Therapeutic targeting of platelet-derived growth factor receptors in solid tumors

Abstract

Introduction: Genetic aberrations that are associated with platelet-derived growth factor receptor (PDGFR) activity are frequently found in glioblastomas (10 - 15%), dermatofibrosarcoma protuberans (≤ 100%) and gastrointestinal stromal tumors (5%). Sequencing studies have also identified mutations at lower frequency in common cancer types. Preclinical evidence further suggests tumor stimulatory roles of PDGFRs expressed by tumor stroma cells and indicates a deleterious effect of stromal PDGFRs on intratumoral drug uptake.

Areas covered: This review summarizes the present understanding of PDGF signaling in solid tumors based on experimental studies and clinical findings. It also provides a discussion of selected ongoing efforts to develop novel cancer therapies involving PDGFR inhibition with tyrosine kinase inhibitors or PDGFR-targeting monoclonal antibodies.

Expert opinion: An increased molecular understanding of response and resistance mechanisms will be essential for therapeutic advances in PDGFR-directed cancer therapy. Further developments rely on clinical studies where systematic analyses of target status in malignant cells and in cells of the tumor stroma are included. Studies with combination therapies will be facilitated by selective PDGFR inhibitors with reduced side effects. Finally, development of improved companion diagnostics is of critical importance for patient selection and monitoring of therapeutic effects.