J Erriquez1, P Becco2, M Olivero3, R Ponzone4, F Maggiorotto4, A Ferrero5, M S Scalzo6, E M Canuto7, A Sapino6, L Verdun di Cantogno6, P Bruna7, M Aglietta8, M F Di Renzo9, G Valabrega8. 1. Laboratory of Cancer Genetics of the Candiolo Cancer Institute, FPO-IRCCS, Italy. 2. Medical Oncology I of the Candiolo Cancer Institute, FPO-IRCCS, Italy. 3. Department of Oncology, University of Torino, Candiolo, Italy; Laboratory of Cancer Genetics of the Candiolo Cancer Institute, FPO-IRCCS, Italy. 4. Division of Gynecological Oncology, Candiolo Cancer Institute, FPO-IRCCS, Italy. 5. Department of Gynecologic Oncology, AO Mauriziano Umberto I, University of Torino, Italy. 6. Department of Medical Sciences, University of Torino, Italy. 7. Division of Medical Oncology Ospedale Mondovì, Italy. 8. Department of Oncology, University of Torino, Candiolo, Italy; Medical Oncology I of the Candiolo Cancer Institute, FPO-IRCCS, Italy. 9. Department of Oncology, University of Torino, Candiolo, Italy; Laboratory of Cancer Genetics of the Candiolo Cancer Institute, FPO-IRCCS, Italy. Electronic address: mariaflavia.direnzo@ircc.it.
Abstract
OBJECTIVE: The treatment of platinum resistant/refractory epithelial ovarian cancer (EOC) is a challenge for oncologists. One of the most utilized drugs in these patients is pegylated liposomal doxorubicin (PLD). As PLD is active only in a small subset of patients and causes side effects, selection of responsive patients is an unmet need and might be guided by the status of the DNA topoisomerase II alpha (TOP2A) that is poisoned by the drug. METHODS: From 176 ovarian cancers treated in three institutions, we selected 38 patients treated with PLD monotherapy as second/third line of treatment. TOP2A gene copies were measured using Fluorescent In Situ Hybridization (FISH) and expression evaluated using immunohistochemistry. Patients' derived xenografts (PDXs) of ovarian cancers were used to assess the correlation between TOP2A protein expression and response to PLD. RESULTS: Clinical data showed that TOP2A gene gain that is paralleled by increased expression of the protein, was associated with a higher probability of clinical benefit from PLD. Treatment of PDXs demonstrated that only xenografts showing a high percentage of TOP2A expressing cells underwent tumor shrinkage when treated with PLD. CONCLUSIONS: These data show that TOP2A gene gain and protein over-expression might predict activity of PLD in platinum resistant/refractory EOC.
OBJECTIVE: The treatment of platinum resistant/refractory epithelial ovarian cancer (EOC) is a challenge for oncologists. One of the most utilized drugs in these patients is pegylated liposomal doxorubicin (PLD). As PLD is active only in a small subset of patients and causes side effects, selection of responsive patients is an unmet need and might be guided by the status of the DNA topoisomerase II alpha (TOP2A) that is poisoned by the drug. METHODS: From 176 ovarian cancers treated in three institutions, we selected 38 patients treated with PLD monotherapy as second/third line of treatment. TOP2A gene copies were measured using Fluorescent In Situ Hybridization (FISH) and expression evaluated using immunohistochemistry. Patients' derived xenografts (PDXs) of ovarian cancers were used to assess the correlation between TOP2A protein expression and response to PLD. RESULTS: Clinical data showed that TOP2A gene gain that is paralleled by increased expression of the protein, was associated with a higher probability of clinical benefit from PLD. Treatment of PDXs demonstrated that only xenografts showing a high percentage of TOP2A expressing cells underwent tumor shrinkage when treated with PLD. CONCLUSIONS: These data show that TOP2A gene gain and protein over-expression might predict activity of PLD in platinum resistant/refractory EOC.
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Authors: Jessica Erriquez; Martina Olivero; Gloria Mittica; Maria Stella Scalzo; Marco Vaira; Michele De Simone; Riccardo Ponzone; Dionyssios Katsaros; Massimo Aglietta; Raffaele Calogero; Maria Flavia Di Renzo; Giorgio Valabrega Journal: Oncotarget Date: 2016-05-03