Addendum to:
http://her2support.org/vbulletin/sho...926#post208251
'Hedgehog' pathway may hold key to anti-cancer therapy
http://www.scienceblog.com/cms/hedge...apy-24481.html
Scientists in Switzerland have discovered a way to block the growth of human colon cancer cells, preventing the disease from reaching advanced stages and the development of liver metastases. The research, published today in EMBO Molecular Medicine, shows that
blocking the so-called Hedgehog-GLI pathway can prevent the growth of tumours, metastatic lesions and cancer stem cells, the cells thought to lie at the root of cancer growth.
Colon cancer often begins in a treatable form when it is confined to the bowel wall, but in frequent cases it can develop to an incurable metastatic stage. A Geneva-based research team has discovered the essential role played by HH-GLI in the progression of colon cancer to these late and incurable stages. HH-GLI is a signalling pathway used by cells to communicate with each other, often used to determine position, growth and survival.
"Previous works hinted at the possible role of HH-GLI in colon cancer, but this was denied by other studies, so its involvement was never entirely clear," said lead researcher Professor Ariel Ruiz i Altaba of Geneva University. "In this study we have proven that HH-GLI is essential for the development and growth of colon cancers. The research demonstrates the active presence of HH-GLI signalling in epithelial cells of colon cancers. Moreover, we find that
metastatic tumours rely on this pathway for sustained growth. This identifies HH-GLI as a target for novel anti-cancer therapies against so far incurable forms of colon cancer in distant organs, such as the liver."
This research
opens the possibility of new anti-cancer therapies, specifically the use of RNA interference and of Cyclopamine, a plant product known to block Hedgehog pathway activity. This and other similar molecules can now be considered for future research as a treatment for terminal patients with metastatic disease and to fight resurgent forms of the disease.
"Recurrence is a major problem in treatment. Even after a patient has displayed an apparent complete recovery from a primary tumour, recurrence at nearby or distal locations has a poor prognosis," said Ruiz i Altaba.
"While monitoring recovering mice we noted that tumours began to recur in all cases except for those treated with Cyclopamine for a short period of time after tumour disappearance. The treated mice were kept for up to one year after the treatment and remained healthy and tumour free."
Using these genetic or pharmacologic methods to block HH-GLI activity also prevents cancer stem cell self-renewal. Using a new in vivo assay to test the participation of cells in a growing tumour, the research team demonstrated the essential role of this pathway for the maintenance and survival of cancer cells.
"This work firmly establishes the critical action of HH-GLI in human colon cancer cells, providing the platform for preclinical and future clinical work." concluded Ruiz i Altaba. "The finding that
a blockade of HH-GLI for a relatively short period was sufficient to eliminate the tumour and prevent recurrence, without negatively affecting the health of the mice, opens the possibility for the use of a therapeutic window to eradicate the tumour without major side effects."
From Wikipedia:
"Studies suggest that cyclopamine acts as a primary inhibitor of the so-called "hedgehog" signal-transduction pathway in cells. This pathway named for the ligand for the signal protein, is used by cells to help them react to external chemical signals. The pathway carries out important functions in embryonic development and when it goes awry, deformities can occur. However, errant activation of the pathway can also trigger cancer in adult humans, leading to basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, and prostate, pancreatic and breast cancers. A way of controlling the pathway using cyclopamine could turn this problem on its head and provide a way to treat cancer. Many anticancer drugs are paradoxically carcinogenic in healthy individuals
[3"
Experimental Anti-cancer Drug Kills Brain Tumor Stem Cells
ScienceDaily (Aug. 31, 2007)
http://www.sciencedaily.com/releases...0830155859.htm
Hedgehog signaling regulates proliferation of prostate cancer cells via stathmin1. (2009 Sep 25)
http://www.ncbi.nlm.nih.gov/pubmed/1...ubmed_RVDocSum
Therapy for metastatic basal cell skin cancer investigated
http://www.lifesciencelab.com.au/art...ed/497734.aspx
(excerpt,
GDC-
0449 is a derivate of cyclopamine)
The results demonstrated GDC-0449, a Hedgehog Pathway Inhibitor, appears to shrink tumours in locally advanced and metastatic BCC.
Known as the “Hedgehog” trial, the clinicians observed a durable clinical benefit —defined as tumour shrinkage visible on X-ray or other physical exam or improvement in symptoms without tumour growth— in 18 of 33 patients evaluated.
Others had stable disease for prolonged periods of time. Only 4 patients had progression of disease.
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