The incidence of renal cell carcinoma (RCC) in United States has been projected to reach 56,000 cases/year in 2007 and has been rising since 1970 for both men and women and for whites as well as blacks. Improved survival rates are associated with early detection of RCC. Currently, about 30% of kidney cancer patients present with metastatic disease at the time of diagnosis and the 5-year survival rate for these patients is approximately 5%. Early diagnosis while the disease is still localized increases the rate of survival to close to 50-95%. But even if detected early, patients with localized disease undergoing curative nephrectomy have a 20-50% chance of local or systemic relapse and a long-term risk of kidney cancer in the contralateral kidney. Recent advances in targeted therapy of metastatic RCC have opened a new set of possibilities and questions that urgently call for the development of reliable RCC biomarkers. For example, the duration of treatment for small molecule inhibitors, patient crossover among arms in multi-arm clinical trials, testing of rational combinations of small molecules, and selection of patients for adjuvant therapy could be facilitated and expedited by evaluating disease activity with RCC-specific biomarker(s). Furthermore, biomarkers may detect minimal residual disease already present after nephrectomy for seemingly localized disease or an early relapse. Targeted/anti-angiogenic therapy may be more efficient against minimal residual than clinically detectable disease. Inactivation of the Von Hippel Lindau (VHL) tumor suppressor gene and the resulting constitutive upregulation of hypoxia inducible factor (HIF) are hallmarks of the majority of clear cell RCC and the earliest known signal transduction defect in this cancer. Loss of VHL is also associated with increased proteolytic activity in RCC. We took advantage of the availability of human RCC cell lines deficient in VHL to interrogate the global gene expression changes linked to loss of VHL function as a first step in RCC biomarker discovery. We then selected, as candidate biomarkers, specific genes with restricted adult tissue expression that are upregulated by loss of VHL. We found that these cell line derived biomarkers (CDBs) are also upregulated in all patient RCC tumors examined when compared to matched normal renal parenchyma obtained from the same individual. The overall goal of this proposal is to validate the CDBs as circulating biomarkers of tumor activity in RCC. We also propose to use blood and urine obtained from RCC patients and tumor bearing mice to discover additional RCC biomarkers. Because of increased proteolytic activity in RCC tumors we propose to survey selectively the peptidome of urine and to cross-reference these findings with RCC related plasma peptidome and proteome changes. Finally we describe how we will develop a statistical rule for early detection of RCC relapse. This proposal is a collaborative effort between the Iliopoulos Laboratory (Massachusetts General Hospital Cancer Center) and the Barnett Institute of Chemistry and Chemical Biology (Northeastern University). This collaboration also includes Drs. Steve Skates (MGH Department of Biostatistics) and Patrick Sluss (Laboratory of Reproductive Endocrinology).
The impact of such marker identification is of direct interest to the public. Available biomarker or set of biomarkers for renal cell carcinoma may allow patients at high risk for local and/or systemic relapse and without clinically obvious disease to get additional therapy that prevents recurrence of their disease. In addition they may be used as surrogate markers for response to therapy and allow for early changes in biotherapy or targeted molecular therapy in case these latter ones do not work.
|Gbormittah, Francisca O; Bones, Jonathan; Hincapie, Marina et al. (2015) Clusterin glycopeptide variant characterization reveals significant site-specific glycan changes in the plasma of clear cell renal cell carcinoma. J Proteome Res 14:2425-36|
|Nicolay, Brandon N; Gameiro, Paulo A; Tschop, Katrin et al. (2013) Loss of RBF1 changes glutamine catabolism. Genes Dev 27:182-96|
|Gameiro, Paulo A; Laviolette, Laura A; Kelleher, Joanne K et al. (2013) Cofactor balance by nicotinamide nucleotide transhydrogenase (NNT) coordinates reductive carboxylation and glucose catabolism in the tricarboxylic acid (TCA) cycle. J Biol Chem 288:12967-77|
|Gameiro, Paulo A; Yang, Juanjuan; Metelo, Ana M et al. (2013) In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation. Cell Metab 17:372-85|
|Heddleston, J M; Wu, Q; Rivera, M et al. (2012) Hypoxia-induced mixed-lineage leukemia 1 regulates glioma stem cell tumorigenic potential. Cell Death Differ 19:428-39|
|Tousi, Fateme; Bones, Jonathan; Iliopoulos, Othon et al. (2012) Multidimensional liquid chromatography platform for profiling alterations of clusterin N-glycosylation in the plasma of patients with renal cell carcinoma. J Chromatogr A 1256:121-8|
|Rafalko, Agnes; Dai, Shujia; Hancock, William S et al. (2012) Development of a Chip/Chip/SRM platform using digital chip isoelectric focusing and LC-Chip mass spectrometry for enrichment and quantitation of low abundance protein biomarkers in human plasma. J Proteome Res 11:808-17|
|Scherber, Cally; Aranyosi, Alexander J; Kulemann, Birte et al. (2012) Epithelial cell guidance by self-generated EGF gradients. Integr Biol (Camb) 4:259-69|
|Metallo, Christian M; Gameiro, Paulo A; Bell, Eric L et al. (2012) Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481:380-4|
|Zimmer, Michael; Lamb, Justin; Ebert, Benjamin L et al. (2010) The connectivity map links iron regulatory protein-1-mediated inhibition of hypoxia-inducible factor-2a translation to the anti-inflammatory 15-deoxy-delta12,14-prostaglandin J2. Cancer Res 70:3071-9|
Showing the most recent 10 out of 11 publications