title: Preclinical activity profile and therapeutic efficacy of the HSP90 inhibitor ganetespib in triple-negative breast cancer.
abstract: OBJECTIVE
  Treatment options for patients with triple-negative breast cancer (TNBC) are largely limited to systemic chemotherapies, which have shown disappointing efficacy in the metastatic setting. Here, we undertook a comprehensive evaluation of the activity of ganetespib, a potent inhibitor of HSP90, in this malignancy.
  
  
  METHODS
  The antitumor and antimetastatic activity of ganetespib was investigated using TNBC cell lines and xenograft models. Combinatorial drug analyses were performed with chemotherapeutic agents and concomitant effects on DNA damage and cell-cycle disruption were assessed in vitro; antitumor efficacy was assessed in vivo. Metabolic and objective tumor responses were evaluated in patients with metastatic TNBC undergoing ganetespib treatment.
  
  
  RESULTS
  Ganetespib simultaneously deactivated multiple oncogenic pathways to potently reduce cell viability in TNBC cell lines, and suppressed lung metastases in experimental models. Ganetespib potentiated the cytotoxic activity of doxorubicin via enhanced DNA damage and mitotic arrest, conferring superior efficacy to the doxorubicin-cyclophosphamide regimen in TNBC xenografts. Ganetespib also promoted mitotic catastrophe and apoptosis in combination with taxanes in vitro, and these effects translated to significantly improved combinatorial activity in vivo. Marked tumor shrinkage of metastatic lung and lymphatic lesions were seen in patients on ganetespib monotherapy.
  
  
  CONCLUSIONS
  The preclinical activity profile and clinical evidence of tumor regression suggest that ganetespib offers considerable promise as a new therapeutic candidate to target TNBC.
authors.affiliation: Authors' Affiliations: Synta Pharmaceuticals Corp., Lexington; Early Drug Development Center, Breast Oncology Center, Dana-Farber Cancer Institute, Boston, Massachusetts; and Department of Medicine, Duke University Medical Center, Durham, North Carolina.
authors.forename: David A
authors.initials: DA
authors.lastname: Proia
authors.forename: Chaohua
authors.initials: C
authors.lastname: Zhang
authors.forename: Manuel
authors.initials: M
authors.lastname: Sequeira
authors.forename: John-Paul
authors.initials: JP
authors.lastname: Jimenez
authors.forename: Suqin
authors.initials: S
authors.lastname: He
authors.forename: Neil
authors.initials: N
authors.lastname: Spector
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: Sara
authors.initials: S
authors.lastname: Tolaney
authors.forename: Masazumi
authors.initials: M
authors.lastname: Nagai
authors.forename: Jaime
authors.initials: J
authors.lastname: Acquaviva
authors.forename: Donald L
authors.initials: DL
authors.lastname: Smith
authors.forename: Jim
authors.initials: J
authors.lastname: Sang
authors.forename: Richard C
authors.initials: RC
authors.lastname: Bates
authors.forename: Iman
authors.initials: I
authors.lastname: El-Hariry
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000556:secondary; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D049268:Positron-Emission Tomography; D014057:Tomography, X-Ray Computed; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use; D064726:Triple Negative Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; C533237:STA 9090; D014230:Triazoles