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Published on: January 22, 2013
Druggable Biomarkers Altered in Clear Cell Renal Cell Carcinoma: Strategy for the Development of Mechanism-Based
Youcef M Rustum1,2, Ryan Reis3,4, Tara M Rustum5
1Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Abstract:
Targeted therapeutics made significant advances in the treatment of patients with advanced clear cell renal cell carcinoma (ccRCC). Resistance and serious adverse events associated with standard therapy of patients with advanced ccRCC highlight the need to identify alternative 'druggable' targets to those currently under clinical development. Although the Von Hippel-Lindau (VHL) and Polybromo1 (PBRM1) tumor-suppressor genes are the two most frequently mutated genes and represent the hallmark of the ccRCC phenotype, stable expression of hypoxia-inducible factor-1α/2α (HIFs), microRNAs-210 and -155 (miRS), transforming growth factor-beta (TGF-ß), nuclear factor erythroid 2-related factor 2 (Nrf2), and thymidine phosphorylase (TP) are targets overexpressed in the majority of ccRCC tumors. Collectively, these altered biomarkers are highly interactive and are considered master regulators of processes implicated in increased tumor angiogenesis, metastasis, drug resistance, and immune evasion. In recognition of the therapeutic potential of the indicated biomarkers, considerable efforts are underway to develop therapeutically effective and selective inhibitors of individual targets. It was demonstrated that HIFS, miRS, Nrf2, and TGF-ß are targeted by a defined dose and schedule of a specific type of selenium-containing molecules, seleno-L-methionine (SLM) and methylselenocystein (MSC). Collectively, the demonstrated pleiotropic effects of selenium were associated with the normalization of tumor vasculature, and enhanced drug delivery and distribution to tumor tissue, resulting in enhanced efficacy of multiple chemotherapeutic drugs and biologically targeted molecules. Higher selenium doses than those used in clinical prevention trials inhibit multiple targets altered in ccRCC tumors, which could offer the potential for the development of a new and novel therapeutic modality for cancer patients with similar selenium target expression. Better understanding of the underlying mechanisms of selenium modulation of specific targets altered in ccRCC could potentially have a significant impact on the development of a more efficacious and selective mechanism-based combination for the treatment of patients with cancer.
Insights
Selenium compounds like seleno-L-methionine and methylselenocysteine show promise in targeting key biomarkers in advanced clear cell renal cell carcinoma (ccRCC). These molecules may offer a novel therapeutic approach by enhancing drug delivery and efficacy in ccRCC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Advanced clear cell renal cell carcinoma (ccRCC) presents treatment challenges due to resistance and adverse events.
- While VHL and PBRM1 mutations are common, other biomarkers like HIFs, miRs, TGF-ß, Nrf2, and TP are frequently overexpressed and drive tumor progression.
- These biomarkers regulate angiogenesis, metastasis, drug resistance, and immune evasion, representing potential therapeutic targets.
Purpose of the Study:
- To explore the potential of selenium-containing molecules as therapeutic agents targeting key biomarkers in ccRCC.
- To investigate the effects of seleno-L-methionine (SLM) and methylselenocysteine (MSC) on specific ccRCC-associated targets.
Main Methods:
- The study focused on the molecular mechanisms by which SLM and MSC affect specific ccRCC biomarkers.
- Experimental evidence demonstrated the targeting of HIFs, miRs, Nrf2, and TGF-ß by these selenium compounds.
Main Results:
- Selenium compounds (SLM, MSC) were shown to target multiple altered biomarkers in ccRCC.
- These compounds exhibited pleiotropic effects, including normalization of tumor vasculature.
- Enhanced drug delivery and distribution to tumor tissue were observed, leading to improved efficacy of other therapies.
Conclusions:
- Higher doses of selenium than those used in prevention trials can inhibit multiple ccRCC targets.
- Selenium-based molecules offer potential as a novel therapeutic modality for ccRCC patients with specific target expression.
- Further understanding of selenium's mechanisms in ccRCC could lead to more effective combination therapies.
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