Von Hoff DD, LoRusso PM, Rudin CM et al.Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med 361:1164-1172

Translational Genomics Research Institute and Scottsdale Healthcare, Scottsdale, AZ, USA.
New England Journal of Medicine (Impact Factor: 55.87). 10/2009; 361(12):1164-72. DOI: 10.1056/NEJMoa0905360
Source: PubMed


Mutations in hedgehog pathway genes, primarily genes encoding patched homologue 1 (PTCH1) and smoothened homologue (SMO), occur in basal-cell carcinoma. In a phase 1 clinical trial, we assessed the safety and pharmacokinetics of GDC-0449, a small-molecule inhibitor of SMO, and responses of metastatic or locally advanced basal-cell carcinoma to the drug.
We selected 33 patients with metastatic or locally advanced basal-cell carcinoma to receive oral GDC-0449 at one of three doses; 17 patients received 150 mg per day, 15 patients received 270 mg per day, and 1 patient received 540 mg per day. We assessed tumor responses with the use of Response Evaluation Criteria in Solid Tumors (RECIST), physical examination, or both. Molecular aspects of the tumors were examined.
The median duration of the study treatment was 9.8 months. Of the 33 patients, 18 had an objective response to GDC-0449, according to assessment on imaging (7 patients), physical examination (10 patients), or both (1 patient). Of the patients who had a response, 2 had a complete response and 16 had a partial response. The other 15 patients had either stable disease (11 patients) or progressive disease (4 patients). Eight grade 3 adverse events that were deemed to be possibly related to the study drug were reported in six patients, including four with fatigue, two with hyponatremia, one with muscle spasm, and one with atrial fibrillation. One grade 4 event, asymptomatic hyponatremia, was judged to be unrelated to GDC-0449. One patient withdrew from the study because of adverse events. We found evidence of hedgehog signaling in tumors that responded to the treatment.
GDC-0449, an orally active small molecule that targets the hedgehog pathway, appears to have antitumor activity in locally advanced or metastatic basal-cell carcinoma. ( number, NCT00607724.)

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Available from: Daniel D. Von Hoff, Jan 20, 2014
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    • "A wide array of small molecules that target Smo, including the canonical Hh inhibitor cyclopamine, have been shown to affect tumor progression (Taipale et al., 2000; Carney and Ingham , 2013). Additionally, the Smo antagonist vismodegib is approved by the United States Food and Drug Administration (FDA) for the treatment of advanced BCC (Robarge et al., 2009; Von Hoff et al., 2009). However, oncogenic mutations downstream of Smo and acquired resistance due to Smobinding pocket mutations have limited the efficacy of this and other clinically promising therapeutics (Yauch et al., 2009). "
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    ABSTRACT: Hedgehog (Hh) signaling plays an integral role in vertebrate development, and its dysregulation has been accepted widely as a driver of numerous malignancies. While a variety of small molecules target Smoothened (Smo) as a strategy for Hh inhibition, Smo gain-of-function mutations have limited their clinical implementation. Modulation of targets downstream of Smo could define a paradigm for treatment of Hh-dependent cancers. Here, we describe eggmanone, a small molecule identified from a chemical genetic zebrafish screen, which induced an Hh-null phenotype. Eggmanone exerts its Hh-inhibitory effects through selective antagonism of phosphodiesterase 4 (PDE4), leading to protein kinase A activation and subsequent Hh blockade. Our study implicates PDE4 as a target for Hh inhibition, suggests an improved strategy for Hh-dependent cancer therapy, and identifies a unique probe of downstream-of-Smo Hh modulation. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 03/2015; 11(1). DOI:10.1016/j.celrep.2015.03.001 · 8.36 Impact Factor
    • "Combination therapy strategy in BTC clinical setting (Von Hoff et al, 2009; Wong et al, 2011). As noted earlier, the crosstalk between the mTOR/S6K1 and Hh signalling pathway is through S6K1-mediated regulation of Gli1 in oesophageal cancer, thus p70 S6K1 was chosen for measurement of mTOR activity (Wang et al, 2012). "
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    ABSTRACT: Background: Activation of the PI3K/mTOR and Hedgehog (Hh) signalling pathways occurs frequently in biliary tract cancer (BTC). Crosstalk between these pathways occurs in other gastrointestinal cancers. The respective signalling inhibitors rapamycin and vismodegib may inhibit BTC synergistically and suppress cancer stem cells (CSCs). Methods: Gene expression profiling for p70S6k and Gli1 was performed with BTC cell lines. Tumour and pathway inhibitory effects of rapamycin and vismodegib were investigated in BTC preclinical models and CSCs. Results: Rapamycin and vismodegib synergistically reduced BTC cell viability and proliferation. This drug combination arrested BTC Mz-ChA-1 cells in the G1 phase but had no significant effect on the cell cycle of BTC Sk-ChA-1 cells. Combined treatment inhibited the proliferation of CSCs and ALDH-positive cells. Nanog and Oct-4 expression in CSCs was decreased by the combination treatment. Western blotting results showed the p-p70S6K, p-Gli1, p-mTOR, and p-AKT protein expression were inhibited by the combination treatment in BTC cells. In an Mz-ChA-1 xenograft model, combination treatment resulted in 80% inhibition of tumour growth and prolonged tumour doubling time. In 4 of 10 human BTC specimens, tumour p-p70S6K and Gli1 protein expression levels were decreased with the combination treatment. Conclusions: Targeted inhibition of the PI3K/mTOR and Hhpathways indicates a new avenue for BTC treatment with combination therapy.
    British Journal of Cancer 03/2015; 112(6). DOI:10.1038/bjc.2014.625 · 4.84 Impact Factor
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    • "Its regulation first appeared to be strictly dependent on the presence of specific levels of HH ligands. Indeed, GLI1 transcription is so far the only general biomarker of a cell's response to HH ligands [12], it can be a diagnostic tool for HH pathway activity [52] and is used to measure the efficiency of SMOH blockers in clinical samples [61–63]. "
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    ABSTRACT: Canonical Hedgehog (HH) signaling leads to the regulation of the GLI code: the sum of all positive and negative functions of all GLI proteins. In humans, the three GLI factors encode context-dependent activities with GLI1 being mostly an activator and GLI3 often a repressor. Modulation of GLI activity occurs at multiple levels, including by co-factors and by direct modification of GLI structure. Surprisingly, the GLI proteins, and thus the GLI code, is also regulated by multiple inputs beyond HH signaling. In normal development and homeostasis these include a multitude of signaling pathways that regulate proto-oncogenes, which boost positive GLI function, as well as tumor suppressors, which restrict positive GLI activity. In cancer, the acquisition of oncogenic mutations and the loss of tumor suppressors - the oncogenic load - regulates the GLI code towards progressively more activating states. The fine and reversible balance of GLI activating GLIA and GLI repressing GLIR states is lost in cancer. Here, the acquisition of GLIA levels above a given threshold is predicted to lead to advanced malignant stages. In this review we highlight the concepts of the GLI code, the oncogenic load, the context-dependency of GLI action, and different modes of signaling integration such as that of HH and EGF. Targeting the GLI code directly or indirectly promises therapeutic benefits beyond the direct blockade of individual pathways.
    Seminars in Cell and Developmental Biology 09/2014; 33(100). DOI:10.1016/j.semcdb.2014.05.003 · 6.27 Impact Factor
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