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Final RATHER Update

Final Summary of RATHER Project, September 2018

RATHER (Rational therapy for breast cancer: individualised treatment for difficult-to-treat breast cancer subtypes) aimed to identify new therapeutic targets for two difficult to treat subtypes of breast cancer. A quarter of all breast cancer patients are diagnosed with these difficult-to-treat subtypes of breast cancer; Invasive Lobular Carcinoma (ILC), an aggressive form of breast cancer that is resistant to standard therapies (10% of cases globally), or Triple Negative (TN) breast cancer which lacks the common targets for treatment; estrogen, progesterone and HER2 receptors (15% of cases globally). Both are linked with poor prognosis and there are currently no effective therapies available.

RATHER was a large multidisciplinary collaborative project funded by the EU under the FP7 programme (€6 million) led by University College Dublin. The consortium comprised 8 partners from the academic and private sectors; University College Dublin (Ireland), OncoMark (Ireland), Agendia (the Netherlands), Netherlands Cancer Institute (the Netherlands), Institut Curie (France), Vall d’Hebron Hospital (Spain), Cambridge University (UK), and Lund University (Sweden).

The RATHER consortium aimed to better understand difficult-to-treat breast cancers by studying kinases, which are activated in many cancer types and which have been shown to play a role in cancer. In cancer, there is a strong correlation between genetic mutations and a patient’s response to drugs. Therefore, the RATHER consortium looked to investigate mutations in kinases to deliver personalised therapeutic interventions to the 25% of patients who currently lack effective targeted therapies.

To survey kinases to identify novel biomarkers for new molecular diagnostic assays or novel drug targets for new therapeutic approaches, the consortium used a multidisciplinary approach applying comprehensive genomic, transcriptomic and functional analysis and data integration, leading to the validation of targets / biomarkers, the selection of lead candidates, and the initiation of a Phase Ib/II clinical trial.

The RATHER project integrated clinical and preclinical research, establishing collaborations between academia and industry delivering a number of important results and outputs throughout the duration of the project. The results from the RATHER project have been published in international scientific journals and presented at international conferences, with a number of manuscripts still in preparation pending further validation of results. Work on the promising targets identified during the project will be brought to completion beyond RATHER, facilitated by the relationships and collaborations established during this project.

Some major outputs from the RATHER project include one ongoing clinical trial (POSEIDON) directly funded by the RATHER project, 3 clinical trials entered into by RATHER consortium partners (GELATO, I-SPY2 and SUBITO), a validated assay for ILC (MammaPrint), a new biomarker signature for ILC (immune/hormone related), a new biomarker signature for TN breast cancer (BRCAness), a new biomarker for TN breast cancer (CDK7), a new treatment strategy for ILC (MAP3K1/MAP2K4 genotype-dependent) and a new treatment strategy for TN breast cancer (CDK7 & BCL-2/XL-targeted).

In summary, the RATHER consortium have published 27 articles (19 peer-reviewed original articles, 3 review articles, 4 abstracts) and 1 book chapter, have delivered 57 presentations (32 international, 25 national) and presented 28 posters. Four patents have been filed.


RATHER Year 6 Update

Irish-led research discovers potential new way to treat aggressive type of breast cancer, Monday, 17 th July

Research led by Irish scientists has found a potential new approach to treating one of the most difficult-to-treat forms of breast cancer, which currently has limited treatment options. Scientists from BREAST-PREDICT, an Irish Cancer Society Collaborative Cancer Research Centre, in collaboration with RATHER, an EU-funded research consortium, have shown that a new drug, called THZ-1, can prevent the growth of triple negative breast cancer. Their findings have been published in the journal Cancer Research.

Triple negative breast cancer affects approximately one in five women diagnosed with breast cancer, and is more often diagnosed in younger women. This aggressive subtype lacks three important proteins or biomarkers in the tumour cells, namely estrogen receptor, progesterone receptor and HER2. This means that patients with this type of breast cancer cannot receive ‘targeted therapies’ such as hormone therapy (e.g. Tamoxifen) or Herceptin. Instead, the only effective treatment for these patients is chemotherapy, making this type of cancer one of the most difficult to treat. Although many of these patients do respond well to chemotherapy, resistance of the tumour to this treatment is a common problem. Patients with resistant disease have a poor prognosis, and their tumours are more likely to return and spread following treatment. Doctors and researchers are urgently looking for new treatment options for these patients.

This most recent study focused on a protein called CDK7, which the researchers found to be present at high levels in triple negative breast cancers. Interestingly, patients with high levels of CDK7 present in their tumour were more likely to experience a disease relapse following standard chemotherapy treatment. This means that high CDK7 levels could be used as a ‘biomarker’ to identify patients unlikely to respond well to chemotherapy. This type of test could be very useful to their doctors, as they could then prioritise these patients for a more aggressive treatment regime.

The researchers also tested a drug that acts on CDK7, called THZ-1, to investigate if this could be a novel treatment for triple negative breast cancer. Remarkably, treating triple negative breast cancer cells grown in the laboratory with THZ-1 halted their growth, both on its own and in combination with other treatments. The researchers proposed THZ-1 as a novel treatment option for this aggressive cancer type, particularly in combination with existing treatments, to improve their success rate.

Commenting on the findings, Prof. William Gallagher, the lead investigator on the study and Professor of Cancer Biology at UCD, said: “This study has uncovered an important new treatment possibility for patients with triple negative breast cancer, a particularly aggressive subtype of the disease. This success was only possible through a concerted team-based approach from multiple national and international collaborators.”

This study was supported by the Irish Cancer Society Collaborative Cancer Research Centre BREAST-PREDICT and the EU-funded RATHER project, an international research consortium focused on tackling difficult-to- treat subtypes of breast cancer; both of which are co-ordinated by Prof. Gallagher. While further research is needed on this novel treatment before it can be used in breast cancer patients, this work is a key step in opening up a wider range of new and less toxic treatment options for triple negative breast cancer patients.

Head of Research at the Irish Cancer Society, Dr Robert O’Connor, hailed the development as a significant milestone in the ongoing work of BREAST-PREDICT: “This paper highlights the vital work which the Irish Cancer Society invests in through the generous support of the public. As Director of BREAST-PREDICT, Prof Gallagher has been pivotal in overseeing the work of more than 50 breast cancer researchers, funded by generous donations to the Irish Cancer Society. Through his leadership, BREAST-PREDICT is making huge strides in breast cancer research, making new discoveries about these cancers which will potentially lead to more ways to prevent, detect and treat the disease and ensure more cancer survivors live longer, happier lives.”


RATHER Year 5 Review Meeting

Netherlands Cancer Institute, Amsterdam, 19 January 2016

Members of the RATHER team met recently at the Netherlands Cancer Institute (NKI) in Amsterdam to discuss the progress of the project and the RATHER-funded clinical trial, POSEIDON. The scientific component of RATHER is nearing completion, with several publications in peer-reviewed scientific and medical journals detailing findings on triple negative breast cancer and invasive lobular carcinoma. A number of potential biomarkers have been identified as part of the RATHER programme, and several clinical trials are due to begin shortly that will study their utility in patients.

The two industrial partners in RATHER, OncoMark (Ireland, www.oncomark.com) and Agendia (the Netherlands, www.agendia.com) are continuing their development of assays that will help breast cancer patients to decide whether therapies will be beneficial to them. Updates regarding these developments will be published on their websites.

The POSEIDON clinical trial (www.clinicaltrials.gov identifier NCT02285179) is progressing well, with phase Ib complete (to determine a dose of the investigational drug), and phase II expected to begin this Spring. Patients will be recruited at several clinical centres in the Netherlands, Spain, France and the UK, and will be studied to see whether the investigational drug (taselisib, developed by Genentec Inc.) is effective at treating women with breast cancer, particularly those with aggressive invasive lobular carcinoma.


Ground-breaking European clinical trial testing new investigational drug for the treatment of breast cancer

05 October 2015

Cancer researchers, oncologists and international pharmaceutical company join forces to test a new investigational drug for breast cancer

The progress of a large pan-European clinical trial (POSEIDON) into a novel targeted study drug (called taselisib or GDC-0032) for breast cancer was announced today by the collaborative RATHER project funded by the European Commission. The POSEIDON clinical trial centres, based in the Netherlands Cancer Institute (Amsterdam), Cambridge Cancer Centre (UK), and the Vall d’Hebron Hospital (Barcelona, Spain), began to study patients treated with this investigational drug in December 2014.

Breast cancer is the most frequently diagnosed cancer in women, accounting for one quarter of all female cancers, and is the second leading cause of death from cancer. The RATHER project focuses on finding new drug targets for two types of breast cancer – invasive lobular carcinoma (ILC), an aggressive cancer that does not respond well to current treatments, and triple negative breast cancer which lacks the oestrogen, progesterone and HER2 receptors- common and effective drug targets in other types of breast cancer. These cancers account for one quarter of all breast cancers, and have a very poor prognosis.

There has been considerable success in targeting gene mutations with specific drugs in other cancers, and so the RATHER project team are aiming to find other possible drug targets, by focusing on protein kinases such as PI3K, the protein inhibited by the novel investigational drug. Taselisib has been developed by Genentech, Inc. (a member of the Roche Group), and is an isoform-specific inhibitor of the protein PI3K. Genes encoding PI3K are often mutated in breast cancer, particularly in ILC, suggesting that targeting these genes could effectively halt the growth of cancers that are ‘driven’ by kinases.

Now that the dose escalation part of the POSEIDON trial has been completed, we look forward to opening the randomised phase II part of the trial later this year to assess its effectiveness at treating hormone receptor-positive (HER2-negative) breast cancer patients. It is expected that phase II will be completed by the end of 2017, with nearly 300 patients from several European countries including the Netherlands, UK, Spain and France participating in the trial.

The joint leaders of the POSEIDON clinical trial, and members of the RATHER programme, Prof. Sabine Linn (Netherlands Cancer Institute) and Dr. Richard Baird (University of Cambridge, UK), said “we are delighted that recruitment to the POSEIDON trial is going so well; the combination of taselisib with endocrine therapy is an important new therapeutic approach to test for patients with hormone-driven advanced breast cancer”.

The Coordinator of the RATHER project, Prof. William Gallagher (University College Dublin, Ireland), emphasised the importance of this clinical trial and ongoing research into breast cancer, saying “This investigator-led clinical trial provides an exciting opportunity to further extend the arsenal of therapeutic weapons against breast cancer and, importantly, in a highly targeted way. Indeed, this ground-breaking clinical trial is a prime example of the prevalence and power of personalised cancer medicine”.

The POSEIDON clinical trial is funded by RATHER, EurocanPlatform (another EU-funded collaborative project), the Netherlands Cancer Institute, and by Genentech. Further details of the POSEIDON trial are posted on www.clinicaltrials.gov.

About the RATHER Project: The main aim of RATHER (www.ratherproject.com) is to find new drug targets for two aggressive types of breast cancer, for which there are currently a lack of effective therapies. RATHER is a collaboration between 8 European partners – 6 academic institutions, in Ireland (University College Dublin), the UK (Cambridge University), The Netherlands (Netherlands Cancer Institute), France (Institut Curie), Sweden (Lund University) and Spain (Vall d’Hebron Hospital), and 2 SMEs, based in Ireland (OncoMark) and The Netherlands (Agendia). Funding: The RATHER project is funded by the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 258967.

Contact information: Prof. Sabine Linn, POSEIDON trial chief investigator, Netherlands Cancer Institute (NKI), Amsterdam, s.linn@nki.nl, Dr. Richard Baird, POSEIDON trial co-investigator, University of Cambridge, UK, richard.baird@medschl.cam.ac.uk, Prof. William Gallagher, RATHER coordinator, University College Dublin, Ireland, +353 1 7166743, william.gallagher@ucd.ie.  

Targeting the drivers of difficult-to-treat breast cancers

HORIZON 2020, World Cancer Day, 4 February 2015

One quarter of breast cancer cases belong to two subtypes that are difficult to treat. EU-funded researchers are identifying new therapeutic targets for these patient groups. The research has already led to new diagnostic tools, while patients are already being enrolled for clinical trials.

Continue reading on the HORIZON 2020 website.


RATHER Year 4 Review Meeting

Dublin, 20 January – 21 January 2015

The 4th annual RATHER meeting took place recently in Dublin, hosted jointly by UCD and OncoMark. An interactive workshop took place in the UCD Conway Institute on Tuesday the 20th of January, followed that afternoon by a successful mini-symposium entitled ‘Leveraging the power of systems medicine in personalised oncology’.

The symposium was hosted jointly by RATHER and BREAST-PREDICT (www.breastpredict.com), and featured speakers who are experts in utilising innovative methods to analyse and model individual patient biology and response to treatment, in order to discover and develop new therapies for cancer. Speakers included Prof. Carlos Caldas, an oncologist and Chair of Cancer Medicine in Cambridge, Dr Nicolas Stransky, a senior scientist at Blueprint Medicines in Boston, Prof. Lodewyk Wessels, a computational biologist at the Netherlands Cancer Institute, Prof. Walter Kolch, the Director of the UCD Conway Institute, and Prof. Jochen Prehn, Director of the RCSI Centre for Systems Medicine. An enjoyable dinner was held that evening for RATHER members and symposium guests to mingle and network.

The main RATHER progress meeting was held on the following day in the NovaUCD buildings, where OncoMark are based. A review of the project’s progress by Prof. William Gallagher of UCD emphasised the success of RATHER so far, with the majority of the data collected and the ongoing analyses and integration of different platforms yielding encouraging results. With a 12 month extension of the RATHER programme approved by the EU, in order to accommodate an exciting clinical trial, the remaining two years of the programme promise to be very interesting. The landmark pan-European clinical trial of a novel breast cancer therapy, led by investigators within RATHER and another EU FP7-funded network, EurocanPlatform, began to recruit and treat patients in November 2014. More details of the clinical trial will be published in the coming weeks.


EU breast cancer research targets personalised treatment

Brussels, 27 October 2014

Today, in most developed countries, one in eight women will likely develop breast cancer during their lifetime. Boosting support for early detection, more effective treatments and better palliative care has been the focus of Breast Cancer Awareness Month this October. One promising avenue which a number of EU-funded research projects are taking is personalised medicine – adjusting treatment to a patient’s specific circumstances and condition.

From lab to clinic
The EU project TRANSBIG has been linking laboratory work more closely to treatment with ‘translational’ research, says scientific director Fatima Cardoso of the Champalimaud Clinical Center in Lisbon, Portugal.: “TRANSBIG contributed to tackling the fragmentation in breast cancer translational research by strengthening relationships between leading European researchers in the field. It has also led to the successful launch of what is viewed as one of Europe’s most innovative breast cancer trials of the past decade.”

The results of the trial, known as MINDACT, will be available in 2015. The trial is investigating whether genomic analysis can help physicians make better decisions on whether a patient can avoid chemotherapy after breast cancer surgery.

Clinical trials have shown that chemotherapy, while effective, can also lead to secondary cancers, damage to the heart, early menopause and reduced cognitive functions. And a substantial proportion of patients with early-stage breast cancer are thought to be over-treated, says Cardoso. MINDACT may avoid chemotherapy in 10 – 20 % of patients.

MINDACT has enrolled more than 6 600 women in 9 countries for the research, managed by the European Organisation for the Research and Treatment of Cancer (EORTC), and developed in collaboration with the Breast International Group (BIG), coordinator of TRANSBIG.

“Hundreds of thousands of women can benefit from translating research breakthroughs to life-saving treatments for breast cancer,” said EU Research, Innovation and Science Commissioner Máire Geoghegan-Quinn. “Cancer research has been a priority for EU research funding. Some €1.4 billion was devoted to translational cancer research from 2007 to 2013. We will continue that focus under Horizon 2020, speeding up the transfer of basic knowledge to early diagnosis, preventive and therapeutic approaches.”

Other EU research projects on breast cancer include EPIC, which studied how changes to a person’s diet could potentially prevent breast cancer. The CareMore and CTCTRAP projects are focusing on circulating tumour cells and DNA in a patient’s blood to guide early diagnosis and treatments for women with metastatic breast cancer. Meanwhile ASSURE is looking at ways to tailor breast cancer screening to an individual’s needs, and is developing alternatives to mammography – unsuitable for cancer detection in women with dense breasts.

Another project, RATHER, is identifying novel treatments, along with personalised diagnostic techniques, for women with triple-negative and invasive lobular breast cancer. These are difficult-to-treat cancers for which no targeted therapies are currently available. Finally, the MERIT project is developing a way to treat triple-negative breast cancers with personalised RNA vaccines that are unique to each patient.

Breast cancer remains the second most common cancer in the world, and kills more women than any other cancer type. In the EU, a record 364 449 women found out they had the disease in 2012. The EU invested €160 million in breast cancer research from 2007 to 2013 and that support will continue through Horizon 2020, the new research and innovation programme for 2014-2020.

On 1 January 2014, the European Union launched a new research and innovation funding programme called Horizon 2020. Over the next seven years almost €80 billion will be invested in research and innovation projects to support Europe’s economic competitiveness and extend the frontiers of human knowledge. The EU research budget is focused mainly on improving everyday life in areas like health, the environment, transport, food and energy.



EU Prize for Women Innovators 2014

Brussels, 10 March 2014

Left to right: Laura van’t Veer (Chief Research Officer, Agendia NV), Mark Rutte (Prime Minister of the Netherlands)

Left to right: Máire Geoghegan-Quinn (European Commissioner for Research, Innovation and Science), Mark Rutte (Prime Minister of the Netherlands), Laura van’t Veer (Co-founder and Chief Research Officer, Agendia NV), Saskia Biskup (Co-founder and Chief Executive Officer, CeGaT GmbH), Ana Maiques (Co-founder and Chief Executive Officer, Starlab), José Manuel Barroso (President of the European Commission)

Laura van’t Veer, co-founder and Chief Research Officer at Agendia NV, has been announced as the second place winner of the EU Prize for Women Innovators 2014. Laura, part of the RATHER team, was presented with her award on Monday 10 March. The RATHER team is very proud of Laura and this exceptional achievement!

See Prize Website for additional details.

RATHER Year 3 Review Meeting

Barcelona, 21 January – 22 January 2014

The RATHER Year 3 Review Meeting took place in Vall d’Hebron Hospital, Barcelona. Consortium members delivered updates on their work, and a series of productive discussions were held. Particular focus was placed on future experimental plans, data integration techniques and the clinical trial arm of the project.

RATHER Integration Workshop

Dublin, 8 July – 12 July 2013

The RATHER Consortium has generated large quantities of data from a number of different platforms – kinome sequencing, RNA sequencing, DNA microarrays, RNA microarrays and reverse phase protein lysate arrays. A key challenge involved in any project of this complexity is the successful integration of these data to maximise biological insight. To this end, a group of RATHER researchers attended a week-long meeting in Dublin to discuss and apply bioinformatic integration techniques to the data generated thus far. This meeting was highly productive, and succeeded in producing a comprehensive integration plan that will direct the group’s efforts over the coming months.


AACR Annual Meeting 2013

Washington DC, 6 April – 10 April 2013

Several members of the RATHER team attended the American Association for Cancer Research Annual Meeting in Washington DC. More than 18,000 cancer researchers from around the world attended the event, and the theme – ‘Personalising Cancer Care Through Discovery Science’ – complemented the interest of the RATHER Consortium in personalised treatments for breast cancer.

Two RATHER researchers were selected to present their scientific research at the AACR meeting. Justine Peeters (Agendia) presented a poster titled ‘Development of comprehensive molecular portraits of lobular breast cancer within the RATHER (Rational Therapy for Breast Cancer) Consortium’, and Tesa Severson from the NKI presented a poster titled ‘Investigation of BRCA1-like signature in triple negative breast cancers within the RATHER (Rational Therapy for Breast Cancer) Consortium’. Both posters received a lot of interest from cancer researchers.

RATHER researchers who were attending the AACR held a separate meeting to discuss recent progress and the preparation of the Consortium’s first manuscript for peer-reviewed scientific publication. The two Coordinators of the RATHER Consortium, Prof. William Gallagher and Prof. René Bernards also had a productive meeting with the members of the RATHER Scientific Advisory Board who were pleased with the progress of the project.

RATHER Year 2 Review Meeting

Paris, 28 January – 29 January 2013

The RATHER Year 2 Review Meeting was held under the watchful eyes of Marie and Pierre Curie who have been immortalised by a statue outside the Institut du Radium, part of the Institut Curie in Paris.

35 members of the RATHER Consortium attended the two day meeting, which included individual presentations of the research that is being conducted in each Institution, as well as productive round-table discussions about the future plans for the RATHER project. We were fortunate to have Prof. Elaine Kay from Beaumont Hospital in Dublin in attendance to provide expert independent advice.

Day 1 ended with a very enjoyable dinner at a local restaurant, enabling the members of each team to meet and catch up.

The meeting continued the following day with fruitful discussions about how to merge and integrate the large volumes of data generated by each member. To facilitate this, a working group was set up to start the complex tasks of data integration and normalisation, and we expect this to produce some very exciting results in the coming months.

The meeting was an important opportunity for the members of RATHER to meet and to discuss in person the progress of the project as well as the future implications of this research on the breast cancer field. 2013 should be an exciting year for RATHER!

ESOF 2012: Scientific Session

Dublin, 15 July 2012

On the final day of the highly successful EuroScience Open Forum 2012 conference, which was held from 11th – 15th July 2012, a focused session on The True Cost of Personalised Medicine was held. This event was chaired by Professor William Gallagher (Associate Professor of Cancer Biology, University College Dublin, and RATHER administrative co-ordinator).

Three speakers from academia and industry provided context for the session: Dr. Catherine Kelly (Mater Misericordiae University Hospital) delivered an oncologist’s perspective on selecting appropriate drugs for individual patients, while Dr. Iris Simon (Agendia NV, and RATHER work package leader) discussed her industry perspective on the development of personalised molecular diagnostics for cancer patients. Finally, Prof. Nils Wilking (Karolinska Institute) addressed the economic cost of personalised cancer medicine.

Following the talks, the speakers engaged with an enthusiastic audience of 70+ for a fruitful discussion on the topics raised.

Left to right: Prof. Nils Wilking, Dr. Catherine Kelly, Dr. Iris Simon and Prof. William Gallagher

AACR Annual Meeting 2012

Chicago, 31 March – 1 April 2012

The scientific coordinator of the RATHER project, Rene Bernards, delivered an update on the project at the annual AACR conference in Chicago. His slides are available here.

RATHER Year 1 Review Meeting

Amsterdam, 8 February 2012

The RATHER Year 1 Review Meeting was held in early February at the Sheraton Amsterdam Hotel, comfortably shielded from the sub-zero outdoor temperatures that froze the city’s canals.

The meeting offered a great opportunity for consortium members to reflect on a very productive first year and, more importantly, to discuss and refine our plans for the next 12 months and beyond. Excellent progress was reported across our various work packages, and the teams are looking forward to another fast-paced year ahead.

René arranged an enjoyable networking event for the evening, where the teams were able to catch up on a personal level and introduce their newest members.

RATHER Kick-Off Meeting

Dublin, 15 February 2011

The RATHER kick-off meeting was held in the Radisson Blu St Helens Hotel, Stillorgan in Dublin on the 15/16th February 2011.


New EU-Funded Cancer Research Projects

Brussels, 4 February 2011

To mark World Cancer Day, this news alert outlines some of the 19 new cancer research projects which will be financed by the European Union to the tune of almost €95 million. With this new investment, EU financial support for cancer research since 2003 amounts to close to €1 billion, funding 183 projects. This support has created the necessary collaboration between cancer centres, researchers and patient advocacy groups in different countries to improve the way in which rare cancers are tackled, help make the best treatments available to everyone and reach more patients.

A survey among cancer experts has identified the need to reinforce networking and alignment of existing national and EU initiatives, to develop further support infrastructures for research purposes and to encourage collaboration between the major European centres for research and treatment of cancer.

To address these needs, European collaborative efforts in EU cancer projects have taken a problem-solving approach, focusing on overarching issues of prevention, pathogenesis, early detection, diagnosis and treatment of cancers, as well as care of cancer patients. Big efforts are being made on breast cancer and rare cancers, melanoma, leukaemia and cancer imaging. Cancer in women and children receives special attention, and, for the first time in Europe, a project will focus on the long-term side effects of treatment in childhood cancer survivors.

Examples of new research projects on cancer

RATHER — Rational Therapy for Breast Cancer: Individualized Treatment for Difficult-to-Treat Breast Cancer Subtypes

There are currently no effective targeted therapies for one quarter of all breast cancer patients. The RATHER project is expected to deliver proof-of-concept for novel therapeutic interventions, together with matched personalised diagnostic approaches for patients for whom there are no targeted therapies available. The two difficult-to-treat subtypes to be investigated are “triple negative” breast tumours (15% of all breast cancers) and invasive lobular carcinomas of the breast (10% of breast tumours).

— Duration: 4 years
— EU contribution: €6 million
— Coordinator: Prof. William Gallagher, UCD Conway Institute, University College Dublin, IE, william.gallagher@ucd.ie
— Partners from: IE, NL, FR, SE, ES, UK


RATHER Rational Therapy for Breast Cancer: Individualized Treatment for Difficult-to-Treat Breast Cancer Subtypes

Coordinator: Liam GALLAGHER
Project Number: 258967
EC contribution: € 5,995,786
Project website: http://www.ratherproject.com

Cancer genotyping has identified a number of correlations between mutations in specific genes and responses to targeted anti-cancer drugs, with many mutations occurring in kinases or downstream signaling components. While there are several ongoing large-scale genome re-sequencing studies for the major cancer types, there is no systematic effort to investigate kinase mutations in distinct biological subtypes of these cancers. Here, we will explore the rate of activation of all kinases (the “kinome”) in two poor-prognosis subtypes of breast cancer for which there are currently no targeted therapies available, namely “triple negative” (TN) breast tumors lacking the estrogen-, progesterone- and HER2 receptors, constituting 15% of breast cancers, and invasive lobular carcinomas (ILC) of the breast, which represent 10% of breast tumors. Thus, we lack effective targeted therapies for one quarter of all breast cancer patients. In this project, we will identify and validate novel kinase targets for therapy for these TN and ILC subtypes. Kinase targets will be identified via a 4-pronged approach:

  1. direct re-sequencing of the kinome of 150 TN and 150 ILC tumors,
  2. determination of abundance and activation status of kinases in these tumors by reverse phase protein array and tissue microarray technologies,
  3. determination of copy number variation by SNP arrays, and
  4. mRNA quantitation of the kinome using DNA microarrays.

Potential kinase targets for therapy will be validated in preclinical models using RNA interference. Finally, we will perform an adaptive phase I/II clinical trial with specific small molecular (antibody-based) kinase inhibitors for the validated kinase targets (or downstream signaling pathway) in patients with the specific kinase alterations identified. The project will deliver proof-of-concept for novel therapeutic interventions, together with matched molecular diagnostic approaches for patient stratification, for up to 25% of breast cancer patients.