Curis Hedgehog and Beyond --plus multi-targeting cancer inhibitors

All of the following compounds work at blocking the activating forms of a Hh signaling protein called "SMO." IP-926 team took a well known inhibitor and made it work better. GDC-0449 said I know I want to inhibit SMO lets make a brand new inhibitor (or class of molecules). Itraconazole was found during a Stanford screen and has been in use for the last 25 years for fungal infections.

--IP-926 synthetic derivative of Cyclopamine ...

Very interesting article and is a very different approach compared to GDC-0449

LDE225 (Hedgehog inhibitor)

• Cream Form
• CONS: May not take help Odontogenic keratocyst and Plantar Pits in these patients. Will not prevent new BCCs (Unless they take the cream lotion on a regular basis)
• PROS: Min/No side effects. No hair loss or muscle spasms

GDC-0449 (Hedgehog inhibitor)

• Systemic
• CONS: Higher incidence side effects.
• PROS: Will probably prevent new BCCs for forming. Will ...

Abstract
BACKGROUND: Odontogenic keratocysts of the jaw are a central feature of basal cell nevus syndrome (BCNS) and arise from the basal cell layer of the surface epithelium. Although they are benign, they tend to be aggressive, with local invasion of bony structures, extensive growth, and potential for substantial disfigurement and speech dysfunction. Complete surgical resection is the current standard of care; however, the procedures are often technically challenging and are followed by high recurrence ...

Abstract Number: LB-1
Presentation Title: An investigator-initiated, phase II randomized, double-blind, placebo-controlled trial of GDC-0449 for prevention of BCCs in basal cell nevus syndrome (BCNS) patients
Presentation Time: Sunday, Apr 03, 2011, 10:30 AM -10:50 AM
Location: West Hall D, Orange County Convention Center
Author Block: Jean Y. Tang, Julian M. Mackay-Wiggan, Michelle Aszterbaum, Joselyn Lindgren, Kris Chang, Carol Coppola, Angela Campbell, Anita Chanana, Jackleen Marji, Chris Callahan, Robert Yauch, David R. Bickers, Ervin H. ...

Itraconazole, is an already approved drug as an oral antifungal but it has been show by a research team to also inhibit the Hh pathway. It was also shown to inhibit the pathway differently than the current SMO inhibitors in the clinic.

http://clinicaltrials.gov/ct2/show/NCT01108094

BCCs are the most common human cancer in the US and affect over 1 million people. There is no effective drug to prevent basal cell carcinomas ...

NEW ORLEANS - An oral inhibitor of the hedgehog pathway proved dramatically effective for the treatment and prevention of basal cell carcinomas in patients with basal cell nevus syndrome in a phase II study.

Indeed, the randomized double-blind trial was halted early for ethical reasons because patients assigned to vismodegib, formerly known as GDC-0449, demonstrated a 25-fold reduction in the rate of new basal cell carcinomas (BCCs), compared with placebo-treated controls, Dr. Jean Y. Tang ...

A Study of TAK-441 in Adult Patients With Advanced Nonhematologic Malignancies P1
http://clinicaltrials.gov/ct2/show/NCT01204073
This is the first study in which TAK-441 is administered to humans. The patient population will consist of adults aged 18 or older who have advanced nonhematologic malignancies and for whom standard treatment is no longer effective or does not offer curative or life-prolonging potential. Following completion of the dose escalation study, patients will be enrolled as part of 2 expansion cohorts. ...

The emergence of new small molecules with capacity of blocking the Hedgehog signaling pathway provides a novel therapeutic approach in pancreatic adenocarcinoma treating the primary tumor, stroma, systemic metastases and pancreatic cancer stem cells by hedgehog pathway inhibition. This phase 2 clinical trial will evaluate the progression free survival (PFS) in patients with previously untreated metastatic pancreatic adenocarcinoma. We hypothesize that the combination of cytotoxic agents (gemcitabine and nab-paclitaxel) with the Hedgehog inhibitor GDC-0449 may ...

Like other cancer drugs there is a growing body of evidence that Cancers can adapt to single mono-therapy of Hedgehog SMO inhibitors

• Mutation in SMO (the protein that the first generation of Hh inhibitors work on)
• Increased amplification of downstream targets in the pathway such as Gli2
• Increased expression and activation of phosphatidylinositol-3-kinase (PI3K)

Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma

The Hedgehog (Hh) signaling pathway is inappropriately activated in ...

Human Invasive Prostate Cancer Cells

Altogether, these observations suggest that EGFR and sonic hedgehog cascades may represent the potential therapeutic targets of great clinical interest to eradicate the total prostate cancer cell mass and improve the current docetaxel-based therapies against locally advanced and invasive prostate cancers, and thereby prevent metastases and disease relapse.
http://www.ncbi.nlm.nih.gov/pubmed/20179163

origin of basal cell carcinoma

http://www.ncbi.nlm.nih.gov/pubmed/20154679

Increased expression of the hedgehog signaling pathway in pediatric ...