The MErCuRIC Phase I trial was presented at the ESMO 2016 Congress in Copenhagen (7 – 11 Oct 2016).
MErCuRIC1: A phase 1a study of MEK1/2 inhibitor PD-0325901 with cMET inhibitor crizotinib in patients with advanced solid tumours (Poster: 480P)
R. Wilson, M. Middleton, J. Houlden, S. Van Schaeybroeck, C. Rolfo, E. Elez, J. Taieb , T. André, A. Bardelli , P. Laurent-Puig, J. Tabernero, M. Peeters, T. Maughan, C. Roberts, S. Love, M. Lawler , M. Salto-Tellez, M. Grayson, V. Popovici, F. Di Nicolantonio
The summer 2016 newsletter for the European Patients’ Academy (EUPATI) is now available. In this issue, you can access the Patient Expert Training Course, now available in English, as well as learn about the growing national EUPATI teams that function as patient involvement groups locally.
Congratulations to Prof. Alberto Bardelli of UNITO on his election as President of the European Association for Cancer Research (EACR)!
You can read more here.
While the ever-advancing landscape of precision medicine in oncology undoubtedly brings fresh hope for patients, it also poses many yet unanswered questions as to how we move forward, without the real risk of burn-out of those who treat them – particularly with regards to the up-and- coming generation of young oncologists, the future of our profession and practice.
Established in 2001, the Young Oncologists Committee (YOC) of the European Society for Medical Oncology (ESMO) focuses on identifying real solutions matched to responding to the needs of more junior colleagues to relieve the burden they face and thus avert the real threat of some of the brightest future talents ultimately exiting from oncology.
Just one of the Committee´s major achievements marked to-date was the European-wide survey on burnout in young oncologists presented during the ESMO 2014 Congress in Madrid by YOC member and lead author Susana Banerjee. The survey evidenced that as many as 84% of respondents suffer in central Europe, compared with over 50% in the North. Despite these variations, the best case scenario of half of the respondents clearly represents a major problem. Thanks to the YOC, important steps are thankfully being taken to help reverse this alarming trend.
YOC is currently chaired by Matthias Preusser, Medical University of Vienna (Austria), and mentored by Josep Tabernero, Director of the Vall d´Hebron Institute of Oncology (VHIO), Barcelona (Spain), ESMO President-Elect, and PI of MErCuRIC´s future multicenter phase II study. It both devises and leads important educational and scientific programs aimed at delivering on the requirements of young oncologists in today´s era of precision science and medicine against cancer. YOC´s inspired range of activities and platforms include the Young Oncologists Corner, Journal Club, Preceptorship meetings, and special Young Oncologist sessions at national oncology congresses and ESMO specialty meetings.
Concerning the latter, Guillem Argilés, Medical Oncologist and Clinical Researcher of VHIO´s Gastrointestinal & Endocrine Tumors Group headed by Josep Tabernero, and a MErCuRIC phase II study co-collaborator, recently led an ESMO Session entitled Focus on Young Medical Oncologists during one of the Society´s leading annual oncology meetings: the 18 th World Congress on Gastrointestinal Cancer, 29 June – 02 July, Barcelona, Spain.
Co-chaired by Josep Tabernero, this unique educational opportunity paired a mentorship session with two scientific presentations delivered by young oncologists. More specifically, in mentorship, Eduardo Vilar Sanchez of the University of Texas MD Anderson Cancer Center, Houston (USA), provided participants with expert advice on how best to build a solid CV in the molecular oncology era and achieve a balance between bench and bedside, followed by invaluable pointers from Richard M. Goldberg, the Ohio State University Comprehensive Cancer Center, Columbus (USA), on how best to find a good mentor in GI oncology.
The second half of the session showcased latest research delivered by young oncologists Rodrigo Dienstmann, Principal Investigator of VHIO´s Oncology Data Science (ODysSey) Group, and Loredana Vecchione, the Netherlands Cancer Institute (NKI), Amsterdam (The Netherlands), who presented on the Clinical implications of transcriptional subtyping in mCRC, and Beyond NGS, towards functional prescreening models in therapeutic decisions in cancer, respectively.
“Divided into two parts, Mentorship and Scientific, this special session delivered on the main mission of ESMO´s Young Oncologists Committee by providing opportunity to strengthen young oncologists’ skills, knowledge and expertise, as well as a platform for networking with other medical oncologists and oncology professionals”, observes Guillem who was appointed as a Member of ESMO´s YOC back in January this year.
“Important actions implemented and developed thanks to the enthusiasm and drive of the YOC will undoubtedly continue to provide the necessary support and educational opportunity for ESMO´s younger members. As appointed Mentor of this Committee, I am devoted to guiding and flanking these dedicated efforts”, says Josep Tabernero.
Under the chairmanship of Matthias Preusser, Guillem and co-YOC members are currently finalizing the Young Oncologists (YO) Track at the forthcoming ESMO 2016 Congress, 07 – 11 October 2016, Copenhagen Denmark. Along with the extremely popular and established YO Track opportunities from previous ESMO Congresses including YO Brunch, Masterclass and Mentorship Sessions, the 2016 Vesalius Talk will focus on developing an effective collaboration between basic scientists and oncologists.
To discover more about ESMO, its Young Oncologists Committee, the recently celebrated 18 th World Congress on Gastrointestinal Cancer, well as the forthcoming ESMO 2016 Congress, visit: www.esmo.org.
Josep Tabernero, Director of the Vall d´Hebron Institute of Oncology (VHIO), ESMO President-Elect, and PI of MErCuRIC´s future multicenter phase II study
Guillem Argilés, Medical Oncologist and Clinical Researcher of VHIO´s Gastrointestinal & Endocrine Tumors Group and a MErCuRIC phase II study co-collaborator
In June 2016, the Northern Ireland Cancer Research Consumer Forum and its Bowel Cancer Research Interest Group hosted a public event – ‘Delivering 21st Century Medicine for bowel cancer patients’.
A MErCuRIC poster was displayed at the event in Belfast. The event was opened by a member of the Local Assembly and speakers included MErCuRIC researcher Prof. Mark Lawler, who talked about precision medicine. During the break, the audience also had the opportunity to visit bowel cancer information stands.
A systems model of BCL-2 dependent apoptosis to predict stage II CRC patients benefiting from adjuvant chemotherapy and as a prognostic tool for stage III CRC patients with increased risk of recurrence – Abstract 3584
Caspase modelling to predict personalised risk in stage III colorectal cancer (CRC) patients – Abstract 11592
‘Validation of a MEK/MET-specific NGS panel for early phase trial interrogation‘ and ‘Upregulation of the MET transcript is consistently associated with invasion and tumor budding in colorectal cancer‘ were presented at the AACR Annual Meeting on 18 Apr 2016 in New Orleans. Mariangela Russo from UNITO also presented related work (Abstract 878).
Validation of a MEK/MET-specific NGS panel for early phase trial interrogation
Introduction – MErCuRIC is a Phase Ib/II clinical trial study using a combined MEK1/2 – cMET inhibition in RAS MT and RAS WT (with aberrant c[[unable to display character: ‐]]MET) colorectal cancer patients. As part of the discovery efforts on the cases enrolled in Phase I, we aimed to analyze the mutation status of 10 genes that could potentially be associated to the doublet MEK/MET inhibition. This study compared the MEK/MET-specific panel with the Ion Torrent 50 gene panel, aiming to compare: long-established, commercially available panels against this newly developed panel; the Ion Torrent PGM2 platform against Illumina MiSeq v.3 600 bp chemistry; hot-spot-based against full exomes-designed; and to compare the use of different bioinformatics reporter systems. The overlapping genes between the panels were: EGFR (n=3); BRAF (n=4); KRAS (n=8); NRAS (n=1); MET (n=8); PIK3CA (n=6); and ERBB2 (n=5).
Summary of Method – NGS Design – The Multiplicom – MErCuRIC specific MASTR assay includes PTEN, MAP2K1 (MEK), EGFR, KRAS, NRAS, BRAF, PIK3CA, ERBB2, MET and PIK3R1, involving 257 amplicons in 4 plexes covering all coding exons of the 10 genes. Of the 257, 21 are control amplicons to allow for gene deletions/amplifications. The average length of the amplicons is 198 bp ranging from 124 bp to 255 bp.
Validation – From a pool of 120 routine tumour samples characterised with a 50 gene mutation panel (Ion Torrent PGM2) and confirmed by Sanger sequencing and/or COBAS (Roche) QPCR, 24 FFPE cases were selected representing colorectal cancer and 4 other solid tumour types; all included a variety of DNA quality, and DNA concentration was standardized prior to library preparation. Pre-analytical handling was in accordance with established protocols in a laboratory, clinically-accredited in the UK for tissue-based, anatomical pathology testing.
Results – The evaluation of this MEK/MET-specific panel (Illumina MiSeq platform) resulted in 100% coverage of all targets, a higher than 97% on target reads and higher than 99% of all amplicons within 20% of mean coverage. The design minimized the areas of low coverage. A small part of exon 9 of ERBB2 was covered suboptimally: the low covered region is 30 bp in size located at the 5’ end of exon 9. It is unlikely that this low coverage led to false negative results since no mutations are reported in the COSMIC database for this DNA fragment. The results were concordant in relation to mutations involved in the genes stated above. Importantly, the percentages of allele frequency between both methods were similar, with variations ranging from 0.2% to 11.5% with an average variation of 5.2%. Insertion/deletion (Indel) detection however, required alternative bioinformatics pathways.
Conclusion – After combining well-established quality metrics to cover pre-analytical aspects with suitable technologies such as the MiSeq platform (Illumina) and appropriate bioinformatics, we recognize that this MEK/MET-specific NGS panel is fit for purpose.
Upregulation of the MET transcript is consistently associated with invasion and tumor budding in colorectal cancer
Background – The c-MET proto-oncogene is frequently overexpressed (50-60%), amplified (1-3%), and mutated (1-3%) in colorectal cancer (CRC). Hepatocyte growth factor (HGF)-dependent and independent activation of c-MET has been associated with increased survival and resistance to targeted therapies. This study aimed to investigate the role of the HGF/c-MET axis in regulating migration/invasion in CRC, using pre-clinical models and clinical samples.
Methods – In order to model CRC tumour cell invasion, we have generated invasive CRC subpopulations using Boyden Invasion chambers. To model the CRC microenvironment, we have used a range of co-culture techniques with CRC cells and colon fibroblasts. Migration/invasion was determined using xCELLigence System (Roche). c-MET expression in parental and invasive cell lines was measured using Western blotting and qRT-PCR. c-MET expression in CRC FFPE tissues was measured using IHC and RNAScope®.
Results – We identified marked upregulated expression of c-MET at both the protein and transcript levels in our invasive CRC cell line models. Importantly, both parental and invasive subpopulations were found to be inherently dependent on c-MET for migration, as RNAi against c-MET abrogated migration/invasion in both parental and invasive models. We also demonstrated that stimulation of CRC cells with rh-HGF resulted in increased CRC cell migration/invasion. In addition, co-culture of CRC cells with colonic myofibroblasts, resulted in marked increases in migratory and invasive capacity, and this was dependent on HGF/c-MET signaling. Interestingly, stimulation with myofibroblast conditioned medium or HGF promotes rapid degradation of c-MET at the protein level, followed by recycling, while METtranscript remains unaltered, illustrating a dynamic expression of c-MET protein in response to activation. We further showed that MET is transcriptionally upregulated in tumour budding foci at the invasive front of a cohort of stage III CRC tumors. Intriguingly, c-MET protein levels do not correlate with the transcript, most likely due to a similar protein degradation process observed in our aforementioned in vitro models.
Conclusions – We show for the first time a key role for transcriptional upregulation of MET as a molecular driver of tumour invasion, both in vitro and in stage III CRC tumours.
MErCuRIC is funded by the European Community’s Framework Programme Seven (FP7) under contract #602901. The material presented and views expressed here are the responsibility of the author(s) only. The EU Commission takes no responsibility for any use made of the information set out.