Druggable Biomarkers Altered in Clear Cell Renal Cell Carcinoma: Strategy for the Development of Mechanism-Based Combination Therapy

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 (miR_S), 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 HIF_S, miR_S, 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.

Keywords: clear cell renal cell carcinoma; druggable targets; selenium; therapeutics potential.

Figure 1

Molecular and immunologic targets expressed in ccRCC tumors and associated microenvironment implicated in tumor angiogenesis, unstable microenvironment, drug resistance, and immune evasion. TGF-ß, transforming growth factor-ß; HIFs, hypoxia-inducible factor1α/2α; onco-miRs, oncogenic microRNAs; TSmiR_S, tumor-suppressor microRNA_S; P-gp, p-glycoprotein; PHD, prolyl hydroxylase; PD-1/PD-L1, programmed death-1 and its ligand; GPDL1, glycerol-3-phosphate dehydrogenase 1-like; TP, thymidine phosphorylase; CPT1A, carnitine palmitoyl transferase IA; PLIN2, Perilipin 2; mVHL, mutated Von Hippel-Lindau tumor-suppressor gene; ↑ upregulated; ↓ downregulated. *: SLM/MSC targets.

Figure 2

Objective response rate (ORR, (CR + PR)) and complete response (CR) of previously untreated patients with advanced ccRCC with and without sarcomatoid differentiation treated with a combination of biologically targeted molecules: randomized phase 3 clinical trial [1]. The number indicated on the x-axis represents the number of patients included in each clinical trial. Ipilimumab/Nivolumab (blue), Avelumab/axitinib (red), Pembrolizumab/Axitinib (green), Atezolizumab/Bevacizumab (purple), sunitinib (orange).

Figure 3

Biomarkers’ expression associated with the overexpressed nuclear factor erythroid 2-related factor 2 (Nrf2). ↑ Activator and inhibitor. Onco-miRs, oncogenic microRNAs; HIFs, hypoxia-inducible factor-1α/2α; KRAS, BRAF, c-myc, Kristen rat sarcoma virus, B-raf proto-oncogene, serine/threonine kinase, and c-myc is a proto-oncogene; TGF-ß, transforming growth factor-ß; Th17, T-helper 17 cells; Foxp3/Treg, transcription factor forkhead box protein/T regulatory cell; PD-L1, programmed death ligand 1; GSK-3ß, glycogen synthase kinase-3-beta; VEGF, vascular endothelial growth factor; Th1/2, T-helper-type 1/2 cells; MDSC, myeloid-derived suppressor cells [75].

Figure 4

Differential regulation of Nrf2 expression by methylselenocystein (Se) in tumor and normal tissues [72]. Se upregulates Nrf2 in normal mouse tissues and downregulates its expression in tumor tissues.