Radiation-Induced Fibrosis: Mechanisms and Opportunities to Mitigate. Report of an NCI Workshop, September 19, 2016

Abstract

A workshop entitled "Radiation-Induced Fibrosis: Mechanisms and Opportunities to Mitigate" (held in Rockville, MD, September 19, 2016) was organized by the Radiation Research Program and Radiation Oncology Branch of the Center for Cancer Research (CCR) of the National Cancer Institute (NCI), to identify critical research areas and directions that will advance the understanding of radiation-induced fibrosis (RIF) and accelerate the development of strategies to mitigate or treat it. Experts in radiation biology, radiation oncology and related fields met to identify and prioritize the key areas for future research and clinical translation. The consensus was that several known and newly identified targets can prevent or mitigate RIF in pre-clinical models. Further, basic and translational research and focused clinical trials are needed to identify optimal agents and strategies for therapeutic use. It was felt that optimally designed preclinical models are needed to better study biomarkers that predict for development of RIF, as well as to understand when effective therapies need to be initiated in relationship to manifestation of injury. Integrating appropriate endpoints and defining efficacy in clinical trials testing treatment of RIF were felt to be critical to demonstrating efficacy. The objective of this meeting report is to (a) highlight the significance of RIF in a global context, (b) summarize recent advances in our understanding of mechanisms of RIF,

Trial registration: ClinicalTrials.gov NCT02567799.

(c) discuss opportunities for pharmacological mitigation, intervention and modulation of specific molecular pathways, (d) consider the design of optimal clinical trials for mitigation and treatment and (e) outline key regulatory nonprescriptive frameworks for approval.

Figures

FIG. 1

Mechanisms of pulmonary fibrosis. Injury, inflammation and repair each play contributing roles to RIF. The immediate injury can result in loss of parenchyma, loss of barrier function and an initiation of inflammation. Acute inflammation, although noted to be critical for wound repair, can result in additional injury, oxidative stress and eventual tissue remodeling and chronic inflammation. The chronic inflammatory process further contributes to ongoing injury and stress. Late RIF in the lung is a failed attempt at regeneration of lost tissue.

FIG. 2

The central role of TGF-β in radiation fibrosis. TGF-β activation after irradiation can occur via reactive oxygen species or other indirect mechanisms. Once activated, TGF-β signaling results in activation of SMAD signaling pathways, with can stimulate fibroblast proliferation and extracellular matrix (ECM) deposition. These changes can contribute to hypoxia, which further contributes to the progression of fibrosis. Note: DAMPs are Death Associated Molecule Patterns.

FIG. 3

Onset and manifestation of fibrosis. Quiescent fibroblasts, which are characterized the presence of extracellular matrix (ECM), Type I collagens, and fibronectin are activated by external stress such as ROS, TGF-β, hypoxia or other cytokines. Activated fibroblasts have plasticity and are characterized by a secretory phenotype, leading to differential cross linking of ECM, production of fibronectin, TGF-β, CCL-5 and IL-6. Activated fibroblasts also demonstrate cytoskeletal remodeling. Fibrosis associated fibroblasts are characterized by an enhanced secretory phenotype and production of MMP-1, -2, -3 and -9.

FIG. 4

Targeting mTOR in fibrosis. First generation mTOR inhibitors are effective at targeting the mTORC1 complex, which is implicated in the control of protein and limped synthesis, autophagy, and senescence. mTORC1 inhibition may not suppress the pathway sufficiently in some cases due to compensatory Akt activation. Second generation agents capable of suppressing mTORC1 and mTORC2 more effectively blunt signaling through these pathways.