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• W2000827218 abstract "The bulk of tumor is thought to be composed of differentiated cancer cells, with only a small fraction consisting of pluripotent self-renewing putative cancer stem cells (CSCs) (1Weiss GJ Von Hoff DD Hunting the hedgehog pathway.Clin Pharmacol Ther. 2010; 87: 743-747Crossref PubMed Scopus (13) Google Scholar). Recurrence or progression of tumor after treatment is often caused by growth and differentiation of the CSCs, enabled by increased signaling of Hedgehog (1Weiss GJ Von Hoff DD Hunting the hedgehog pathway.Clin Pharmacol Ther. 2010; 87: 743-747Crossref PubMed Scopus (13) Google Scholar) and Notch in CSCs (2Alison MR Lin WR Lim SM Nicholson LJ Cancer stem cells: in the line of fire.Cancer Treat Rev. 2012; 38: 589-598Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar). Preclinical studies report that CSCs are more resistant to systemic radiotherapy than differentiated cancer cells that are often observed in the bulk of tumor mass (2Alison MR Lin WR Lim SM Nicholson LJ Cancer stem cells: in the line of fire.Cancer Treat Rev. 2012; 38: 589-598Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar). Therefore, curative therapy for advanced/metastatic lung cancer may require doubling down, a two-pronged approach: cytotoxic or appropriate molecular-targeted therapy to debulk the majority of tumor cells in combination with Notch and/or Hedgehog signaling inhibitors to eliminate the CSCs to prevent tumor growth/recurrence (1Weiss GJ Von Hoff DD Hunting the hedgehog pathway.Clin Pharmacol Ther. 2010; 87: 743-747Crossref PubMed Scopus (13) Google Scholar). In our quest to improve outcomes for patients with advanced malignancies, targeting the Notch signaling pathway (NSP) and Hedgehog signaling pathway (HHSP) may lead to knocking out CSCs. Targeting these pathways is an attractive means to inhibit CSC growth and differentiation. An overview of putative CSCs, NSP, and HHSP was provided by Dr. Carbone. An important regulator of development and cell fate in various tissues, the NSP has four highly conserved transmembrane receptors (Notch1–4) (3Malhotra GK Zhao X Band H Band V Shared signaling pathways in normal and breast cancer stem cells.J Carcinog. 2011; 10: 38Crossref PubMed Scopus (37) Google Scholar). The Notch receptor undergoes a two-stage cleavage by tumor necrosis factor-α-converting enzyme and γ-secretase when bound by an appropriate ligand (3Malhotra GK Zhao X Band H Band V Shared signaling pathways in normal and breast cancer stem cells.J Carcinog. 2011; 10: 38Crossref PubMed Scopus (37) Google Scholar). All agents in clinical trials that target the NSP are inhibitors of γ-secretase. An important regulator of tissue polarity, patterning, and stem cells maintenance in various tissues, the HHSP has two Patched (PTCH) transmembrane receptors (PTCH1 and PTCH2) (1Weiss GJ Von Hoff DD Hunting the hedgehog pathway.Clin Pharmacol Ther. 2010; 87: 743-747Crossref PubMed Scopus (13) Google Scholar, 3Malhotra GK Zhao X Band H Band V Shared signaling pathways in normal and breast cancer stem cells.J Carcinog. 2011; 10: 38Crossref PubMed Scopus (37) Google Scholar). When the appropriate ligand binds to the PTCH receptor, Smoothened (SMO) is derepressed and a cascade of events ultimately leads to Glioma-associated oncogene homologue (GLI) transcription activation (1Weiss GJ Von Hoff DD Hunting the hedgehog pathway.Clin Pharmacol Ther. 2010; 87: 743-747Crossref PubMed Scopus (13) Google Scholar). All agents in clinical trials that target the HHSP are inhibitors of SMO. To date, clinical results on at least three drugs that target NSP and five drugs that target the HHSP have now been formally presented at national meetings. A few of these agents were highlighted at this meeting. Dr. Stewart provided some additional background on Notch, stating that it is commonly expressed in non–small-cell lung cancer (NSCLC), its expression is increased by hypoxia, and CSCs, defined by aldehyde dehydrogenase and CD133 positive staining, have increased Notch signaling activity. In preclinical NSCLC studies, γ-secretase inhibitors increased poly adenosine diphosphate ribose polymerase cleavage and apoptosis and decreased cell line and tumor xenograft growth. In the phase I study with the γ-secretase inhibitor, RO4929097, a patient with colorectal cancer had a partial response, a patient with an epithelial sarcoma had a mixed response, and two patients with melanoma had minor responses. In NSCLC, this agent is being evaluated in a maintenance study for nonprogressing advanced patients after first-line therapy. A phase I/II study is evaluating this drug in combination with erlotinib in advanced-stage NSCLC. Dr. Wang presented the γ-secretase inhibitor, PF-03084014, currently in a phase I trial in solid tumors. This agent is dosed orally twice a day for 21 of 28 days; one patient with papillary thyroid cancer had a complete response and two patients with desmoid tumor had a partial response. At the last formal presentation of this study, eight patients were still on study, with three individuals receiving drug for longer than 1 year. Dr. Melemed presented the SMO antagonist, LY2940680, currently in a phase I trial in solid tumors. The maximum tolerated dose of 400 mg has been identified. Toxicities were common class side effects including dysgeusia, fatigue, alopecia, as well as, nausea and vomiting. Plans are in the works for a phase Ib/II trial combination with carboplatin/etoposide in patients with extensive-stage small-cell lung cancer (SCLC). I presented the preclinical and clinical development of vismodegib (formerly known as GDC-0449), a synthetic SMO antagonist that has completed phase I/II studies. In two long-term–treated patients with basal cell carcinoma (BCC) treated with vismodegib, no major safety signals were reported with dosing out to nearly 3 years (4Weiss GJ Tibes R Blaydorn L Jameson G Downhour M White E et al.Long-term safety, tolerability, and efficacy of vismodegib in two patients with metastatic basal cell carcinoma and basal cell nevus syndrome.Dermatol Reports. 2011; 3: e55Crossref Scopus (5) Google Scholar). This agent demonstrated clinical activity as a single agent in locally advanced and metastatic BCC (5Von Hoff DD LoRusso PM Rudin CM et al.Inhibition of the hedgehog pathway in advanced basal-cell carcinoma.N Engl J Med. 2009; 361: 1164-1172Crossref PubMed Scopus (893) Google Scholar) and was approved by the Food and Drug Administration for use in this tumor type on January 30, 2012 (http://www.cancer.gov/cancertopics/druginfo/fda-vismodegib). Vismodegib is being evaluated in a number of clinical trials in combination with chemotherapy and/or targeted therapy. One of these is the E1508 trial that randomizes extensive-stage SCLC patients to cisplatin plus etoposide or an experimental arm, one of which consists of cisplatin plus etoposide plus vismodegib (www.clinicaltrials.gov). At the 12th Annual Targeted Therapies of the Treatment of Lung Cancer meeting, several investigators presented data on recent developments surrounding agents that target NSP and HHSP. It is still too early to determine whether the strategies of targeting NSP via γ-secretase inhibition will lead to statistically significant and meaningful gains that justify drug approval in NSCLC. The initial barrier for demonstration of efficacy has been overcome for at least one SMO antagonist, vismodegib, in advanced BCC. There are a variety of phase II trials ongoing with a number of SMO antagonists, including the E1508 trial that combines an SMO antagonist with cytotoxic chemotherapy in first-line therapy for extensive-stage SCLC. If the results of this particular study are statistically significant in favor of the experimental arm with an acceptable toxicity profile, then we may see an approval strategy for SCLC that would, hopefully, improve the armamentarium for this disease. For solid tumors such as NSCLC and SCLC, the strategy for maximum efficacy will likely involve targeting CSCs by doubling down inhibition of NSP and/or HHSP combined with tumor mass debulking via delivery of systemic cytotoxic or specific targeted therapies." @default.
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• W2000827218 date "2012-12-01" @default.
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• W2000827218 title "Doubling Down with Inhibitors of Notch and Hedgehog Signaling Pathways" @default.
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