A novel combinatorial treatment option for metastatic uveal melanoma
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Dudi Shneor1,2, Shay Tayeb1,3, Jacob Pe’er2, Hanna Voropaev1,2, Maria Gimmelshein1,2, Nathalie Cassoux4,5, Alik Honigman1,3,* and Shahar Frenkel2,*
1Department of Biochemistry and Molecular Biology, IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem, Israel
2Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
3Hadassah Academic College, Jerusalem, Israel
4Department of Ocular Oncology, Institut Curie, Paris, France
5Université Paris V Descartes, Paris, France
*These authors have contributed equally to this work
Shahar Frenkel, email: [email protected]
Keywords: cancer; chemotherapy; replicative competent retroviruses (RCR); CREB; combinatorial targeted treatment
Received: February 16, 2018 Accepted: April 28, 2018 Published: May 25, 2018
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.
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