Grant Archive - Page 130 of 139

Mohit Jain, M.D., Ph.D.

Funded by the 2014 Wine Celebration in Honor of

David Reynolds and Colleen Buckley

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.

Maximilian Diehn, M.D., Ph.D.

Funded by the Michael and Carole Marks Family

Albert Wyrick V Scholar Award

Kara Bernstein, Ph.D.

2014 V Foundation Wine Celebration

Volunteer Grant in Honor of John and Lily Kogan

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.

Omar Abdel-Wahab, M.D.

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.

Michael J. Emanuele, Ph.D.

Angela Fleischman, M.D., Ph.D.

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.

Weizhou Zhang, Ph.D.

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.

Ash A. Alizadeh, M.D., Ph.D.

Abeloff V Scholar*

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.

Chad V. Pecot, M.D.

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.