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.
Myeloproliferative neoplasm (MPN) is a chronic leukemia characterized with no curative treatments other than bone marrow transplantation. MPN results from the acquisition of a mutation in a blood stem cell that drives the unrestrained production of myeloid blood cells. Mutations in the gene calreticulin have been recently identified in a large proportion of MPN patients, it is currently unknown how calreticulin mutations drive MPN. Our goal is to identify the mechanism by which calreticulin mutations cause the manifestations of MPN and to develop drugs targeting calreticulin to treat this disease.
Obesity, defined by body-mass index over 30.0, influences more than 30% of American adults and is associated with increased incidence and/or bad prognosis of various cancers including esophagus, pancreas, colon and rectum, breast, and endometrium etc. Obesity contributes directly to the 34,000 new cancer cases in men (4% of all cancer) and 50,500 in women (7% of all cancer) in 2007, based on the NCI Surveillance, Epidemiology, and End Results (SEER) data. In addition, obesity increases the risk for many different types of cancer including breast cancer and decreases patient survival and is associated with bad outcome. Obesity always correlates with increased basal level inflammation. It is unknown, however, if obesity-associated inflammation promotes cancer progression and what is the molecular sensor for obese tumor microenvironment. Here we found that sterile inflammation–a type of inflammation without clear infections and activated by danger signals released by tissue damage–in the obese tumor microenvironment, led to Nlrc4-inflammasome activation. We found that interleukin-1beta is the major downstream mediator for Nlrc4-inflammasome activation that provides a pro-inflammatory signal to be required for tumor growth in obese mice, but not in normal-weight ones, by promoting angiogenesis in obese tumors. Our goals are to understand how obesity contributes to cancer progression, and to develop treatments to obese cancer patients.
The proposed study has ground-breaking impacts on basic cancer biology and cancer therapy to obese cancer patients. For cancer biology, we identified the molecular sensor in obese tumor microenvironment and aim to detect ‘danger signal’ from obese tumors, which, in turn, promotes cancer progression via activation of interleukin-1beta. For cancer therapy, given that ~30% Americans are obese and many cancer types are influenced by obesity, our study will have big impact on cancer patients. Anakinra is a known decoy receptor to inhibit interleukin-1 receptor-mediated signaling and has been improved drug to treat rheumatic arthritis. Caspase-1 (the major enzyme for inflammasome-mediated interleukin-1beta activation) inhibitors have been in several clinical trials. In addition, we found that metformin reduces obesity-associated tumor growth. These drugs can be easily and quickly adapted for treating obese cancer patients, together with current standard care for cancer patients.
Early detection of cancer represents a critically important goal in the improvement of survival outcome in common cancers. However, existing tests have shortcomings in sensitivity and accuracy, and false positive results often lead to additional expensive tests, risks inducing anxiety in patients and their families, and even potential harm if complications result from follow-up studies. To address these shortcomings, our proposal will develop a cutting-edge, highly-sensitive genome-wide approach for cancer screening and monitoring of tumor-derived DNA in easily-accessible body fluids. We will focus on developing this minimally-invasive “liquid biopsy” approach on non-small cell lung cancer (NSCLC), the leading cause of cancer death globally, and on Diffuse Large B-cell Lymphoma (DLBCL), the most common type of blood cancer. Once developed, we will apply this approach in populations at risk for NSCLC and lymphomas to validate early detection of these tumors. We thus anticipate that we can devise a sensitive method for early disease detection and monitoring that will be broadly applicable to many other cancers.
Cancer is a leading cause of death in the U.S. and the world, largely due to our inability to block the spread of disease (termed metastases). However, over the past several years the roles of recently discovered genes, called microRNAs, have been shown to play vital roles in controlling cancer growth and metastases. One group of these microRNAs, called the miR-200 family, has shown particular promise by blocking many critical functions known to drive cancer. Recently, we discovered that the miR-200 family could block the formation of new blood vessels inside tumors, which resulted in decreased metastases. Our proposal focuses on understanding how miR-200 blocks formation of blood vessels in cancer, and further explores the use of miR-200 delivery as a new therapeutic option to treat cancer.
Funded by the Dick Vitale Gala in Memory of Eddie Livingston
Interaction of immune system with tumor is a complex and dynamic process, which dictates tumour initiation, progression and responses to therapy. Mounting evidence indicates that strengthening the amplitude and quality of T cell-mediated adaptive response is one of the most promising approaches to enhance therapeutic anti-tumor immunity. Functional and effective immune response requires a metabolic rewiring of immune cells to meet their energetic and anabolic demands. As such, tumor microenvironment represents a dramatic example of metabolic derangement, where the highly metabolic demanding tumor cells may compromise the function of some immune cells by competing nutrients (a form of intercellular competition), meanwhile may support the function of other immune cells by forming a metabolic symbiosis (a form of intercellular collaboration). Here, we propose to decipher the metabolic communications between tumor cells and immune system and understand how such communications impact on anti-tumor immunity.
Each year, in the U.S. alone, over 50,000 people are diagnosed with myeloid cancers of the blood. Some myeloid cancers have been found to lose all or a portion of chromosome 7 [-7/del(7q)], and these cases are particularly difficult to treat. The overall survival for these patients is less than one year. -7/del(7q) also occurs in half of therapy-related myeloid neoplasms/cancers (t-MN). t-MN arise as a side effect of chemotherapy/radiation and occur in u to 8% of cancer survivors. There is clearly an urgent need to develop better therapies for -7/del(7q) disease. It has long been thought that one or more genes on chromosome 7 prevents cancer growth – “tumor suppressor genes.” I used genomic technologies and animal models to map this tumor suppressor gene, implicating CUX1. The long-term goal of the current proposal is to improve the outcome for patients with this type of disease. This proposal is designed to accomplish this by identifying CUX1-regulated pathways that may be potential drug targets as well as establish animal models for future use in preclinical therapy development. The contribution of the proposed research is expected to bhe characterization of the biological outcomes and altered pathways caused by CUX1 loss–the first step toward developing therapies. The significance of this work is not limited to leukemia; CUX1 is mutated in endrometial cancer, gastric cancer, and melanoma, among other tumors. Thus, the understanding of CUX1 function in myeloid disease may guide our knowledge of the role of CUX1 in other cancers.
Human-associated bacterial communities (e.g., the “microbiome”) are an integral part of the healthy human body, yet pathogenic shifts leading to increased and/or decreased diversity in the healthy-state microbiome composition are linked to disease development. We hypothesize that prostate infections that result from pathogenic shifts in the urinary tract microbiome contribute to prostate cancer development. As such, we aim to investigate associations between altered urogenital microbiome signatures and the presence of prostate cancer and/or high grade disease. Furthermore, we aim to correlate urinary tract microbiome signatures to prostatic inflammation in prostate cancer patients, as we hypothesize that microorganisms that may contribute to prostate cancer etiology do so via the induction of chronic inflammation in the prostate. These studies can be coupled to ongoing studies in our laboratory aimed at the identification of microbial signatures in prostate cancer tissues, and ongoing efforts to identify causal microorganisms in prostate cancer etiology. The proposed research project will represent an essential initial study linking urinary tract microbiome to genitourinary disease. Whereas the project is primarily focused on prostate cancer, this work may lay the important groundwork for additional studies linking urinary tract microbiome to other genitourinary malignancies such as kidney, urothelial, or bladder cancer.
A set of proteins are highly active in cancer. They can add small groups to a series of target proteins. These uncommon additions are often linked with tumors found in breast, liver, and other tissues. To date, it is still unclear how those aberrant proteins cause cancer. To answer this question, it is crucial to know all the targets that they act on in live cancer cells. But no method has been made available to resolve this key issue. In this project we are aimed to create an innovative platform to achieve this goal. Our research plan will use chemistry and biotechnology to make new tools for target identification. A particular member in this group will be chosen for this work. Because it shows much higher activities in diverse types of cancer. The full range of targets for this protein in live cancer cells will be clearly assigned for each specific type of cells. Moreover, the patterns, levels, and time courses of such additions in live cells can be directly viewed and precisely measured by our creative approach. These findings will lead to unveil the interaction networks of this cancerous protein to guide our further studies. The fundamental knowledge obtained from this work will advance our understanding of cancer. Importantly, it will foster the development of new approaches for cancer detection and treatment.
Prostate cancer is the second most frequently diagnosed cancer worldwide. In the US, more than 230,000 cases are diagnosed yearly, affecting 1 in 7 men. If detected early, the cure rate for these cancers is high – nearly all patients will be disease-free after five years. However, in patients whose cancers either re-appear after treatment or spread to other organs, therapies are limited mainly to symptomatic relief. Patients diagnosed at this stage usually live no longer than 20 months. Therefore, a major challenge in treating advanced prostate cancer is that the standard therapies, including radiation and medicine, are not effective in killing these cancer cells.
A small proportion of tumor cells, known as cancer stem cells (CSCs), is particularly important in promoting cancer, because they 1) can give rise to an entire tumor from a single cell, and 2) are more resistant to treatment than other tumor cells. Efforts to identify and then kill CSCs hold the key to effective prostate cancer treatment. The goal of our work is to define the molecular mechanisms that drive growth of prostate cancer CSCs. Once identified, those factors could serve as “biomarkers” or diagnostics. In addition, drugs could be designed to target those factors as a way of blocking tumor growth.
