Reply to the letter from Barra et al.

Abstract

We thank the Editor-in Chief, Professor Amrita Ahluwalia, for her fair handling of the letter from Barra et al. (2018), as well as her openness. We acknowledge the interest of Barra et al. in our work, but we are obliged to respond to their letter.The major concern of Barra et al. (2018) is the future clinical use of MK2206, an Akt inhibitor, in patients with endometriosis. First, we would like to clarify that the results of our in vitro and animal experiments (Matsuzaki et al., 2018) did not support future clinical trials of MK2206 alone, chloroquine (CQ) alone, or combination MK2206 + CQ in patients with endometriosis.There are two main reasons why MK2206 + CQ treatment should not be evaluated in future clinical trials, as we discussed in the article (Matsuzaki et al., 2018). First, treatment with MK2206 + CQ or CQ alone affects growth of endometrial stromal cells (EES) rather than that of endometriotic stromal cells (DES). Endometriosis, a common gynaecological disorder that causes infertility and pelvic pain, affects approximately 10% of women of reproductive age. Therefore, the ideal drugs for patients with endometriosis should affect only diseased endometriotic lesions and should not affect 'normal' endometrium within the same patients. However, we showed that the IC 50 of MK2206 + CQ treatment was significantly lower in EES compared to that in DES within the same patients. Furthermore, our clonogenic assay demonstrated that CQ alone affected survival of EES rather than that of DES, within the same patients.Second, DES have the potential to regrow after discontinuation of MK2206 alone, CQ alone, or MK2206 + CQ. A high recurrence rate after treatment, with or without surgery, is a major clinical problem for patients with endometriosis. Before validation of the effects of candidate molecules can be performed in animal experiments or clinical trials, it is important to evaluate whether candidate molecules can prevent regrowth of endometriotic cells in vitro.The results of the present mouse study are not consistent with those of previous animal studies with the mTOR inhibitors. Kacan et al. (2017) demonstrated that in an autologous rat model of endometriosis, treatment with everolimus alone disrupted the epithelial cells of endometriotic implants. Lee and Kim (2014) did not investigate the effect of either temsirolimus or everolimus in a rat model of endometriosis. In a study not cited by Barra et al., temsirolimus disrupted the lesion histopathology of deep endometriotic endometriosis in a mouse xenograft model of endometriosis (Leconte et al., 2011). However, our study clearly showed that MK2206 alone is not effective in reducing the size of implants or inducing apoptosis in a xenograft model of endometriosis (Matsuzaki et al., 2018).The rationale of our study was not based on the important role of the PI3K/Akt/mTOR pathway in the pathogenesis of endometriosis, but on our previous findings that MK2206 treatment may induce a cytoprotective autophagy in endometriosis (Matsuzaki et al., 2017). Our previous stud...