title: Preclinical and clinical studies of gamma secretase inhibitors with docetaxel on human breast tumors.
abstract: OBJECTIVE
  Accumulating evidence supports the existence of breast cancer stem cells (BCSC), which are characterized by their capacity to self-renew and divide indefinitely and resistance to conventional therapies. The Notch pathway is important for stem cell renewal and is a potential target for BCSC-directed therapy.
  
  
  METHODS
  Using human breast tumorgraft studies, we evaluated the impact of gamma secretase inhibitors (GSI) on the BCSC population and the efficacy of combining GSI with docetaxel treatment. The mouse experimental therapy paralleled a concurrent clinical trial in patients with advanced breast cancer, designed to determine the maximum-tolerated dose of the GSI, MK-0752, administered sequentially with docetaxel, and to evaluate BCSC markers in serial tumor biopsies.
  
  
  RESULTS
  Treatment with GSI reduced BCSCs in MC1 and BCM-2147 tumorgrafts by inhibition of the Notch pathway. GSI enhanced the efficacy of docetaxel in preclinical studies. In the clinical trial, 30 patients with advanced breast cancer were treated with escalating doses of MK-0752 plus docetaxel. Clinically, meaningful doses of both drugs were possible with manageable toxicity and preliminary evidence of efficacy. A decrease in CD44(+)/CD24(-), ALDH(+), and mammosphere-forming efficiency were observed in tumors of patients undergoing serial biopsies.
  
  
  CONCLUSIONS
  These preclinical data show that pharmacologic inhibition of the Notch pathway can reduce BCSCs in breast tumorgraft models. The clinical trial shows feasibility of combination GSI and chemotherapy, and together these results encourage further study of Notch pathway inhibitors in combination with chemotherapy in breast cancer.
authors: University of Michigan, Ann Arbor, Michigan 48109, USA. aschott@umich.edu
authors: Anne F
authors: AF
authors: Schott
authors: Melissa D
authors: MD
authors: Landis
authors: Gabriela
authors: G
authors: Dontu
authors: Kent A
authors: KA
authors: Griffith
authors: Rachel M
authors: RM
authors: Layman
authors: Ian
authors: I
authors: Krop
authors: Lacey A
authors: LA
authors: Paskett
authors: Helen
authors: H
authors: Wong
authors: Lacey E
authors: LE
authors: Dobrolecki
authors: Michael T
authors: MT
authors: Lewis
authors: Amber M
authors: AM
authors: Froehlich
authors: Jaya
authors: J
authors: Paranilam
authors: Daniel F
authors: DF
authors: Hayes
authors: Max S
authors: MS
authors: Wicha
authors: Jenny C
authors: JC
authors: Chang
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001555:Benzene Derivatives / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077143:Docetaxel; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D051379:Mice; D009367:Neoplasm Staging; D011422:Propionates / Q000008:administration & dosage* / Q000009:adverse effects; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D013450:Sulfones / Q000008:administration & dosage* / Q000009:adverse effects; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C554093:3-(4-((4-chlorophenyl)sulfonyl)-4-(2,5-difluorophenyl)cyclohexyl)propanoic acid; D001555:Benzene Derivatives; D011422:Propionates; D051880:Receptors, Notch; D013450:Sulfones; D043823:Taxoids; D000077143:Docetaxel; D053829:Amyloid Precursor Protein Secretases