Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a recently identified hereditary form of kidney cancer linked to germline mutations of the FH gene which encodes the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase. HLRCC kidney cancers are remarkable for their biologic aggressiveness. Unfortunately, effective systemic therapies are lacking for patients with advanced kidney cancer. Affected individuals are also at risk for leiomyomas of the skin and uterus. In addition, intervention for women affected by HLRCC fibroids often requires surgical intervention at an early age. Interestingly, FH mutations have also been identified in a subset of sporadic uterine leiomyomas. HLRCC tumor formation may result from the biochemical consequences of loss of FH activity. In particular, aberrant stabilization of the transcription factor hypoxia inducible factor (HIF), a phenomenon referred to as pseudohypoxia, may result in tumor formation via upregulation of potentially carcinogenic genes. Pseudohypoxia has also been implicated in the pathogenesis of several other tumors including the most common variant of kidney cancer. Preliminary data from our laboratory indicates that loss of FH activity is associated with heightened cellular levels of reactive oxygen species (ROS). As such, we hypothesize that ROS drives pseudohypoxia in HLRCC. In order to test this hypothesis, a five-year mentored research plan is outlined under the guidance of experts in cancer biology and renal redox physiology. This plan will enable the candidate to become an independent physician-scientist whose goal is to further understanding of renal cell carcinoma through the study of inherited forms of kidney cancer. The long term objective will be to translate these findings into effective clinical therapeutics. First, the basic mechanisms by which loss of FH leads to elevated cellular ROS will be determined. Secondly, the contribution of reactive oxygen species to pseudohypoxia in FH null tumors will be assessed by examining the effects of ROS on post-translational modifications of HIF-11 in this system. Third, the biologic significance of our findings will be determined in an orthotopic tumor model of HLRCC. These studies will be achieved through a combination of gene replacement and gene knockdown cellular models of HLRCC. Overall, this proposal will utilize HLRCC as model system to identify new therapeutic strategies for patients with cancers that may be driven by ROS-mediated HIF stabilization.

Public Health Relevance

Kidney cancer is an increasingly common malignancy in the United States. This proposal aims to utilize a hereditary form of kidney cancer, referred to as Hereditary Leiomyomatosis and Renal Cell Cancer, to provide insight into more common variants of kidney cancer in the general population. Elucidation of the molecular pathways of this particular variant may help develop novel therapeutic strategies for individuals with cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
7K08CA138774-04
Application #
8319559
Study Section
Subcommittee G - Education (NCI)
Program Officer
Perkins, Susan N
Project Start
2009-09-28
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$172,800
Indirect Cost
$12,800
Name
University of Alabama Birmingham
Department
Surgery
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Shim, Eun-Hee; Livi, Carolina B; Rakheja, Dinesh et al. (2014) L-2-Hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer. Cancer Discov 4:1290-8
Shanmugasundaram, Karthigayan; Nayak, Bijaya; Shim, Eun-Hee et al. (2014) The oncometabolite fumarate promotes pseudohypoxia through noncanonical activation of NF-?B signaling. J Biol Chem 289:24691-9
Sudarshan, Sunil; Karam, Jose A; Brugarolas, James et al. (2013) Metabolism of kidney cancer: from the lab to clinical practice. Eur Urol 63:244-51
Nayak, B K; Feliers, D; Sudarshan, S et al. (2013) Stabilization of HIF-2* through redox regulation of mTORC2 activation and initiation of mRNA translation. Oncogene 32:3147-55
Shanmugasundaram, K; Block, K; Nayak, B K et al. (2013) PI3K regulation of the SKP-2/p27 axis through mTORC2. Oncogene 32:2027-36
Fitzgerald, John P; Nayak, Bijaya; Shanmugasundaram, Karthigayan et al. (2012) Nox4 mediates renal cell carcinoma cell invasion through hypoxia-induced interleukin 6- and 8- production. PLoS One 7:e30712
Sudarshan, Sunil; Shanmugasundaram, Karthigayan; Naylor, Susan L et al. (2011) Reduced expression of fumarate hydratase in clear cell renal cancer mediates HIF-2? accumulation and promotes migration and invasion. PLoS One 6:e21037