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ADAM22/LGI1 complex as a new actionable target for breast cancer brain metastasis.

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posted on 16.12.2020, 17:33 by Sara Charmsaz, Ben Doherty, Sinead Cocchiglia, Damir Vareslija, Attilio Marino, Nicola Cosgrove, Ricardo Marques, Nolan Priedigkeit, Siobhan Purcell, Fiona Bane, Jarlath Bolger, Christopher Byrne, Philip J O’Halloran, Francesca Brett, Katherine Sheehan, Kieran Brennan, Ann Hopkins, Stephen Keelan, Petra Jagust, Stephen Madden, Chiara Martinelli, Matteo Battaglini, Steffi Oesterreich, Adrian V Lee, Gianni Ciofani, Arnold Hill, Leonie Young

Background: Metastatic breast cancer is a major cause of cancer-related deaths in woman. Brain metastasis is a common and devastating site of relapse for several breast cancer molecular subtypes, including oestrogen receptor-positive disease, with life expectancy of less than a year. While efforts have been devoted to developing therapeutics for extra-cranial metastasis, drug penetration of blood–brain barrier (BBB) remains a major clinical challenge. Defining molecular alterations in breast cancer brain metastasis enables the identification of novel actionable targets.


Methods: Global transcriptomic analysis of matched primary and metastatic patient tumours (n = 35 patients, 70 tumour samples) identified a putative new actionable target for advanced breast cancer which was further validated in vivo and in breast cancer patient tumour tissue (n = 843 patients). A peptide mimetic of the target’s natural ligand was designed in silico and its efficacy assessed in in vitro, ex vivo and in vivo models of breast cancer metastasis.


Results: Bioinformatic analysis of over-represented pathways in metastatic breast cancer identified ADAM22 as a top ranked member of the ECM-related druggable genome specific to brain metastases. ADAM22 was validated as an actionable target in in vitro, ex vivo and in patient tumour tissue (n = 843 patients). A peptide mimetic of the ADAM22 ligand LGI1, LGI1MIM, was designed in silico. The efficacy of LGI1MIM and its ability to penetrate the BBB were assessed in vitro, ex vivo and in brain metastasis BBB 3D biometric biohybrid models, respectively. Treatment with LGI1MIM in vivo inhibited disease progression, in particular the development of brain metastasis.


Conclusion: ADAM22 expression in advanced breast cancer supports development of breast cancer brain metastasis. Targeting ADAM22 with a peptide mimetic LGI1MIM represents a new therapeutic option to treat metastatic brain disease

Funding

SFI Pfizer Biotherapeutics Award

Irish Cancer Society Collaborative Cancer Research Centre grant, CCRC13GAL

Science Foundation Ireland Investigator Award 12/IA/ 1294

Breast Cancer Ireland Programme Grant EU- FP7-IAPP

Breast Cancer NOW grant, 2018JulPR1094

SFI Strategic Partnership Programme POI, 18/SPP/5322

Breast Cancer NOW Fellowship 2019AugSF1310

Science Foundation Ireland Frontiers Award

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The original article is available at www.biomedcentral.com

Published Citation

Charmsaz S, Doherty B, Cocchiglia S, Varešlija D, Marino A, Cosgrove N, Marques R, Priedigkeit N, Purcell S, Bane F, Bolger J, Byrne C, O'Halloran PJ, Brett F, Sheehan K, Brennan K, Hopkins AM, Keelan S, Jagust P, Madden S, Martinelli C, Battaglini M, Oesterreich S, Lee AV, Ciofani G, Hill ADK, Young LS. ADAM22/LGI1 complex as a new actionable target for breast cancer brain metastasis. BMC Medicine. 2020;18(1):349.

Publication Date

19 November 2020

PubMed ID

33208158

Department/Unit

  • Beaumont Hospital
  • Data Science Centre
  • Pathology
  • Surgery

Research Area

  • Neurological and Psychiatric Disorders
  • Gynaecology, Obstetrics and Perinatal Health
  • Cancer

Publisher

BiomedCentral

Version

  • Published Version (Version of Record)

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Royal College of Surgeons in Ireland

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