June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Evaluating Cannabinoid Receptors as A Therapeutic Target for Uveal Melanoma
Author Affiliations & Notes
  • Marzia Pendino
    University College Dublin, Dublin, Dublin 4, Ireland
    University College Dublin Conway Institute of Biomolecular and Biomedical Research, Dublin, Dublin 4, Ireland
  • Sandra Garcia Mulero
    Institut Catala de Tecnologia, Barcelona, Catalunya, Spain
  • Rebecca Sanz Pamplona
    Institut Catala de Tecnologia, Barcelona, Catalunya, Spain
  • Simone Marcone
    The University of Dublin Trinity College, Dublin, Ireland
  • Kayleigh Slater
    University College Dublin Conway Institute of Biomolecular and Biomedical Research, Dublin, Dublin 4, Ireland
  • Josep M. Piulats
    Institut Catala de Tecnologia, Barcelona, Catalunya, Spain
  • Breandan N Kennedy
    University College Dublin Conway Institute of Biomolecular and Biomedical Research, Dublin, Dublin 4, Ireland
  • Footnotes
    Commercial Relationships   Marzia Pendino None; Sandra Garcia Mulero None; Rebecca Sanz Pamplona None; Simone Marcone None; Kayleigh Slater None; Josep M. Piulats None; Breandan Kennedy None
  • Footnotes
    Support  No. EPSPG/2020/160
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 3577 – A0006. doi:
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    • Get Citation

      Marzia Pendino, Sandra Garcia Mulero, Rebecca Sanz Pamplona, Simone Marcone, Kayleigh Slater, Josep M. Piulats, Breandan N Kennedy; Evaluating Cannabinoid Receptors as A Therapeutic Target for Uveal Melanoma. Invest. Ophthalmol. Vis. Sci. 2022;63(7):3577 – A0006.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : This research evaluates the disease relevance of cannabinoid receptors in UM patient samples and the therapeutic potential of synthetic cannabinoids in uveal melanoma (UM) cell lines. UM is a rare cancer, but the most common intraocular malignancy in adults that arises from melanocytes within the uveal tract. Unfortunately, up to 50% of patients develop liver metastases that rapidly progress to mortality. There are no effective therapies available for metastatic UM.

Methods : Cannabinoid receptor gene expression in 80 primary UM samples within The Cancer Genome Atlas was analysed for association with disease-free and overall survival. Gene set variation analysis enriched for molecular functions and biological pathways linked to high or low cannabinoid receptor expression. In vitro assays utilised Mel285 and OMM2.5 human UM cell lines derived from a tumour of the eye and a liver metastasis, respectively. Cell viability was examined at 96 hours after treatment with the synthetic cannabinoid HU210 by measuring metabolic activity. Colony formation assays assessed long-term UM cell proliferation. Multiplex ELISA determined the secreted levels of 10 inflammatory factors at 4 and 24 hours after treatment with HU210 in the OMM2.5 cell line. Western Blot analysed expression of CB1.

Results : Kaplan-Meier survival curves demonstrate a significant corelation between high CB1 expression and disease-free survival in UM patients. The CB1/CB2 agonist HU210 results in a dose-dependent reduction in Mel 285 and OMM2.5 cell viability with 20 µM HU210 reducing cell viability by around 80%, p〈0.0001 whereas 150 µM of the more selective CB2 agonist JWH133 was required to significantly reduced viability by 80%, p=0.0001 in both UM cell lines. 10 µM rimonabant hydrochloride and 10 µM SR144528, CB1 and CB2 selective antagonists, respectively, were the maximum tolerated concentrations not affecting cell viability. 20 µM HU210 results in a reduction of long-term proliferation of clones in both UM cell lines. Western blot analysis confirmed expression of CB1 in Mel285, Mel290, OMM2.5 cells.

Conclusions : Significant corelations between high CB1 expression and disease-free survival in UM patients was identified. HU210 reduces viability and clone proliferation of UM cell lines and modulated inflammatory pathways. Future directions will evaluate the key receptor mediating HU210 effects using antagonists and investigate the mechanism of action.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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