A novel combinatorial treatment option for metastatic uveal melanoma

Dudi Shneor, Shay Tayeb, Jacob Pe'er, Hanna Voropaev, Maria Gimmelshein, Nathalie Cassoux, Alik Honigman, Shahar Frenkel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Uveal melanoma (UM) is the most frequent intraocular tumor in adult patients. When metastases occur, systemic therapy with alkylating agents (fotemustine or dacarbazine (DTIC)) has shown only modest efficacy. The common chemotherapeutic drug doxorubicin (DOX) is not used to treat metastatic UM (mUM). To expand the chemotherapeutic arsenal for mUM, we tested the effect of DOX on UM cell mortality. We have previously shown that CREB knockdown enhances sensitivity to DOX. UM cells infected with recombinant MuLV-based replicative competent retroviruses (RCR) expressing shRNA targeting CREB were co-treated with either DTIC or DOX. We found that CREB knockdown increases the sensitivity of these cells to both DOX and DTIC in normoxia and more so in hypoxia as measured by cell survival and Caspase 3 activation. The ability to combine CREB knockdown by infection with the RCR recombinant virus which preferentially infects replicating tumor cells and chemotherapy to achieve the same amount of cell death in lower concentrations may result in fewer side effects of the drugs. This combination is a possible new treatment for mUM.

Original languageEnglish
Pages (from-to)26096-26108
Number of pages13
JournalOncotarget
Volume9
Issue number40
DOIs
StatePublished - 2018

Bibliographical note

Publisher Copyright:
© Shneor et al.

Keywords

  • Cancer
  • Chemotherapy
  • Combinatorial targeted treatment
  • CREB
  • Replicative competent retroviruses (RCR)

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