New Target Proposed for Fighting Clear Cell RCC

Histopathologic image of clear cell carcinoma of the kidney. Copyright 2005 KGH.

Scientists have discovered a new molecular target for therapy to fight clear cell renal cell carcinoma (RCC), neuronal pentraxin 2 (NPTX2). According to the results of a study published in Cancer Research,NPTX2, a gene that controls brain growth and development, is overexpressed in clear cell RCC and has the potential to serve as a predictive biomarker of metastatic disease.

“We found that a gene known to play a role in the healthy brain is also the No. 1 gene associated with this most lethal of all urological cancers,” study investigator and molecular biologist John A. Copland, PhD, said in a press release. “We also have very promising ideas about how to attack the NPTX2 protein-which may provide a much-needed new strategy to treat this kidney cancer.”

Copland and colleagues at the Mayo Clinic, Florida, used genomic profiling to study more than 100 kidney cancer patient samples. The researchers identified genes in the cancer samples that were over- or under-expressed when compared with normal kidney tissue samples. Each of the top 200 altered genes was then individually silenced to analyze the effect on tumor growth. Thirty-one genes were identified as being important to cell growth and proliferation, of which NPTX2 was found to be a key gene to cancer viability.

Results of the study showed that NPTX2 expression was significantly increased in each stage of clear cell RCC. Analysis at the protein level with immunohistochemistry staining confirmed elevated expression of NPTX2. In addition, the researchers found that NPTX2 expression was correlated specifically with clear cell RCC compared with granular, papillary, and chromophobe RCC.

The researchers then searched for prevalence of the NPTX2 gene in kidney cancer using nine public genomic datasets, representing thousands of patients, and found it to be the top aberrantly expressed gene associated with this cancer.

“Meta-analysis of public datasets revealed that NPTX2 is consistently up-regulated at the transcript level in clear cell RCC, and that NPTX2 expression is more strongly correlated with advanced clear cell RCC lesions vs low grade lesions,” they wrote.

Next, Copland and colleagues identified GluR4 as a receptor for NPTX2 by evaluating expression of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor subunits GluR1-4. The analysis showed a threefold increase in GluR4 mRNA expression in clear cell RCC. According to the researchers, this finding shows that GluR4 “is important for clear cell RCC viability and invasion.”

NPTX2 causes multiple GluR4 proteins to unite and form a channel into the cell, which allows calcium to flow in. “Elevated calcium triggers multiple signaling pathways that promote cell doubling, survival, and changes in the cell that promote cancer invasion and metastasis,” Copland said in a press release.

Finally, the researchers showed that this calcium flow can be suppressed with treatment with CFM-2, an allosteric AMPA receptor antagonist.