Showing papers by "Philip A. Beachy published in 2012"

Scube/You activity mediates release of dually lipid-modified Hedgehog signal in soluble form

Abstract: Owing to their covalent modification by cholesterol and palmitate, Hedgehog (Hh) signaling proteins are localized predominantly to the plasma membrane of expressing cells. Yet Hh proteins are also capable of mobilizing to and eliciting direct responses from distant cells. The zebrafish you gene, identified genetically >15 years ago, was more recently shown to encode a secreted glycoprotein that acts cell-nonautonomously in the Hh signaling pathway by an unknown mechanism. We investigated the function of the protein encoded by murine Scube2, an ortholog of you, and found that it mediates release in soluble form of the mature, cholesterol- and palmitate-modified Sonic hedgehog protein signal (ShhNp) when added to cultured cells or purified detergent-resistant membrane microdomains containing ShhNp. The efficiency of Scube2-mediated release of ShhNp is enhanced by the palmitate adduct of ShhNp and by coexpression in ShhNp-producing cells of mDispatchedA (mDispA), a transporter-like protein with a previously defined role in the release of lipid-modified Hh signals. The structural determinants of Scube2 required for its activity in cultured cell assays match those required for rescue of you mutant zebrafish embryos, and we thus conclude that the role of Scube/You proteins in Hh signaling in vivo is to facilitate the release and mobilization of Hh proteins for distant action.

Topical itraconazole formulations and uses thereof

Abstract: Methods of transdermally delivering a therapeutic amount of a triazole-triazolone compound are provided, e.g. for the prevention or treatment of basal cell carcinoma (BCC) in a subject. A therapeutic level of a triazole-triazolone compound such as itraconazole is delivered transdermally to a subject. Also provided are topical triazole-triazolone compositions that find use in practicing the subject methods.

Use of fk506 for the treatment of pulmonary arterial hypertension

Abstract: A method of reducing pulmonary arterial hypertension in a mammal that employs FK506 is provided. In certain embodiments, the method comprises administering FK506 to a mammal having pulmonary arterial hypertension associated with defective MBPR2 signaling at a dosage sufficient to reduce blood pressure in the pulmonary artery of the mammal.

Abstract LB-223: An open-label, exploratory phase II study of oral itraconazole for the treatment of basal cell carcinoma

Abstract: Purpose: Itraconazole is an FDA-approved antifungal drug that has been recently shown to antagonize the Hedgehog (Hh) signaling pathway, a crucial driver of basal cell carcinoma (BCC) tumorigenesis. As oral itraconazole reduced BCC growth in mice, we assessed itraconazole9s efficacy in treating human BCC tumors in an open-label, exploratory phase II study. Patients and Methods: Patients with at least one BCC tumor greater than 4 mm in diameter and with no co-morbidities were eligible to enroll. Patients were enrolled in 2 cohorts to receive oral itraconazole 200 mg twice-daily for one month (Cohort A) or 100 mg twice-daily for a longer duration (Cohort B). The primary endpoint was to determine changes in tumor size, proliferation (Ki67 levels), and a target gene of the Hh pathway (GLI1 mRNA). Results: Of the 29 patients that enrolled in the clinical trial, 19 patients were treated with itraconazole. Itraconazole caused 2 treatment-related adverse events (grade 2 fatigue and grade 4 CHF). Tumors treated with itraconazole showed a 23% reduction in clinical tumor area (95% CI: 17.2% to 28.1%), a 45% reduction in cell proliferation (P=0.04), and a 65% reduction in Hedgehog activity (P=0.03). Eight subjects with multiple tumors were assessed for clinical size changes: 4 subjects had partial response and 4 had stable disease. Tumors from control patients and patients previously treated with other Hedgehog inhibitors saw no significant changes in cell proliferation or Hedgehog activity. Conclusion: Itraconazole reduced BCC tumor size, tumor proliferation, and Hedgehog pathway activity in this exploratory study. Additional studies with larger numbers of patients are needed to validate these findings, however this proof-of-concept study demonstrates the possibility of repurposing FDA approved drugs for the treatment of cancers driven by the Hedgehog signaling pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-223. doi:1538-7445.AM2012-LB-223