Novel Hsp90 Inhibitor NXD30001 Induces Tumor ression in a Genetically Engineered Mouse

wnloaded blastoma multiforme (GBM) has an abysmal prognosis. We now know that the epidermal growth receptor (EGFR) signaling pathway and the loss of function of the tumor suppressor genes p16Ink4a/ F and PTEN play a crucial role in GBM pathogenesis: initiating the early stages of tumor development, ning tumor growth, promoting infiltration, and mediating resistance to therapy. We have recently that this genetic combination is sufficient to promote the development of GBM in adult mice. eutic agents raised against single targets of the EGFR signaling pathway have proven rather inefficient M therapy, showing the need for combinatorial therapeutic approaches. An effective strategy for rrent disruption of multiple signaling pathways is via the inhibition of the molecular chaperone heat protein 90 (Hsp90). Hsp90 inhibition leads to the degradation of so-called client proteins, many of are key effectors of GBM pathogenesis. NXD30001 is a novel second generation Hsp90 inhibitor that improved pharmacokinetic parameters. Here we show that NXD30001 is a potent inhibitor of GBM owth in vitro consistent with its capacity to inhibit several key targets and regulators of GBM biology. so show the efficacy of NXD30001 in vivo in an EGFR-driven genetically engineered mouse model . Our findings establish that the Hsp90 inhibitor NXD30001 is a therapeutically multivalent molecule, of GBM whose actions strike GBM at the core of its drivers of tumorigenesis and represent a compelling rationale for its use in GBM treatment. Mol Cancer Ther; 9(9); 2618–26. ©2010 AACR.