Invasive, chemotherapy-resistant cancer cells often flourish despite being continually challenged by a variety of factors in their microenvironment. One such factor, proteotoxic stress, occurs when more proteins become unfolded, increasing the probability of intracellular aggregates. These aggregates, if not disposed of, can lead to cell death. Strategies for targeting the protein homeostasis machinery have therefore been the focus of industry and academic efforts for oncology therapeutics; clinical successes of the proteasome inhibitors bortezomib and carfilzomib have validated the ubiquitin proteasome system as an attractive therapeutic target. However other potential drug discovery opportunities exist in the two major intracellular protein degradation pathways - the ubiquitin proteasome system and the autophagy system. One key regulator of both systems is the ATPase p97, an ATPase associated with diverse cellular activities (AAA) which extracts misfolded proteins from membranes such as the endoplasmic reticulum and chaperones them to the proteasome for degradation.
Mark Rolfe will review the discovery and early development of a novel first-in-class inhibitor of p97, CB-5083, and describe plans for evaluation of the molecule in multiple myeloma as well as solid tumors.
Dr. Rolfe is an experienced oncology drug discovery and development executive with extensive expertise in small molecule and antibody therapeutics. Most recently he was CSO of CytomX Therapeutics, a venture backed start-up developing a novel class of protease activated therapeutic antibodies called Probodies. Prior to joining CytomX he was SVP, CSO and Interim CMO at Facet Biotech, which was acquired by Abbott Laboratories in April 2010. Prior to Facet he spent 10 years at Millennium Pharmaceuticals. For the last five years of his tenure at Millennium he was Vice President, Oncology Discovery; during this period his group progressed several novel first or best-in-class molecules into development including two novel protein kinase inhibitors, a 2nd generation proteasome inhibitor and the first in class nedd8 activating inhibitor MLN4924. From 1993-1999 he was at Mitotix Inc., where he initiated a drug-discovery effort in the nascent field of ubiquitination and also contributed extensively to various cell cycle kinase projects.
Mark began his biotech career at Celltech (now UCB Pharma) in the UK. He graduated with his BA and MA from Oxford University, obtained his PhD degree from the Medical Research Council and completed Post-Doctoral Fellowships at the Imperial Cancer Research Fund in London and Columbia University College of Physicians and Surgeons in New York. He has published extensively in the areas of antibody therapeutics, cancer biology and the ubiquitin proteasome system and has been an invited speaker at numerous international cancer conferences including AACR, ASCO, The Japanese Cancer Association and the EORTC/NCI/AACR Molecular Targets in Cancer Conference.