title: Strategically Timing Inhibition of Phosphatidylinositol 3-Kinase to Maximize Therapeutic Index in Estrogen Receptor Alpha-Positive, PIK3CA-Mutant Breast Cancer.
abstract: Phosphatidylinositol 3-kinase (PI3K) inhibitors are being developed for the treatment of estrogen receptor α (ER)-positive breast cancer in combination with antiestrogens. Understanding the temporal response and pharmacodynamic effects of PI3K inhibition in ER(+) breast cancer will provide a rationale for treatment scheduling to maximize therapeutic index.
  
  
  
  Antiestrogen-sensitive and antiestrogen-resistant ER(+) human breast cancer cell lines and mice bearing PIK3CA-mutant xenografts were treated with the antiestrogen fulvestrant, the PI3K inhibitor GDC-0941 (pictilisib; varied doses/schedules that provided similar amounts of drug each week), or combinations. Cell viability, signaling pathway inhibition, proliferation, apoptosis, tumor volume, and GDC-0941 concentrations in plasma and tumors were temporally measured.
  
  
  
  Treatment with the combination of fulvestrant and GDC-0941, regardless of dose/schedule, was significantly more effective than that with single-agent treatments in fulvestrant-resistant tumors. Short-term, complete PI3K inhibition blocked cell growth in vitro more effectively than chronic, incomplete inhibition. Longer-term PI3K inhibition hypersensitized cells to growth factor signaling upon drug withdrawal. Different schedules of GDC-0941 elicited similar tumor responses. While weekly high-dose GDC-0941 with fulvestrant continuously suppressed PI3K signaling for 72 hours, inducing a bolus of apoptosis and inhibiting proliferation, PI3K reactivation upon GDC-0941 washout induced a proliferative burst. Fulvestrant with daily low-dose GDC-0941 metronomically suppressed PI3K for 6 to 9 hours/day, repeatedly inducing small amounts of apoptosis and temporarily inhibiting proliferation, followed by proliferative rebound compared with fulvestrant alone.
  
  
  
  Continuous and metronomic PI3K inhibition elicits robust anticancer effects in ER(+), PIK3CA-mutant breast cancer. Clinical exploration of alternate treatment schedules of PI3K inhibitors with antiestrogens is warranted. Clin Cancer Res; 22(9); 2250-60. ©2016 AACRSee related commentary by Toska and Baselga, p. 2099.
authors.affiliation: Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Hosford
authors.affiliation: Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Lloye M
authors.initials: LM
authors.lastname: Dillon
authors.affiliation: Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Kevin
authors.initials: K
authors.lastname: Shee
authors.affiliation: Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Bean
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics, South San Francisco, California.
authors.forename: Laurent
authors.initials: L
authors.lastname: Salphati
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics, South San Francisco, California.
authors.forename: Jodie
authors.initials: J
authors.lastname: Pang
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics, South San Francisco, California.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Translational Oncology, Genentech, Inc., South San Francisco, California.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Nannini
authors.affiliation: Department of Community and Family Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Eugene
authors.initials: E
authors.lastname: Demidenko
authors.affiliation: Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Darcy
authors.initials: D
authors.lastname: Bates
authors.affiliation: Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Lionel D
authors.initials: LD
authors.lastname: Lewis
authors.affiliation: Department of Pathology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. Comprehensive Breast Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Marotti
authors.affiliation: Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Eastman
authors.affiliation: Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. Comprehensive Breast Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. Todd.W.Miller@Dartmouth.edu.
authors.forename: Todd W
authors.initials: TW
authors.lastname: Miller
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D061986:MCF-7 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D009154:Mutation / Q000187:drug effects / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D000076162:Therapeutic Index
chemical_list: C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D007191:Indazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077267:Fulvestrant; D004958:Estradiol; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human