new discovery on why some do not respond to anti-her2 therapy/possible prediction of

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who they might be

10-Jun-2014
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Contact: Yolanda Kennedy
yokenned@tcd.ie
353-189-63551
Trinity College Dublin
New research could provide key to overcoming resistance to HER2 targeted cancer treatments

Scientists have discovered an important new biomarker which could improve HER2 targeted cancer treatments

Dublin, Ireland, June 11th, 2014 – Scientists from the School of Pharmacy & Pharmaceutical Sciences, Trinity College Dublin have made a significant discovery of a new biomarker which may help overcome resistance to newer and more targeted anti-cancer drugs, such as Herceptin, for HER2 positive cancers. These findings may also help the early identification of patients who will benefit more from these treatments.

The researchers, led by Professor Lorraine O'Driscoll, Associate Professor of Pharmacology, Trinity, studied breast cancer cells and their extracellular vesicles (exosomes), which are 'packages' of information released out of cells. They discovered a molecule called Neuromedin U (NmU) which is strongly associated with resistance to the new anti-cancer drugs for HER2 positive cancers. This suggests NmU could be used as a biological marker to indicate the likelihood of responsiveness in a particular patient and may also be very important in the management of resistance to these drugs. The findings have just been published in leading international, peer reviewed journal: Cancer Research, the most frequently cited cancer journal in the world.

About one quarter of breast cancer patients are known as being HER2 positive, where the protein HER2 is found at greater amounts on cancer cells compared to normal cells and which is associated with a poorer prognosis for the patient. A relatively new range of targeted anti-cancer drugs became available in recent years to treat patients with HER2 positive breast cancer and some other cancers such as HER2 positive gastric cancer. The best known one is Herceptin (trastuzumab), but there are other newer drugs in this family, including lapatinib, neratinib, afatinib, pertuzumab, T-DM1.

Speaking about the challenges some patients face with these newer anti-cancer drugs, Professor O'Driscoll said: "Many patients with HER2 positive tumours gain huge benefit from these drugs. Unfortunately, however, some who seem suitable candidates based on a HER2 test, don't gain the maximum intended benefit from these treatments. They may have a natural level of resistance to the treatment which is not detectable with currently available tests, while some other patients respond at first but may then become unresponsive or develop resistance to the treatments."

Professor O'Driscoll continued: "Clinicians urgently need ways of predicting which patients with 'HER2 tumours' are likely to gain real benefit, both to ensure patients are given the optimal treatments and to ensure these very costly drugs are used where they will have the most benefit. Our discovery may offer a new way to predict or identify both innate and acquired resistance, overcome it and potentially block or prevent resistance. This would allow patients to get the full benefit from these particular anti-cancer treatments and help other patients to be more quickly identified and receive the treatment options which are more appropriate for them."

The scientists also found that the levels of NmU outside the cells reflects that within the cells indicating it may be used as an 'extracellular' blood-based marker. This could allow clinicians to access and sample the levels of NmU through a minimally-invasive blood test compared to testing biomarkers within tissues.

They also found that by tweaking NmU's amounts in the cells, they could restore sensitivity to this family of anti-cancer drugs and offer an approach which may help prevent or overcome the serious resistance problem.

The research team conducted other studies which found that blocking NmU also significantly slowed the tumour's growth in the body and they plan to conduct further studies in this area.

The intellectual property has been protected to facilitate the translation of these discoveries to the benefit of patients with two patents pending in Europe and the US. This will be aided by the team's collaboration with the All Ireland Oncology Research Group (ICORG).

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These studies, by Professor Lorraine O'Driscoll and her research group based at School of Pharmacy & Pharmaceutical Sciences/Trinity Biomedical Sciences Institute, and in collaboration with St. Vincent's University Hospital, Dublin City University and Royal College of Surgeons in Ireland, were supported by Science Foundation Ireland as part of Molecular Therapeutics for Cancer Ireland (MTCI), the Marie Keating Foundation and EU FP7 Cooperation in Science & Technology ME-HaD.

The paper is available online here: http://cancerres.aacrjournals.org/co...-2053.abstract

For media queries contact:

Press Officer for the Faculty of Health Sciences, Trinity College Dublin, Yolanda Kennedy, tel:+353-1-8963551; yokenned@tcd.ie


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Neuromedin U: a candidate biomarker and therapeutic target to predict and overcome resistance to HER kinase inhibitors
Sweta Rani1, Claire Corcoran2, Liam Shiels3, Serena Germano4, Susan Breslin5, Stephen Madden6, Martina S McDermott7, Brigid C Browne7, Norma O'Donovan8, John Crown9, Martina Gogarty10, Annette T Byrne3, and Lorraine O'Driscoll11,*
+ Author Affiliations

1school of pharmacy and pharmaceutical sciences, tcd
2School of Pharmacy & Pharmaceutical Sciences, Trinity College Dublin
3Department of Physiology and Medical Physics & Centre for Systems Medicine, Royal College of Surgeons in Ireland
4DISCAFF Dept. and DFB Center, University of Piemonte orientale
5chool of Pharmacy and Pharmaceutical Sciences & Trinity Biomedical Sciences Institute, Trinity College Dublin
6Dublin City University, National Institute for Cellular Biotechnology
7Molecular Therapeutics for Cancer Ireland (MTCI), Dublin City University
8Dublin City University, National Institute of Cellular Biotechnology
9Oncology, St. Vincent's Hospital
10Trinity College Dublin, School of Pharmacy and Pharmaceutical Science & Trinity Biomedical Sciences Institute
11School of Pharmacy and Pharmaceutical Science & Trinity Biomedical Sciences Institute, Trinity College Dublin
↵* Corresponding Author:
Lorraine O'Driscoll, School of Pharmacy and Pharmaceutical Science & Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Dublin, 002, Ireland lodrisc@tcd.ie
Abstract

Intrinsic and acquired resistance to HER-targeting drugs occurs in a significant proportion of HER2-overexpressing breast cancers. Thus, there remains a need to identify predictive biomarkers that could improve patient selection and circumvent these types of drug resistance. Here we report the identification of neuromedin U (NmU) as an extracellular biomarker in cells resistant to HER-targeted drugs. NmU overexpression occurred in cells with acquired or innate resistance to lapatinib, trastuzumab, neratinib, afatinib, all all of which displayed a similar trend and suggested NmU induction may be an early response. An analysis of 3489 cases of breast cancer showed NmU to be associated with poor patient outcomes, particularly those with HER2-overexpressing tumors independent of established prognostic indicators. Ectopic overexpressino of NmU in drug-sensitive cells conferred resistance to all HER-targeting drugs, whereas RNAi-mediated attentuation sensitized cells exhibiting acquired or innate drug resistance. Mechanistic investigations suggested that NmU acted through HSP27 as partner protein to stabilize HER2 protein levels. We also obtained evidence of functional NmU receptors on HER2-overexpressing cells, with the addition of exogenous NmU eliciting an elevation in HER2 and EGFR expression along with drug resistance. Lastly, we found that NmU appeared to function in cell motility, invasion and anoikis resistance. In vivo studies revealed that NmU attenuation impaired tumor growth and metastasis. Taken together, our results defined NmU as a candidate drug response biomarker for HER2-overexpressing cancers, and a candidate therapeutic target to limit metastatic progression and improve the efficacy of HER-targeted drugs.

Received July 23, 2013.
Revision received April 4, 2014.
Accepted April 28, 2014.
Copyright © 2014, American Association for Cancer Research.