PMID- 28270607
OWN - NLM
STAT- MEDLINE
DCOM- 20180423
LR  - 20181113
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 114
IP  - 12
DP  - 2017 Mar 21
TI  - mTORC1/2 inhibition preserves ovarian function and fertility during genotoxic 
      chemotherapy.
PG  - 3186-3191
LID - 10.1073/pnas.1617233114 [doi]
AB  - The ovary contains oocytes within immature (primordial) follicles that are fixed 
      in number at birth. Activation of follicles within this fixed pool causes an 
      irreversible decline in reproductive capacity, known as the ovarian reserve, 
      until menopause. Premenopausal women undergoing commonly used genotoxic 
      (DNA-damaging) chemotherapy experience an accelerated loss of the ovarian 
      reserve, leading to subfertility and infertility. Therefore, there is 
      considerable interest but little effective progress in preserving ovarian 
      function during chemotherapy. Here we show that blocking the kinase 
      mammalian/mechanistic target of rapamycin (mTOR) with clinically available 
      small-molecule inhibitors preserves ovarian function and fertility during 
      chemotherapy. Using a clinically relevant mouse model of chemotherapy-induced 
      gonadotoxicity by cyclophosphamide, and inhibition of mTOR complex 1 (mTORC1) 
      with the clinically approved drug everolimus (RAD001) or inhibition of mTORC1/2 
      with the experimental drug INK128, we show that mTOR inhibition preserves the 
      ovarian reserve, primordial follicle counts, serum anti-Mullerian hormone levels 
      (a rigorous measure of the ovarian reserve), and fertility. Chemotherapy-treated 
      animals had significantly fewer offspring compared with all other treatment 
      groups, whereas cotreatment with mTOR inhibitors preserved normal fertility. 
      Inhibition of mTORC1 or mTORC1/2 within ovaries was achieved during chemotherapy 
      cotreatment, concomitant with preservation of primordial follicle counts. 
      Importantly, our findings indicate that as little as a two- to fourfold reduction 
      in mTOR activity preserves ovarian function and normal birth numbers. As 
      everolimus is approved for tamoxifen-resistant or relapsing estrogen 
      receptor-positive breast cancer, these findings represent a potentially effective 
      and readily accessible pharmacologic approach to fertility preservation during 
      conventional chemotherapy.
FAU - Goldman, Kara N
AU  - Goldman KN
AD  - Division of Reproductive Endocrinology and Infertility, Department of Obstetrics 
      and Gynecology, New York University School of Medicine, New York, NY 10016.
FAU - Chenette, Devon
AU  - Chenette D
AD  - Department of Microbiology, New York University School of Medicine, New York, NY 
      10016.
FAU - Arju, Rezina
AU  - Arju R
AD  - Department of Microbiology, New York University School of Medicine, New York, NY 
      10016.
FAU - Duncan, Francesca E
AU  - Duncan FE
AD  - Department of Obstetrics and Gynecology, Feinberg School of Medicine, 
      Northwestern University, Chicago, IL 60611.
FAU - Keefe, David L
AU  - Keefe DL
AD  - Division of Reproductive Endocrinology and Infertility, Department of Obstetrics 
      and Gynecology, New York University School of Medicine, New York, NY 10016.
FAU - Grifo, Jamie A
AU  - Grifo JA
AD  - Division of Reproductive Endocrinology and Infertility, Department of Obstetrics 
      and Gynecology, New York University School of Medicine, New York, NY 10016.
FAU - Schneider, Robert J
AU  - Schneider RJ
AUID- ORCID: 0000-0001-5807-5564
AD  - Department of Microbiology, New York University School of Medicine, New York, NY 
      10016; robert.schneider@nyumc.org.
AD  - Perlmutter Cancer Center, New York University School of Medicine, New York, NY 
      10016.
LA  - eng
GR  - P30 CA016087/CA/NCI NIH HHS/United States
GR  - P50 HD076188/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20170307
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Biomarkers)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 80497-65-0 (Anti-Mullerian Hormone)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
SB  - IM
MH  - Animals
MH  - Anti-Mullerian Hormone/blood
MH  - Antineoplastic Agents/*adverse effects/pharmacology
MH  - Biomarkers
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - *Fertility Preservation
MH  - Immunohistochemistry
MH  - Mechanistic Target of Rapamycin Complex 1/*antagonists & inhibitors/metabolism
MH  - Mechanistic Target of Rapamycin Complex 2/*antagonists & inhibitors/metabolism
MH  - Mice
MH  - Ovarian Follicle/drug effects/metabolism
MH  - Ovary/*drug effects/*physiology
MH  - Protein Kinase Inhibitors/pharmacology
PMC - PMC5373380
OTO - NOTNLM
OT  - chemotherapy
OT  - fertility
OT  - mTOR
OT  - ovarian function
OT  - ovary
COIS- The authors declare no conflict of interest.
EDAT- 2017/03/09 06:00
MHDA- 2018/04/24 06:00
PMCR- 2017/09/21
CRDT- 2017/03/09 06:00
PHST- 2017/03/09 06:00 [pubmed]
PHST- 2018/04/24 06:00 [medline]
PHST- 2017/03/09 06:00 [entrez]
PHST- 2017/09/21 00:00 [pmc-release]
AID - 1617233114 [pii]
AID - 201617233 [pii]
AID - 10.1073/pnas.1617233114 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2017 Mar 21;114(12):3186-3191. doi: 
      10.1073/pnas.1617233114. Epub 2017 Mar 7.