Therapeutics in renal disease: the road ahead for antiproliferative targets

Abstract

Discovery into the molecular basis of renal disease is occurring at an unprecedented rate. With the advent of the NIH Roadmap, there is a greater expectation of translating this knowledge into new treatments. Here, we review the therapeutic strategy to preserve renal function in proliferative renal diseases by directly inhibiting the mitogenic pathways within renal parenchymal cells that promote G0 to G1/S cell-cycle phase progression. Reductionist methodologies have identified several antiproliferative molecular targets, and promising preclinical testing of leading small-molecule drugs to modulate these targets has now led to landmark clinical trials. Yet, this advancement into targeted therapy highlights important differences between the therapeutic goals of molecular nephrology versus molecular oncology and, by extension, the poorly understood role of alternative target activity in drug efficacy. Systems research to clarify these issues should accelerate the development of this promising therapeutic strategy.

Fig. 1

Flow chart in the development of a therapeutic strategy. The first step is to identify a potential drug target that is predicted to disrupt a critical step in the pathogenesis of disease. The chosen target may harbor alternative target activity that together increases overall efficacy. This alternative target activity may be due to the ability of a chosen target to control multiple cellular processes involved in the pathogenesis of the disease, a therapeutic activity termed ‘target pleiotropy’, and/or to the existence of unintended or unknown off-targets to the chosen target that are also involved in the pathogenesis of the disease, a therapeutic activity termed ‘target paralogy’. However, target pleiotropy and target paralogy can confuse the therapeutic role of the chosen target if the contribution of the former to efficacy is poorly understood. Drug entities are typically screened and selected for their ability to modulate the chosen target in vitro; it may be discovered after a drug is developed that the drug itself harbors therapeutically relevant alternative target activity, raising questions about the specificity-of-action of the drug. Once a drug entity is identified, it must exhibit favorable absorption, distribution, metabolism, excretion, and toxicity (ADMET) in order to at least undertake proof-of-concept studies of the therapeutic strategy in vivo to proceed to clinical trials. At this stage, the best measurements of efficacy include biomarkers (see table 2) that either directly detect or accurately predict the specificity of drug action in preclinical models and in humans.

Fig. 2

Depiction of the cell-cycle domain of antiproliferative targets in proliferative renal diseases. Molecular oncology targets favor cytotoxic growth arrest of malignant cells and, therefore, have been identified in all phases of the cell-cycle, i.e., G₁, S, G₂, and M (box A). In contrast, ideal targets in molecular nephrology largely fall within the cell-cycle phase from G₀ to the G₁/S cell cycle checkpoint (box B), the phase where physiologic growth arrest can be achieved. Targets beyond the G₁/S cell-cycle checkpoint induce an undesirable, nonphysiologic state of growth arrest and are often cytotoxic to cells.

Fig. 3

Interrogation of targets through systems research in proliferative renal diseases. a The systems biology approach to target identification integrates the interaction of elements of disease biology (depicted by the interaction of circles ‘A’ through ‘D’) to identify emergent, high-impact targets, coined ‘nodes’, that are predicted to function simultaneously in several pathogenic pathways that together contribute to the development of disease. When modulated with drugs, these nodes will theoretically reconfigure the entire disease state back towards normal. b By assuming that any one target (intended or unintended) identified through reductionist methodologies may affect any aspect of proliferative renal disease biology, one can ask if modulation of that one target impacts important parameters of disease, such as parenchymal hyperplasia, other secondary parenchymal disease phenotypes, extrarenal disease phenotypes, or the etiology.