MErCuRIC study published in Molecular Cancer Therapeutics

The MErCuRIC study ‘The unfolded protein response: a novel therapeutic target for poor prognostic BRAF mutant colorectal cancer’ has been recently published in Molecular Cancer Therapeutics. The body of research by Nicholas Forsythe, Alaa Refaat, Arman Javadi, Hajrah Khawaja, Jessica-Anne Weir, Heba Emam, Wendy L Allen, Frank Burkamp, Vlad Popovici, Puthen V Jithesh, Claudio Isella, Melissa J LaBonte, Ian G Mills, Patrick G Johnston, and Sandra Van Schaeybroeck was accepted for publication on 16 February 2018.

Abstract

BRAFV600E mutations occur in 10% of colorectal cancer (CRC) cases, are associated with poor survival and have limited responses to BRAF/MEK inhibition with or without EGFR inhibition. There is an unmet need to understand the biology of poor prognostic BRAFMT CRC. We have used differential gene expression and pathway analyses of untreated stage II and stage III BRAFMT (discovery set: n=31; validation set: n=26) CRC and an siRNA screen to characterize the biology underpinning the BRAFMT subgroup with poorest outcome. These analyses identified the unfolded protein response (UPR) as a novel and druggable pathway associated with the BRAFMT CRC subgroup with poorest outcome. We also found that oncogenic BRAF drives endoplasmic reticulum (ER) stress and unfolded protein response (UPR) pathway activation through MEK/ERK. Furthermore, inhibition of GRP78, the master regulator of the UPR, using siRNA or small molecule inhibition, resulted in acute ER stress and apoptosis, in particular in BRAFMT CRC cells. In addition, dual targeting of protein degradation using combined Carfilzomib (proteasome inhibitor) and ACY-1215 (HDAC6-selective inhibitor) treatment resulted in marked accumulation of protein aggregates, acute ER stress, apoptosis and therapeutic efficacy in BRAFMT in vitro and xenograft models. Mechanistically, we found that the apoptosis following combined Carfilzomib/ACY-1215 treatment is mediated through increased CHOP expression. Taken together, our findings indicate that oncogenic BRAF induces chronic ER stress and that inducers of acute ER stress could be a novel treatment strategy for poor prognostic BRAFMT CRC.

 

Read about the roles of the partner organizations within MErCuRIC here.

doi: 10.1158/1535-7163.MCT-17-0603. [Epub ahead of print]

Read the complete publication here.

Published 18 February 2018

MErCuRIC team from RECETOX, Masarykova Univerzita publish study results

‘A critical comparison of topology-based pathway analysis methods’ authored by the team of Dr Vlad Popovici at the Research Centre for Toxic Compounds in the Environment (RECETOX), Masarykova Univerzita has been recently published in PLoS One. The body of research by Ivana Ihnatova, Vlad Popovici and Eva Budinska appeared online on 25 January 2018.

Abstract

One of the aims of high-throughput gene/protein profiling experiments is the identification of biological processes altered between two or more conditions. Pathway analysis is an umbrella term for a multitude of computational approaches used for this purpose. While in the beginning pathway analysis relied on enrichment-based approaches, a newer generation of methods is now available, exploiting pathway topologies in addition to gene/protein expression levels. However, little effort has been invested in their critical assessment with respect to their performance in different experimental setups. Here, we assessed the performance of seven representative methods identifying differentially expressed pathways between two groups of interest based on gene expression data with prior knowledge of pathway topologies: SPIA, PRS, CePa, TAPPA, TopologyGSA, Clipper and DEGraph. We performed a number of controlled experiments that investigated their sensitivity to sample and pathway size, threshold-based filtering of differentially expressed genes, ability to detect target pathways, ability to exploit the topological information and the sensitivity to different pre-processing strategies. We also verified type I error rates and described the influence of overexpression of single genes, gene sets and topological motifs of various sizes on the detection of a pathway as differentially expressed. The results of our experiments demonstrate a wide variability of the tested methods. We provide a set of recommendations for an informed selection of the proper method for a given data analysis task.

Read about the role of the Masarykova Univerzita within MErCuRIC here.

doi: 10.1371/journal.pone.0191154

Read the complete publication here.

Published 25 January 2018

EuropaColon features a MErCuRIC patient’s perspective and our clinical trial

Through networking and information sharing, MErCuRIC is building bridges with colorectal cancer, personalised medicine and other stakeholder initiatives.

Currently, MErCuRIC is featured on the EuropaColon website with our first patient perspective story written by Ed Goodall. Special thanks to Ed! To read the entire story, click here. In addition, please visit our new web page for patient and carers stories here.

Finally, read about our clinical trial on the EuropaColon web page too.

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Reflections from EAPM 2017 where MErCuRIC PPI was Highlighted

The 1st European Alliance for Personalised Medicine (EAPM) Congress was held in Belfast in November 2017 where Margaret Grayson presented MErCuRIC’s mission and objectives with an emphasis of the Public and Patient Involvement (PPI) aspects of the project. Margaret, Chair, NI Cancer Research Consumer Forum commented, “The conference was a great opportunity for listening, talking, sharing and meeting researchers, politicians, regulators and other patient and public involvement representatives. The Congress highlighted the need for partnership and collaboration and showed the importance of MErCuRIC as a pan Europe study to benefit people diagnosed with bowel cancer. Among those I had the privilege to meet and share information about MErCuRIC with were Barbara and Mark Moss who are Patient Ambassadors. Barbara is a EuropaColon Board member and Chair of the EuropaColon Patient Advisory Group. The poster presentation session gave further time and opportunity to forge links with EuropaColon and other groups with patient initiatives, and to explain MErCuRIC as a study and describe the PPI input into the project’s design.”

Ruth Boyd remarked, ”Majella Woods, Margaret Grayson and I representing the NI Cancer Research Consumer Forum (NICRCF) were delighted to meet ECPC Director, Lydia Makaroff at the 1st EAPM Congress. The motto of the ECPC is ‘Nothing about us, without us!’ an ethos the NICRCF subscribe to too! Lydia Makaroff expertly chaired a conference session entitled ‘The Value of Innovation from the Cancer Patient Perspective.’ Lydia set the scene providing background to the ECPC and their paper on the ‘The Value of Innovation in Oncology.’ Other speakers covered topics such as access to innovation in the National Health Service (UK) (including enrolment to clinical trials), potential innovation in the UK bowel cancer screening programme, disparities across Europe in cancer care and outcomes, and the Data Lab in Scotland. This was a fascinating and thought-provoking agenda offering perspectives on innovation in diagnosis and treatment, equality of access to cancer care, and the significance of data, but the session also offered hope for future cancer outcomes through policy, technological advances, and collective working across all stakeholders.”

Pictured below left to right at EAPM Congress 2017: (left photo) Margaret Grayson with Barbara Moss of EuropaColon and Mark Moss, a Patient Ambassador, and (right photo) Lydia Makaroff ECPC Director, with Majella Woods, Margaret Grayson and Ruth Boyd of the NICRC Forum.

   

EuropaColon Patients’ Survey on The Unmet Needs of Patients Living with Metastatic Colorectal Cancer

Bowel cancer/CRC patients: Please contribute to an important survey that will help EuropaColon understand how patients cope with a diagnosis of metastatic colorectal cancer. EuropaColon aims to unite patients, caregivers, healthcare professionals, politicians, the media and the public in the fight against digestive cancers. The Organisation works with 43 groups in 32 European countries and has been recognised as the voice of colorectal cancer patients in Europe.

 

‘Answers to the survey questions will help support you and other patients more effectively in the future.’

Healthcare in Europe is different in every country. You might live in a country where a healthcare team supports you from diagnosis onward, and you might have access to the latest treatments and medicines for cancer as well as support from the different services. Even so, your experience is important to us because regretfully in some countries patients are not so fortunate.

EuropaColon needs your input and will use your anonymous replies to make recommendations for change: ‘There are no wrong answers – it is all about your experience and that is what EuropaColon seeks to know. Without this information, health ministries will not listen to our arguments.’

This is the first time a survey like this has been commissioned in Europe for colorectal cancer. In order to make this information valuable, EurpoaColon needs to recruit 1000 patients across Europe and aims to get responses from100 patients per country. Please share this information widely!

The survey is available in 14 European languages. Find it here.

MErCuRIC team from the Università degli Studi di Torino publish in Nature

‘Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth’ by authors Giovanni GermanoSimona LambaGiuseppe RospoLudovic BaraultAlessandro MagrìFederica MaioneMariangela RussoGiovanni CrisafulliAlice BartoliniGiulia LerdaGiulia SiravegnaBenedetta MussolinRoberta FrapolliMonica MontoneFederica MoranoFilippo de BraudNabil Amirouchene-AngelozziSilvia MarsoniMaurizio D’IncalciArmando OrlandiEnrico GiraudoAndrea Sartore-BianchiSalvatore SienaFilippo PietrantonioFederica Di Nicolantonio & Alberto Bardelli was published in Nature and online 29 November 2017.

 

Abstract: Molecular alterations in genes involved in DNA mismatch repair (MMR) promote cancer initiation and foster tumour progression1. Cancers deficient in MMR frequently show favourable prognosis and indolent progression2. The functional basis of the clinical outcome of patients with tumours that are deficient in MMR is not clear. Here we genetically inactivate MutL homologue 1 (MLH1) in colorectal, breast and pancreatic mouse cancer cells. The growth of MMR-deficient cells was comparable to their proficient counterparts in vitro and on transplantation in immunocompromised mice. By contrast, MMR-deficient cancer cells grew poorly when transplanted in syngeneic mice. The inactivation of MMR increased the mutational burden and led to dynamic mutational profiles, which resulted in the persistent renewal of neoantigens in vitro and in vivo, whereas MMR-proficient cells exhibited stable mutational load and neoantigen profiles over time. Immune surveillance improved when cancer cells, in which MLH1 had been inactivated, accumulated neoantigens for several generations. When restricted to a clonal population, the dynamic generation of neoantigens driven by MMR further increased immune surveillance. Inactivation of MMR, driven by acquired resistance to the clinical agent temozolomide, increased mutational load, promoted continuous renewal of neoantigens in human colorectal cancers and triggered immune surveillance in mouse models. These results suggest that targeting DNA repair processes can increase the burden of neoantigens in tumour cells; this has the potential to be exploited in therapeutic approaches.

 

Read about the role of the Universita degli Studi di Tornino in MErCuRIC here.

doi: 10.1038/nature24673

Read the complete publication here.

Published 29 November 2017

 

 

PPI in MErCuRIC is exemplified at the European Alliance for Personalised Medicine Conference, Belfast

Ruth Boyd and Margaret Grayson will present MErCuRIC as a case study in Patient and Public Involvement (PPI) in research at the European Alliance for Personalised Medicine Conference which is being held this week in Belfast, UK. The conference theme is ‘Personalising Your Health: A Global Imperative!’ and runs from 27- 30 November 2017.

Patient and Public Involvement (PPI) has become increasingly established as good practice in cancer research in the UK and, to various degrees, across Europe. INVOLVE defines PPI as ‘research being carried out ‘with’ or ‘by’ members of the public rather than ‘to’, ‘about’ or ‘for’ them. ‘The Northern Ireland Cancer Research Consumer Forum (NICRCF), a group of over 20 people affected by cancer working with researchers, has been a partner group in two large research programmes; the European MErCuRIC project a multicenter phase Ib/II clinical trial assessing a novel drug combination of MEK and MET inhibitors in advanced colorectal cancer (CRC) and S: CORT– a Stratified Medicine Consortium in CRC. These projects are case studies in patient/carer partnerships in personalised and precision medicine (PPM) research.’

For more information for patients interested in MErCuRIC, please click here.

Download the poster here EAPM Final Poster.

 

 

Two MErCuRIC publications from the Università degli Studi di Torino

Our MErCuRIC partners at the University of Torino (UNITO) have recently published two important papers. One appears in the October 5, 2017, edition of Gut, “Discovery of methylated circulating DNA biomarkers for comprehensive non-invasive monitoring of treatment response in metastatic colorectal cancer.” The second paper titled, “Tracking a CAD-ALK gene rearrangement in urine and blood of a colorectal cancer patient treated with an ALK inhibitor” was published in the October 2017 edition of Annals of Oncology. For additional information on these and other MErCuRIC publications, click here.

The team of Prof. Alberto Bardelli in the Department of Oncology at UNITO are pioneers in the tailoring of drug combinations to overcome resistance. During MErCuRIC, the group contribute to translational research aspects of the project and provide expertise in identifying resistance biomarkers, ctDNA based biopsies and xenopatient-based drug testing.

1st European Alliance for Personalised Medicine Congress

The 1st European Alliance for Personalised Medicine Congress – ‘Forward As One: Making personalised medicine a reality at national level’  is being held 27 – 30 Nov 2017 in Belfast, Northern Ireland.

The congress will be interactive, focusing on diseases, general science issues (Big Data, genomics, clinical trials, etc.) and the views, progress and health landscapes across Europe. With involvement from policymakers/regulators, MEPs, national healthcare officials, patient groups, HTA bodies, academics, researchers, healthcare professionals, industry representatives, journalists and more, the aim is to shape the EU health landscape now and into the future.

Registration is open and a preliminary agenda is now available.

Two events in Germany for Patient Advocates and Experts

ESMO Workshop: Science for Advocates Munich – 13 – 15 October 2017

Click here to apply and for further details. Travel grants available in limited number. ‘Science for advocates’ will be a 2-day interactive workshop (Friday afternoon till Sunday lunch-time) with a combination of lectures, independent and group work. To ensure effective communication, the workshop size will be limited to 35-40 European Cancer patient advocates. Participation is upon application only.

Advocates will have the opportunity to suggest a relevant scientific study of their interest as a test case for the workshop. Otherwise, ESMO faculty will be asked to name one recent relevant study per cancer field.

During the weekend, participants will have the opportunity to directly apply learned content to their study of interest, including the statistical background and the calculation of the ESMO MCBS for that therapy, and generate an infographic representation of the content.

EMBL Workshop Lifelong Learning in Biomedical Sciences Heidelberg- 5 – 7 December 2017

Click here to apply and for more details.

Biomedical research scientists and professionals with successful careers contribute to better research and improved outcomes for patients. Effective continuing professional development can be the catalyst to success for both individual careers and medical advances.

The Lifelong Learning in the Biomedical Sciences Conference 2017 will build on the outcomes and experiences of the 2016 Conference, extending to new topics and a wider audience. The conference will incorporate talks, hands-on workshops, and networking and poster sessions.

This second EMBL conference on Lifelong Learning in the Biomedical Sciences will bring together diverse stakeholders from across the academic, industrial, professional and training sectors to share best practice and actively shape the landscape of continuing professional development in the biomedical sciences. We call upon all who are interested in engaging to shape this future.