside, we will 1) determine how specific histone modifications and changes to WIF1 production and Wnt signaling correlate with the disease and its clinical outcomes; 2) analyze the biochemical mechanisms that alter histone modifications to suppress Wnt signaling; and 3) test the effectiveness of two experimental drugs that alter histone modifications to inhibit the tumorigenesis and progression of human lung cancer transplants in mouse models. Successful completion of these studies are expected to unravel important epigenetic pathways that promote Wnt signaling to induce lung cancer, and to identify new drug targets that will suppress Wnt signaling and dramatically improve the outcomes for lung cancer patients.

Michael Walsh, M.D.

Funded by the Dick Vitale Gala

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.

Shizhen (Jane) Zhu, M.D., Ph.D.

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.

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.