title: The novel Hsp90 inhibitor NXD30001 induces tumor regression in a genetically engineered mouse model of glioblastoma multiforme.
abstract: Glioblastoma multiforme (GBM) has an abysmal prognosis. We now know that the epidermal growth factor receptor (EGFR) signaling pathway and the loss of function of the tumor suppressor genes p16Ink4a/p19ARF and PTEN play a crucial role in GBM pathogenesis: initiating the early stages of tumor development, sustaining tumor growth, promoting infiltration, and mediating resistance to therapy. We have recently shown that this genetic combination is sufficient to promote the development of GBM in adult mice. Therapeutic agents raised against single targets of the EGFR signaling pathway have proven rather inefficient in GBM therapy, showing the need for combinatorial therapeutic approaches. An effective strategy for concurrent disruption of multiple signaling pathways is via the inhibition of the molecular chaperone heat shock protein 90 (Hsp90). Hsp90 inhibition leads to the degradation of so-called client proteins, many of which are key effectors of GBM pathogenesis. NXD30001 is a novel second generation Hsp90 inhibitor that shows improved pharmacokinetic parameters. Here we show that NXD30001 is a potent inhibitor of GBM cell growth in vitro consistent with its capacity to inhibit several key targets and regulators of GBM biology. We also show the efficacy of NXD30001 in vivo in an EGFR-driven genetically engineered mouse model of GBM. Our findings establish that the Hsp90 inhibitor NXD30001 is a therapeutically multivalent molecule, whose actions strike GBM at the core of its drivers of tumorigenesis and represent a compelling rationale for its use in GBM treatment.
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111, USA.
authors.forename: Haihao
authors.initials: H
authors.lastname: Zhu
authors.forename: Steve
authors.initials: S
authors.lastname: Woolfenden
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Zahara M
authors.initials: ZM
authors.lastname: Jaffer
authors.forename: Sofia
authors.initials: S
authors.lastname: Barluenga
authors.forename: Nicolas
authors.initials: N
authors.lastname: Winssinger
authors.forename: Allan E
authors.initials: AE
authors.lastname: Rubenstein
authors.forename: Ruihong
authors.initials: R
authors.lastname: Chen
authors.forename: Al
authors.initials: A
authors.lastname: Charest
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D004195:Disease Models, Animal; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007783:Lactones / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010091:Oximes / Q000493:pharmacokinetics / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D018841:HSP90 Heat-Shock Proteins; D007783:Lactones; D010091:Oximes; C555907:pochoxime A