Clinical Discovery Program Meeting
A second meeting of investigators participating in the LICR Clinical Discovery Program—an integrated laboratory and clinical research effort led by Drs. Andy Simpson (LICR Scientific Director) and Lloyd Old (Director, LICR New York Branch) and partly funded by The Atlantic Philanthropies—was held in New York on May 27 and 28. The Clinical Discovery Program incorporates laboratory research and clinical trials aimed at developing new therapeutic modalities for cancer.
Affiliates Drs. Vincenzo Cerundolo (Oxford, UK) and Danila Valmori (Nantes, France)
After a brief welcome, Dr. Simpson started off the meeting’s first session, which focused on the exploration of small molecule inhibitors (SMIs) of oncogenic cell signaling targets. Cell signaling is an area in which LICR has strong laboratory experience and the research has matured to the point where preclinical and clinical investigation of novel therapies is warranted. This was affirmed by the first speaker, Dr. Aristidis Moustakas (LICR Uppsala Branch), who described an ongoing search for SMIs that target oncogenic TGF-beta signaling and potentially could prevent tumor metastasis, and by following speakers who discussed clinical discovery based on studies of mutated JAK kinases (Dr. Stefan Constantinescu, LICR Brussels Branch) and S6 kinases (LICR Affiliate Dr. Ivan Gout, University College London, UK). In addition, Dr. Richard Jove, on behalf of himself and Dr. Hua Yu (both at the City of Hope Comprehensive Cancer Center, USA) discussed the potential of the signaling molecule Stat3 as a target for both SMI and immunotherapy.
Several emerging strategies and technologies that will accelerate the discovery of drug targets and to optimize SMI design were presented. Dr. Pedro Cutillas and Affiliate Dr. Bart Vanhaesebroeck (Barts and the London School of Medicine, UK) described a proteomics platform to monitor intracellular signaling that was developed to assess components of the PI3 kinase signaling network as therapeutic targets. Dr. Victor Velculescu, in depicting a genomic approach taken by the Ludwig Center at Johns Hopkins University, demonstrated how knowledge of the extensive ‘landscape’ of mutations for individual cancer types has revealed new opportunities for therapeutic intervention and diagnostics. A computational approach to drug discovery was presented by Dr. Olivier Michielin (LICR Lausanne Branch). Software developed by his team designs optimal SMIs using evolutionary algorithms and is currently being used in the identification of inhibitors of IDO, an enzyme implicated in the establishment of immune tolerance by tumors.
Cancer-targeting antibodies have emerged as one of the most promising therapeutic for cancer. A number of antibodies have been developed by LICR investigators for clinical application—several of which have been licensed to industrial partners—and research is in progress to improve their clinical performance and to identify new targets. Dr. Andrew Scott (Director, LICR Melbourne Center), outlined these efforts and discussed different strategies to improve the activity of cancer-targeting antibodies, such as antibody-mediated delivery of nanoparticles or toxins to tumors. This was followed by updates on the selection and engineering of antibodies directed against antigenic peptides bound to MHC receptor molecules (Affiliate Dr. Christoph Renner, University Hospital Zürich, Switzerland) and on the characterization of an antigen targeted by MX35, an antibody developed for treatment of ovarian cancer (Dr. Gerd Ritter, New York Branch). Affiliate Dr. Egbert Oosterwijk (University Medical Center Nijmegen, Netherlands) concluded the session by presenting a new approach to identify antibody targets from prostate tumor samples.
Cancer vaccines show strong potential as therapies that, ideally, keep tumor growth and metastasis in check by inducing a strong and sustained immune response against a cancer antigen. Results from clinical studies, however, indicate that several challenges remain before this therapeutic modality will achieve its full clinical potential. One problem, addressed by Affiliate Dr. Robert Schreiber (Washington University School of Medicine, USA), is the capacity of tumors to escape or counteract the immune system. Dr. Schreiber presented recent findings indicating that cancer cells that elude attack by the immune system can linger in a latent state and potentially produce new tumors when the immune system is suppressed. Dr. Sacha Gnjatic (New York Branch) discussed ongoing efforts to identify new vaccine targets and prognostic markers by protein microarray analysis of patient sera. Several prospective adjuvants, compounds (or delivery mechanisms) that potentiate the immune response to cancer antigens, were discussed: CD1d receptor ligands, which have been shown to trigger both innate and adaptive immune responses through the activation of invariant natural killer T (iNKT) cells (Affiliate Dr. Vincenzo Cerundolo, University of Oxford, UK); RNA-based adjuvants (Dr. Steve Pascolo, University Hospital Zürich); and Toll-like receptor (TLR) agonists derived from the parasite Trypanosoma cruzi (Affiliate Dr. Ricardo Gazzinelli, Federal University of Minas Gerais, Brazil). Finally, Affiliates Drs. Maha Ayyoub and Danila Valmori (Regional Nantes-Atlantic Institute of Cancer) presented findings from a clinical study of cancer patients vaccinated with the recombinant protein NY-ESO-1, and discussed variations in the immune responses to this vaccine.
As outlined during the meeting by Dr. Eric Hoffman (Director, LICR Office of Clinical Trials Management), six clinical trials are ongoing under the auspices of the Clinical Discovery Program, including four cancer vaccine trials, one cancer-targeting antibody trial, and one trial assessing an enzymatic therapy. An additional four cancer vaccine trials are also being planned.
The Clinical Discovery Program Meeting brought together 40 participants, including representatives from The Atlantic Philanthropies, the LICR New York Office, the LICR Scientific Advisory Committee, four LICR Branches (Brussels, Lausanne, New York, and Uppsala) and the Melbourne Center, nine Affiliates, three Ludwig Centers (HMS/Dana-Farber Cancer Institute, Johns Hopkins University, Memorial Sloan-Kettering Cancer Center) and a collaborating institution, the City of Hope National Medical Center.
Drs. Aristidis Moustakas (LICR Uppsala Branch), Sacha Gnjatic (LICR New York Branch), Ricardo Gazzinelli (Affiliate, Minas Gerais, Brazil) and Egbert Oosterwijk (Affiliate, Nijmegen, The Netherlands)