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

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 ...

Discovery of 7-(4-(3-Ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDC-101) as a Potent Multi-Acting HDAC, EGFR, and HER2 Inhibitor for the Treatment of Cancer.

http://pubs.acs.org/doi/full/10.1021/jm901453q

By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug ...

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 ...

http://clinicaltrials.gov/ct2/show/NCT01071564

The Notch like the Hedgehog pathway is very important in stem cell maintenance and repair of cells. This is also a Roche Compound.

http://www.cnb.uam.es/~jlpompa/


The second is a blocker of Hh (hedgehog) signaling, GDC-0449, which we are combining with a blocker of gamma secretase (RO4929097) in a novel study for people with recurrent sarcomas. We are seeking funding to perform this multi-center study, focusing on biopsies ...

Genentech:

Genentech Hedgehog Pathway Video

You Tube:

An award-winning short video clip exploring the Sonic Hedgehog Signaling Pathway for an Embryology - CBNS 169 course.
Won the first ever best editing video award for CBNS 169!!! :)
http://www.youtube.com/watch?v=ZryiyO32q-0

Infinity Pharma

http://www.infi.com/images/MOA-Hedge-Function.swf

The Hedgehog signaling pathway is a target of growing interest in the oncology community. It represents a new way ...

The theory of Adult Stem Cells causing some/most cancers goes like this.

There is long-known association between cancer and chronic tissue injury. For example, if you stay out in the sun your are more likely to develop skin cancer. If you smoke you increase your risk for lung cancers. Another example is drinking. Continued chemical insult can also cause many cancers or even environmental factors.

How does this relate to ASC?

Every time your tissue ...

Hedgehog Pathway Cancer and Metastasis

Increase Hh Pathway Activation leads to Increase Snail protein expression and Decreased E-cadherin & Tight Junctions

E-cadherin stretches across the cell membrane and acts as a sort of molecular “glue” that binds neighboring cells together. About 95 percent of human cancers arise from epithelial cell types that rely on E-cadherin adhesion to maintain their orderly structure. Without this E-cadherin glue, cancer cells are able to metastasize. “Our view is that ...

There are three main focuses of research surrounding the Hh pathway that could become relevant in a clinical application

1) Embryonic Stem cells for regenerative medicine (agonist/antagonist)
2) Agonist (turns pathway on)---which encompasses, degenerative diseases, stroke, hair growth in the adult body
3) Antagonist (turns pathway off)----Cancer http://www.pathway2curis.com/the-hedgehog-pathway-and-its-cancers-f7.html

I will touch on the basics of each topic and in the science section of this forum you can dig into the details of each one.

1) ...

http://clinicaltrials.gov/ct2/show/NCT01064622
Gemcitabine Hydrochloride With or Without GDC-0449 in Treating Patients With Recurrent or Metastatic Pancreatic Cancer
Purpose
RATIONALE: Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. GDC-0449 may slow the growth of tumor cells. It is not yet known whether giving gemcitabine hydrochloride together with GDC-0449 is ...