Abstract 5888: Tmem 205-mediated cisplatin resistance in ovarian clear cell carcinoma (OCCC) is overcome by herpes simplex virus (oHSV)/cisplatin combination therapy
Authors: Saini Uksha , Riley Maria , Dorayappan Kalpana Deepa , Bolyard Chelsea , Kaur Balveen , Zingarelli Roman , Konishi Ikuo , Kuppusamy Periannan , Maxwell George Larry , Cohn David E. , Selvendiran Karuppaiyah 
Published: July 2017

Objectives: Ovarian clear cell carcinoma (OCCC) is an aggressive form of ovarian cancer and unfavorable treatment outcomes have been attributed to its relative chemoresistance and recurrence, limiting the available treatment options. Therefore, identifying novel unique protein(s) involved in OCCC chemoresistance and designing a therapeutic modality selectively targeting those proteins would make a significant impact on therapy. TMEM 205 is one such protein which has been recently linked to cisplatin resistance in human epidermoid carcinoma, but the precise molecular mechanism of this resistance still needs to be elucidated. This proposed study was planned to a) decipher the role of TMEM205 expression in OCCC (relative to HGSOC) b) mechanism by which TMEM205 imparts chemoresistance c) evaluate the in vitro and in vivo efficacy of oHSV as a single agent or in combination with standard chemotherapy

Methods: Human patient tissue samples from OCCC patients as well as OCCC cell lines like JHOC, OVTOKO, OVISE and ES2 were analyzed for the expression of TMEM205 using Western blot, IHC/ICC and real time qPCR. In situ pO2 was measured in the cells as well as mice using EPR oximetry. Exosomes were isolated and characterized using NTA. TMEM205 overexpression and knockdown experiments were performed in vitro in OVTOKO cells to confirm the role of TMEM205 in OCCC. Cispaltin accumulation in cells and exosomes was quantified using ICP-MS. oHSV virus therapy was further tested in vitro or in vivo-alone or combined with cisplatin treatment.

Results demonstrate that the OCCC tissues as well as cell lines have high expression of TMEM205. OCCC cells and mice injected with these cells are severely hypoxic and cisplatin accumulation is more in the exosomes derived from them, which goes down with the knockdown of TMEM205. oHSV treatment suppresses TMEM205 expression in OVTOKO and JHOC cells. Further, ICC showed that TMEM205 and oHSV co-localize in the cells, indicating that oHSV may interact with TMEM205 and suppress its expression and activity. oHSV pretreatment followed by treatment with cisplatin (CP) increases apoptosis and decreases cell survival, in vitro within 48 hours as well as in vivo.

Conclusions: TMEM205 mediates drug resistance through exosomes and knockdown of TMEM205 in OCCC contributes to enhanced chemotherapy sensitivity. This will pave the way for exploring the clinical implications of TMEM205 in OCCC, and evaluating whether TMEM205 expression is key to higher risk of resistance and recurrence seen in OCCC.

Citation Format: Uksha Saini, Maria Riley, Kalpana Deepa Dorayappan, Chelsea Bolyard, Balveen Kaur, Roman Zingarelli, Ikuo Konishi, Periannan Kuppusamy, George Larry Maxwell, David E. Cohn, Karuppaiyah Selvendiran. Tmem 205-mediated cisplatin resistance in ovarian clear cell carcinoma (OCCC) is overcome by herpes simplex virus (oHSV)/cisplatin combination therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5888. doi:10.1158/1538-7445.AM2017-5888