Designed to identify, retain and further the careers of talented young investigators. Provides funds directly to scientists developing their own independent laboratory research projects. These grants enable talented young scientists to establish their laboratories and gain a competitive edge necessary to earn additional funding from other sources. The V Scholars determine how to best use the funds in their research projects. The grants are $200,000, two-year commitments.
Bone marrow transplantation is commonly used to replace bone marrow stem cells after chemotherapy. However, a return to normal blood production by these stem cells can take several months after transplantation leaving patients vulnerable to infection. We have previously identified a molecular switch that controls life and death decisions in blood stem cells, and we are now seeking to block the death of blood stem cells following transplantation to accelerate the return of normal blood production. This research will also improve our understanding of how leukemia cells evade cell death.
Cancers are a diverse collection of diseases that are caused by distinct gene mutations. Effective cancer treatment has to be tailored for these patient-specific aberrations. To this end, the cancer genome project has systematically identified mutations in various cancer types and provided a foundation for personalized cancer medicine. However, the cancer genome can be littered with mutations simply due to the fact that cancer cells are highly unstable. Therefore, it is critical to understand which mutations play a causal role in driving cancer progression, i.e. acting as drivers, and which mutations are merely bystanders.
To address this question, we have developed a novel technology for generating personalized breast cancer models that contain mutations found in human patients. Using these models, we will decipher which mutations are functional important, and thus can be useful therapeutic targets. Our work is like to identify novel breast cancer genes and provide new therapeutic targets and biomarkers for selecting most effective treatment.
Successful outcomes of our study will pave the way for developing therapeutic agents for targeting these new breast cancer genes. In addition, the technology perfected through this study will be highly valuable for investigating mutations of other cancer types to identify a catalog of cancer targets that can be tailored for personalized medicine.
Kidney cancer is the 8th most common cancer in the USA, representing 3% of new cancer cases each year and 4% of cancer deaths. Renal cell carcinoma (RCC) is the most common and lethal type of kidney cancer in adults, representing 90-95% of all kidney cancer cases. Approximately 90% of RCCs have mutations in the tumor suppressor gene, von Hippel-Landau (VHL), which is involved in the degradation of hypoxia-inducible factor (HIF) transcription factors. The mutation of VHL leads to huge increases in the levels of HIF, which promotes tumor growth by increasing the blood supply to tumors. Uncovering this pathway of tumor suppression has led to several targeted therapeutics that lower levels of HIF, and are currently used in the clinic. While this has improved the outcome for RCC, the median survival rate for metastatic renal carcinoma patients is still only 22 months. Uncovering additional mechanisms of tumor suppression and new therapeutic targets would bring us closer to our goal of eradicating these cancers. To this end, efforts to identify additional genes mutated in RCC have identified Polybromo-1 (PBRM1) as the second most commonly mutated gene in RCCs (~50%). PBRM1 is part of the SWI/SNF (BAF) chromatin remodeling complex, an important regulator of gene expression. While subunits of the BAF complex are mutated in a spectrum of cancers, mutations in PBRM1 seem to be fairly specific to RCC. We aim to understand the mechanism of tumor suppression by PBRM1 in RCC by 1) uncovering how PBRM1 deletion affects the function of the BAF chromatin remodeling complex, 2) identifying genes regulated by PBRM1 deletion, and 3) identifying pathways important in RCC progression that we can target with novel or known therapeutics.
Cancer arises when mutations to our DNA alter the genetic information and change the way our cells normally function. DNA in our body witnesses thousands of lesions on a daily basis. Among these lesions are breaks that occur on both strands of a chromosome, known as double stranded breaks (DSBs), which are highly toxic. In fact, cells in our body have evolved special ways to ensure that when DSBs occur, they are repaired faithfully and promptly to avoid errors in the coding sequence. There are three pathways to repair a DSB in mammalian cells. The preferred pathway is homology-directed repair (HDR) that fixes DNA breaks without altering the original sequence and is hence error-free. DSBs can also be repaired by two additional pathways that are error-prone – the classical Non-Homologous End-Joining (NHEJ) and the alternative NHEJ (alt-NHEJ) pathways. The activity of HDR pathway is absent in many breast cancer cells, and evidence suggests its replacement by the highly mutagenic alt-NHEJ pathway. Hence, the main focus of our proposal is to study the poorly characterized alt-NHEJ pathway of repair and establish its role in breast cancer progression. Using high throughput technology, we plan to uncover novel genes in this pathway and characterize the mechanism by which this repair pathway operates. Ultimately, we will assess the de-regulation of its key components in inherited and sporadic breast cancers. This will provide key steps towards revealing specific targets that can guide more favorable and effective breast cancer treatment strategies.
The adult mammalian intestine is a rapidly renewing organ that is maintained by stem cells. In order to function properly, these intestinal stem cells often require signals from their cellular neighborhood or “niche”, which consists of Paneth cells. Intestinal cancers often arise from stem cells, yet it is unclear what role the stem cell niche plays in tumor initiation. I will investigate the molecular mechanism of the intestinal stem cell and niche interaction in response to lifespan extending interventions such as calorie restriction, and its relevance to intestinal tumor development.
During the process of cancer transformation, cells hijack their internal metabolic pathways in order to utilize nutrients for the purpose of providing energy and building blocks required for rapid growth. In this V Foundation Award, we propose to use mass spectrometry to provide unprecedented insight into the activities of hundreds of metabolic enzymes in living cells as they become cancerous. We will use this information to identify unique metabolic vulnerabilities in cancer cells, essentially determining those metabolic processes that are required to sustain life and growth in cancer cells but not normal, non-cancerous cells. Ultimately, the work will allow us to design new dietary interventions and pharmacologic agents that selectively target the metabolism of cancer cells, including in breast cancer and colon cancer.
Changes in the DNA, known as mutations, can arise during cancer and in some cases can also be a cause of cancer. For example, the RAD51 paralogues are proteins that are important for fixing broken DNA. Importantly, individuals with mutations in the RAD51 paralogues are more susceptible to getting cancer, particularly breast and ovarian cancers. The goal of our study is to understand why people who have mutations in the RAD51 paralogues are more likely to get cancer, and if we can, identify novel methods for treating their specific cancers. Our goal is to uncover individualized cancer treatment for these particular tumors so that these patients will have the best outcomes.
Over the last 10 years, great progress has been made in identifying the genetic alterations present in the blood systems of patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). One of the most important and unexpected findings from these studies has been the identification of mutations in genes which perform RNA splicing. Mutations in these genes are the single most frequent category of mutations seen in MDS patients but are currently not well understood. Under normal conditions, RNA splicing is responsible for ‘processing’ RNA so that the genetic code can be effectively translated to produce normal proteins. It has been postulated that mutations in this pathway impair RNA splicing. However, how precisely these mutations dysregulate splicing and how this actually results in the development of leukemia is unknown. More importantly, how this genetic knowledge can be translated to yield novel drug targets in leukemia has yet to be investigated. The protein SRSF2 is particularly important, since it is associated with the most clinically dangerous forms of MDS and AML. We have recently generated a number of mouse and human cell leukemia models with and without mutations in SRSF2. We now propose to utilize these models to understand how mutations in SRSF2 cause leukemia and how we can treat the leukemia caused by these mutations.
