title: Enhanced Antitumor Activity of an Anti-5T4 Antibody-Drug Conjugate in Combination with PI3K/mTOR inhibitors or Taxanes.
abstract: OBJECTIVE
  Targeted treatment of solid or liquid tumors with antibody-drug conjugates (ADCs) can lead to promising clinical benefit. The aim of the study is to investigate combination regimens of auristatin-based ADCs in preclinical models of cancer.
  
  
  METHODS
  An auristatin-based anti-5T4 antibody conjugate (5T4-ADC) and auristatin payloads were combined with the dual PI3K/mTOR catalytic site inhibitor PF-05212384 (PF-384) or taxanes in a panel of tumor cell lines. Drug interactions in vitro were evaluated using cell viability assays, apoptosis induction, immunofluorescence, mitotic index, and immunoblotting. Breast cancer cells treated with auristatin analogue or 5T4-ADC were profiled by total- and phospho-proteomics. Antitumor efficacy of selected combinations was evaluated in 5T4-positive human breast or lung tumor xenografts in vivo.
  
  
  RESULTS
  In vitro, auristatin-based agents displayed strong synergistic or additive activity when combined with PF-384 or taxanes, respectively. Further, treatment of 5T4-ADC plus PF-384 resulted in stronger induction of apoptosis and cell line-specific attenuation of pAKT and pGSK. Interestingly, proteomic analysis revealed unique effects of auristatins on multiple components of mRNA translation. Addition of PF-384 further amplified effects of 5T4-ADC on translational components, providing a potential mechanism of synergy between these drugs. In human tumor xenografts, dual targeting with 5T4-ADC/PF-384 or 5T4-ADC/paclitaxel produced substantially greater antitumor effects with longer average survival as compared with monotherapy treatments.
  
  
  CONCLUSIONS
  Our results provide a biologic rationale for combining 5T4-ADC with either PI3K/mTOR pathway inhibitors or taxanes and suggest that mechanisms underlying the synergy may be attributed to cellular effects of the auristatin payload.
authors: Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, New York.
authors: Boris
authors: B
authors: Shor
authors: Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, New York.
authors: Jennifer
authors: J
authors: Kahler
authors: Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, New York.
authors: Maureen
authors: M
authors: Dougher
authors: Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, New York.
authors: Jane
authors: J
authors: Xu
authors: Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, New York.
authors: Michelle
authors: M
authors: Mack
authors: Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, New York.
authors: Ed
authors: E
authors: Rosfjord
authors: Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, New York.
authors: Fang
authors: F
authors: Wang
authors: Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, New York.
authors: Eugene
authors: E
authors: Melamud
authors: Oncology Research Unit, Pfizer Worldwide Research and Development, Pearl River, New York. puja.sapra@pfizer.com.
authors: Puja
authors: P
authors: Sapra
mesh_terms: D062365:Aminobenzoates / Q000494:pharmacology; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004347:Drug Interactions; D005260:Female; D019073:HT29 Cells; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D040901:Proteomics / Q000379:methods; D012333:RNA, Messenger / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D043823:Taxoids / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D062365:Aminobenzoates; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D009842:Oligopeptides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D043823:Taxoids; C543533:auristatin; C063709:trophoblastic glycoprotein 5T4, human; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D017239:Paclitaxel