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Exelixis, Inc. Message Board

  • wilderguide wilderguide Jun 16, 2013 2:04 PM Flag

    XL-888 in NRAS-mutant melanoma

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    Published in Mol Cancer Ther June 2013 issue. Interim sults from the Moffitt Cancer Center study.

    "The HSP90 inhibitor XL888 is effective at reversing BRAF inhibitor resistance in melanoma, including that mediated through acquired NRAS mutations. The present study has investigated the mechanism of action of XL888 in NRAS-mutant melanoma. Treatment of NRAS-mutant melanoma cell lines with XL888 led to an inhibition of growth, G2-M phase cell-cycle arrest, and the inhibition of cell survival in three-dimensional spheroid and colony formation assays. In vitro, HSP90 inhibition led to the degradation of ARAF, CRAF, Wee1, Chk1, and cdc2 and was associated with decreased mitogen-activated protein kinase (MAPK), AKT, mTOR, and c-jun NH2 kinase (JNK) signaling. Apoptosis induction was associated with increased BIM expression and a decrease in the expression of the prosurvival protein Mcl-1. The critical role of increased BIM and decreased Mcl-1 expression in the survival of NRAS-mutant melanoma cell lines was shown through siRNA knockdown and overexpression studies. In an animal xenograft model of NRAS-mutant melanoma, XL888 treatment led to reduced tumor growth and apoptosis induction. Important differences in the pattern of client degradation were noted between the in vivo and in vitro studies. In vivo, XL888 treatment led to degradation of CDK4 and Wee1 and the inhibition of AKT/S6 signaling with little or no effect observed upon ARAF, CRAF, or MAPK. Blockade of Wee1, using either siRNA knockdown or the inhibitor MK1775, was associated with significant levels of growth inhibition and apoptosis induction. Together, these studies have identified Wee1 as a key target of XL888, suggesting novel therapeutic strategies for NRAS-mutant melanoma. Mol Cancer Ther; 12(6); 901-12. ©2013 AACR."
    GLTA

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    • Inhibitor XL888 found to restore chemotherapy sensitivity
      TAMPA, Fla. -- Researchers at Moffitt Cancer Center in Tampa, Fla., and colleagues in California have found that the XL888 inhibitor can prevent resistance to the chemotherapy drug vemurafenib, commonly used for treating patients with melanoma.
      Vemurafenib resistance is characterized by a diminished apoptosis (programmed cancer cell death) response. According to the researchers, the balance between apoptosis and cell survival is regulated by a family of proteins. The survival of melanoma cells is controlled, in part, by an anti-apoptotic protein (Mcl-1) that is regulated by a particular kind of inhibitor.
      Their current findings, tested in six different models of vemurafenib resistance and in both test tube studies and in melanoma patients, demonstrated an induced apoptosis response and tumor regression when the XL888 inhibitor restored the effectiveness of vemurafenib.
      The study appeared in a recent issue of Clinical Cancer Research, a publication of the American Association for Cancer Research.
      "The impressive clinical response of melanoma patients to vemurafenib has been limited by drug resistance, a considerable challenge for which no management strategies previously existed," said study co-author Keiran S. M. Smalley, Ph.D., of Moffitt's departments of Molecular Oncology and Cutaneous Oncology. "However, we have demonstrated for the first time that the heat shock protein-90 (HSP90) inhibitor XL888 overcomes resistance through a number of mechanisms."
      The diversity of resistance mechanism has been expected to complicate the design of future clinical trials to prevent or treat resistance to inhibitors such as vemurafenib.
      "That expectation led us to hypothesize that inhibitor resistance might best be managed through broadly targeted strategies that inhibit multiple pathways simultaneously," explained Smalley.The HSP90 family was known to maintain cancer cells by regulating cancer cells, making it a good target for treatment. According to the authors, the combination of vemurafenib and XL888 overcame vemurafenib resistance by targeting HSP90 through multiple signaling pathways.

      There was already evidence that HSP90 inhibitors could overcome multiple drug chemotherapy resistance mechanisms in a number of cancers, including non-small lung cancer and breast cancer. Because XL888 is a novel, orally available inhibitor of HSP90, the researchers hoped that it would arrest the cancer cell cycle in melanoma cell lines.

      In their study, the inhibition of HSP90 led to the degradation of the anti-apoptopiuc Mcl-1 protein. The responses to XL888 were characterized as "highly durable with no resistant colonies emerging following four weeks of continuous drug treatment." In other studies not using XL888, resistant colonies "emerged in every case," they reported.

      "We have shown for the first time that all of the signaling proteins implicated in vemurafenib resistance are 'clients' of HSP90 and that inhibition of HSP90 can restore sensitivity to vemurafenib," concluded Smalley and his colleagues. "Our study provides the rationale for the dual targeting of HSP90 with XL888 and vemurafenib in treating melanoma patients in order to limit or prevent chemotherapy resistance."

    • Doesn't look like this compound is partnered yet. A brief glance at Selleck chem for HSP90 shows a lot of competitors with better IC50 numbers. XL888 had better be the front-runner in some indication or have a better safety profile.

    • ? What I found was the following:"Home
      XL888
      Developed and owned by Exelixis $EXEL. Efforts on this projects, along with other drugs at EXEL, was halted when the company decided to focus exclusively on cabozantinib (XL184). Prior to this re-prioritization, this asset

      "XL888 is an orally available small molecule inhibitor of HSP90, a chaperone protein that promotes the activity and stability of a range of client proteins, including kinases, which play key regulatory roles in cells. The activity of HSP90 is particularly prominent in tumor cells, where it promotes the activity of proteins controlling proliferation and survival. XL888 is a potent and selective ATP-competitive inhibitor of HSP90, and binds to its target in a manner that is structurally distinct from other HSP90 inhibitors currently in the clinic."

      "XL888 is being evaluated in a phase 1 trial in patients with solid tumors. This trial was initiated based on a substantial body of preclinical data demonstrating that XL888 induces marked degradation of HSP90 client proteins and inhibits the proliferation of a broad panel of human tumor cell lines that are dependent on client proteins. XL888 is highly active in multiple human tumor xenograft models and has a favorable pharmacokinetic profile. The preclinical activity profile of XL888 is highly supportive of its clinical development for the treatment of cancers that are driven by proteins regulated by HSP90."
      Clinical Trials
      Phase 1 Study in patients with solid tumors (NCT00796484) - This study commenced in November 2008 but was terminated by the company in April 2011."

 
EXEL
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