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ADAM22/LGI1 complex as a new actionable target for breast cancer brain metastasis
Sara Charmsaz1, Ben Doherty1, Sinéad Cocchiglia1
1Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
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.
Insights
Targeting ADAM22 with LGI1MIM shows promise for treating brain metastases in advanced breast cancer. This new therapeutic approach addresses the challenge of drug penetration across the blood-brain barrier (BBB).
Area of Science:
- Oncology
- Neuroscience
- Pharmacology
Background:
- Metastatic breast cancer is a leading cause of cancer death in women.
- Brain metastasis is a frequent and severe complication, particularly in estrogen receptor-positive disease, with poor prognosis.
- Drug delivery across the blood-brain barrier (BBB) is a significant hurdle for treating brain metastases.
Purpose of the Study:
- To identify novel, actionable molecular targets in breast cancer brain metastases.
- To develop and evaluate a therapeutic strategy targeting identified molecules, focusing on BBB penetration.
Main Methods:
- Global transcriptomic analysis of primary and metastatic tumors (n=35).
- Bioinformatic identification and validation of ADAM22 as a target in patient tumor tissue (n=843).
- In silico design and in vitro/ex vivo/in vivo assessment of a peptide mimetic (LGI1MIM) targeting ADAM22, including BBB penetration studies.
Main Results:
- ADAM22 was identified as a key target in the druggable genome specific to brain metastases.
- ADAM22 expression is linked to the development of breast cancer brain metastasis.
- LGI1MIM demonstrated efficacy in inhibiting disease progression and brain metastasis in vivo, with successful BBB penetration.
Conclusions:
- ADAM22 is a crucial factor in the development of breast cancer brain metastasis.
- Targeting ADAM22 with the peptide mimetic LGI1MIM offers a potential new therapeutic strategy for treating metastatic brain disease.
