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.
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.
V Scholar Plus Award- extended funding for exceptional V Scholars
Each year over 50,000 people develop a myeloid blood cancer in the United States alone. Some of these cancers have lost all or a portion of genetic material on chromosome 7 [known as -7/del(7q)]. These patients are difficult to treat. The survival for these patients is less then one year. -7/del(7q) also occurs in half of therapy-related myeloid cancers (t-MN), which arise as a side effect of cancer treatment. There is clearly an urgent need to develop new therapies for this disease. The long-term goal of the current work is to improve the outcome for patients with myeloid blood cancer. I used new technology to identify an important gene on chromosome 7, called CUX1. CUX1 normally puts the brakes on cell growth. My lab is identifying CUX1-regulated pathways that may be drug targets. We are establishing animal models of myeloid cancers for testing new therapies. The significance of this work is not limited to blood cancer. A wide range of tumor types also has CUX1 deletion. Thus, our work on CUX1 will guide our knowledge of the role of CUX1 in cancer in general.
Funded by the Stuart Scott Memorial Cancer Research Fund
PSA is a blood test used to check men for harmful prostate cancer (PCa). A man with high levels
of PSA may have harmful PCa, but if we catch it early, it is almost 100% curable. Men with high
PSA may also have harmless PCa or they may not have cancer at all. To diagnose harmful PCa,
doctors take biopsies of the prostate using painful needles. Fortunately, most of the men end up
having large prostates or harmless forms of PCa. This causes many men to suffer through the
biopsy and then worry about potentially having a harmful cancer. Some men with harmless PCa
will have surgery or radiation from fear, but can have bad side effects.
Prostate Health Index (PHI) is an improved version of PSA that better predicts which men have
harmful, PCa. Doctors use PHI to help men avoid prostate biopsies. Unfortunately, PHI was
never tested for accuracy in African American men (AAM). AAM have the highest chance of
dying from harmful PCa. We need to prove that the test works in AAM like it does in White
men. We will compare how well the test works for predicting harmful PCa in 300 African
American men in comparison to 100 White men that are having a prostate biopsy. If PHI works,
we will be able to detect harmful PCa earlier for African American men. This test will reduce
their chances of dying from the disease.
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