Inhibition of PI3K/AKT/mTOR pathway for the treatment of endometriosis.

Dr. Ferrero raised concerns about MK2206 (PI3K/Akt/mTOR inhibitor) and chloroquine on the clinical treatment of endometriosis.

Key Points

Highlight:

• Dr. Matsuzaki et al. published a paper entitled ‘In vitro and in vivo effects of MK2206 and chloroquine combination therapy on endometriosis’ showing that the efficacy of MK2206, an Akt inhibitor, in combination with chloroquine for inducing autophagy in endometriosis.
• In this letter, Dr. Ferrero from Italy raised several concerns about MK2206 and chloroquine on the clinical treatment of endometriosis.

Key points:

• Lack of biomarkers:
• In an oncological setting, patients with specific mutations (i.e. PIK3CA and PTEN) tend to have higher benefit receiving these inhibitors for PI3K/Akt/mTOR pathway.
• However, there are no validated predictive biomarkers for the selection of patients and for monitoring drug efficacy.
• Lack of efficacy and toxicity:
• Also, the majority of these inhibitors are in early phase of clinical development and there is a lack of solid clinical data on their efficacy and toxicity.
• In the previous clinical trial, drug-related adverse events and treatment discontinuation has been reported. Particularly, metabolic, hematological, respiratory, renal and dermatological related toxicities may be partly due to a broad activity profile and crossover inhibition of other ubiquitous lipid and protein kinases.
• Moreover, administration of the double regimen, which is the combination of MK2206 and chloroquine, should be carefully evaluated.  
• May not improve quality of life
• Though this combination of MK2206 and chloroquine may be acceptable for cancer therapy, it is unreasonable to use them in young women with endometriosis where the goal is improving the quality of life.

Conclusion:

• Dr. Ferrero group suggest that MK2206 or its combination with chloroquine may not be a hope in the treatment of women with endometriosis in the near future.

Lay Summary

Dr. Matsuzaki et al. (2018) published a paper entitled ‘In vitro and in vivo effects of MK2206 and chloroquine combination therapy on endometriosis’ showing that the efficacy of MK2206, an Akt inhibitor, in combination with chloroquine for inducing autophagy in endometriosis. Dr. Ferrero group from Italy agreed that the rationale of this study is based on evidence of the important role displayed by PI3K/Akt/mTOR pathway in the pathogenesis of endometriosis, and there are two preclinical studies showing these drugs were able to cause significant reduction of endometriosis implants growth. In this letter, however, the team lead by Dr. Ferrero raised several concerns about MK2206 and chloroquine on the clinical treatment of endometriosis.

The first concern is the lack of biomarkers. In an oncological setting, patients with specific mutations (i.e. PIK3CA and PTEN) tend to have higher benefit receiving these inhibitors for PI3K/Akt/mTOR pathway. However, there are no validated predictive biomarkers for the selection of patients and for monitoring drug efficacy.

The second is the lack of efficacy and toxicity. The majority of these inhibitors are in early phase of clinical development and there is a lack of solid clinical data on their efficacy and toxicity. In the previous clinical trial, drug-related adverse events and treatment discontinuation has been reported. Particularly, metabolic, hematological, respiratory, renal and dermatological related toxicities may be partly due to a broad activity profile and crossover inhibition of other ubiquitous lipid and protein kinases. Moreover, administration of the double regimen, which is the combination of MK2206 and chloroquine, should be carefully evaluated.

Last concern is that this treatment may not improve quality of life. Though this combination of MK2206 and chloroquine may be acceptable for cancer therapy to increase disease-free survival and overall survival, Dr. Ferrero group think it is unreasonable to use them in young women with endometriosis where the goal is improving the quality of life.

Given this background, Dr. Ferrero group conclude that MK2206 or its combination with chloroquine may not have a leading role in the treatment of women with endometriosis in the near future.

Research Source: https://www.ncbi.nlm.nih.gov/pubmed/29984446