EGFR Cascade Meeting Report
San Diego, May 25 & 26
A meeting of LICR investigators and close collaborators who are involved in research on the epidermal growth factor receptor (EGFR) signaling cascade was held to assess the potential for collaborations and explore new opportunities for LICR investigators. Hosted by Dr. Web Cavenee (Director, San Diego Branch), the meeting had 25 attendees, including representatives from the Melbourne, New York, San Diego and UCL Branches, the Melbourne Centre for Clinical Sciences, the New York Office, and two Centers (Johns Hopkins University and Dana-Farber/Harvard) supported by the Virginia & D.K. Ludwig Fund.
After a welcome from Dr. Andy Simpson (Executive Director for Programs & Operations), the meeting kicked off with a comprehensive overview of EGFR in cancer and the potential for therapeutic inhibition by Dr. Tony Burgess (Director, Melbourne Branch), one of the leading investigators in the EGFR structure/function field. This was followed by one of Dr. Burgess’ collaborators, Dr. Mark Lemmon (University of Pennsylvania), who described small angle X-ray scattering (SAXS) studies on the conformation of EGFR and the other ErbB family members and his group’s analyses of the tethered/untethered states of the receptors. Dr. Andrew Clayton (Melbourne Branch) rounded off the session on EGFR structure by describing his studies on the association states of activated EGFR using fluorescence lifetime imaging microscopy (FLIM).
Moving down the EGFR signalling cascade, Dr. Bart Vanhaesebroeck (UCL Branch) discussed his research on the family of phosphoinositide 3-kinase (PI3K) enzymes, which are targets of small molecule inhibitors being developed by LICR spin-off company, PIramed Ltd, with which Dr. Vanhaesebroeck is collaborating. Dr. Ivan Gout (University College London), a former UCL Branch investigator and current James R. Kerr Program investigator, described his research on the acetylation regulation of the S6 kinases, which are downstream of PI3K. Finally, Dr. Karen Arden (San Diego Branch) reviewed her research findings on the FOXO family of forkhead transcription factors, which are also downstream of the PI3Ks and also involved in insulin signaling.
Some of the attendees at the EGFR Cascade meeting in sunny San Diego.
Many of the existing collaborations among the group focus on the role of EGFR in glioma, particularly on the EGFRvIII, or “delta2-7”, deletion. Dr. Frank Furnari (San Diego Branch) reviewed some of the EGFR heterogeneity the San Diego team has found in glioblastoma multiforme, and went on to describe the activation of downstream molecules by paracrine activation of EGFR. Dr. Greg Riggins (Ludwig Center at Johns Hopkins University) rounded off the day by describing the collaboration - between his group, LICR’s Dr. Andy Simpson, and Dr. Robert Strausberg (J. Craig Venter Institute) - searching for EGFR pathway inhibitors in brain tumors and the high throughput DNA sequencing of glioblastoma samples being conducted at the Venter Institute. Dr. Riggins reported some of those results showing activation of PI3Ks and the involvement of members of the FOXO family, and showed preliminary results of an inhibitor for glioblastoma with the EGFRvIII mutation.
The second day moved into the realm of EGFR research models. Dr. Renée Read (Scripps Institute), who is collaborating with Dr. Cavenee, described a fascinating Drosophila model of glioma, while Dr. Kwok Wong (Ludwig Center at Dana-Farber/Harvard) described his research on the EGFRvIII mutation in human NSCLC cell lines and his ongoing collaborations with Drs. Andrew Scott (Director, Melbourne Centre for Clinical Sciences) and Web Cavenee on the sensitivity of those cancers to LICR’s 806 antibody. Drs. Eloiza Tajara (Dept. of Molecular Biology, Paulista State University, Brazil) described the tissue bank resources being collected in Brazil (through Dr. Simpson’s Clinical Genomics Program), reporting that the number of pedigreed samples stands currently in the order of 2000. The team is already collaborating with several of the meeting attendees to provide glioblastoma samples. One of those attendees, Dr. Suely Marie (Dept. of Neurology, Paulista State University, Brazil), who is supported by the James R. Kerr Program, described the latest results on genes identified by microarray analyses of glioblastoma. Her team is now characterizing those genes with siRNA as part of a collaboration with the New York Branch. The Brazil team is also using monoclonal antibodies from the LICR-supported facility in Xi’an, China, to continue the characterization of genes of interest.
Drs. Suely Marie (left, James R. Kerr Program) and Frank Furnari (San Diego Branch) discuss gene expression in glioblastoma samples.
Finally, Dr. Terry Johns (Melbourne Centre) reported on his group’s translational work in combining different signalling inhibitors and antibodies with the 806 antibody in xenograft models. Dr. Andrew Scott finished the presentations by showing results from the first-in-man clinical trial of the 806 antibody (which were presented formally at the American Society of Clinical Oncology meeting a week later). The generation, characterization and now, clinical investigation, of the 806 antibody resulted from a chain of collaborations between the San Diego, New York and Melbourne Branches, and illustrates beautifully the LICR mission of translating our discoveries into early-phase trials through integrated laboratory and clinical research.
The meeting was very successful, with several new collaborations already formed and the transfer/sharing of key reagents and models underway. A sub-committee (Drs. Burgess, Cavenee, Riggins and Simpson) has also been formed to explore ways of accessing high-quality small molecule libraries for the group; one of the principal suggestions in the wrap-up session.
Drs. Huilin Zhou (left, San Diego Branch) and Andrew Clayton (Melbourne Branch) discussing their science interests.