The hedgehog pathway is activated in a variety of cancers. Most cancers have properties of stem cells (they are capable of dividing and renewing themselves for long periods; they are unspecialized; and they can give rise to specialized cell types). However, with cancer they typically don’t specialize into certain cell type rather they stay poorly differentiated.

Cancer has been linked to various repair pathways such as hedgehog, notch, and wnt. These pathways in a simplified way of thinking get stuck on and continue proliferating in a state of continual repair.

The hedgehog pathway helps the cancer survive by activating other pathways to help it survive. It turns on pathways that tell the cell to divide, grow new bloods vessels around the tumor (angiogenic factors), and also prevent it for being detected by the immune system. When the body repairs itself it uses all of these properties to facilitate repair the problem arises when the repair properties are unregulated.

The hope with modulating this pathway when it is unregulated by the body is to turn it off with a inhibitor or Hedgehog Antagonist. This will turn off the hedgehog pathway and in turn modulate a number of other various properties of cancer cells allowing the cell to stop dividing and making it detectable to the immune system.

Also see these articles

http://www.pathway2curis.com/clinical-relevance-of-the-hedgehog-pathway-hh-vt77.html

http://www.pathway2curis.com/how-does-the-hedgehog-pathway-fit-into-cancer-embryonic-vt49.html

It is well known now that cancer originates from the cancer stem cells and their genetic changes, and finding a way a eliminate these cells either by gene protein blockade therapy, apoptosis, or differentiation should lead to curative results. The hedgehog blocker seem to be leading in that direction with so many known trials showing results. But where are the clinical trials in humans? Cyclopamine has shown good preclinical data without harming normal cells in vitro and the mouse model, so humans trials should be feasible. Latest research report at the AACR meeting in Wash. D.C., April 4th, showed that cyclopamine was effective in blocking the myeloma stem cell by inhibiting the hedgehog protein, by Hopkins researchers. So, perhaps we will see some breakthroughs in treatment. Unfortunately, cancer research breakthroughs have been slow since only recently have the cancer stem cells been revealed. Some researchers still have not caught on to the significance of these cells and may be retarding progress. I don't believe researchers are correct when they say 5-10 years needed for results. What researchers need is to find the right direction which now appears to be focused on cancer stem cells. I would hope that Curis is develping some clinical trials. Dr N Padron-Bruce

Hi Cancer researcher,

Thanks for your thoughts.

Were you able to make it to the AACR meeting? I was able to order a few AACR sessions on CD but that they won't ship them for another few weeks. I will post comments when I get them or try to legally make them available on this site.
Yes hopkins actually holds some shares of curis


Yes I think Genentech is heading in that direction. They now have partners that focus on Hedgehog, Wnt, and Notch pathways.

This is a follow-up to my message on cancer stem cells. I have been researching cyclopamine, and have initiated a clinical trial in a patient with myeloma. So, far, this patient has responded to low dose cyclopamine. his m-protein marker has decreased from 0.9 to 0.3 All his other values are in normal range.
Cyclopamine differentiates myeloma stem cells, so they do not produce more cancer cells. This follows the cancer stem cell theory, that says cancer stem cells are the cells that must be eliminated to cure cancer, because they are the only cells that produce more cancer cells. I hope to eliminated the myeloma stem cells in this patient, and hope to xee his m-protein to decrease to 0.0. Then I will order a bone marrow biopsy to see if his plasma cells are decreased or eradicated. PS, T did not attend the AACR meeting, but did note the research report by Johns Hopkins U that cyclopamine did affect myeloma stem cells. Dr P-B

Not sure how you are administering cyclopamine but depending IF there is a mutation on the SMO protein you might not be able to turn off the pathway completely. Cyclopamine can't over come all activating mutations in SMO. I have no idea if myeloma even has been tested for hedgehog pathway gene mutations?



"Assessing changes and proportions of various proteins, particularly M protein, helps track the progression of myeloma disease and response to treatment. Myeloma is characterized by a large increase in M protein, which appears as a "spike" on electrophoresis (see figure)."
if image does not appear click here
http://www.multiplemyeloma.org/images/illustrations/diagnosis_fig1.gif

http://www.multiplemyeloma.org/about_myeloma/2.05.html


email me when you have a chance

hedgehog@pathway2curis.com

Concerning the patient on cyclopamine, the m marker is 0.3 Will retest later. Cyclopamine preclinical data is based on the Hopkins report in April 2006 showing that cyclopamine causes differentiation of mm stem cells so they no longer produce myeloma. Unfortunately, we or hopkins have no way of measuring the mm stem cells in this patient, which would be a direct way of seeing results. We can only measure m-protein, SPEP. DR P-B

Please note the recent PNAS article, feb 27,2007 online or in journal, March 6, 2007, "Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Basically, they show that cyclopamine can eliminate mm stem cells via Hedgehog blockade that causes differentiation. There is another repot that shows combining cyclopamine with a statin increases killing of cancer cells in medulloblastoma. May be worth adding lovastastin to cyclopamine to treat myeloma also.

Yes that is a GREAT article. Did you notice this statement in the paper





These other recent articles I also found interesting

http://www.pathway2curis.com/blockade-of-hedgehog-signaling-inhibits-pancreatic-cancer-i-vt8000.html

http://www.pathway2curis.com/targeted-therapy-for-cancer-stem-cells-the-patched-pathway-vt7788.html

Concerning the patient recently treated with cyclopamine. He was just treated with a new water soluble version of cyclopamine. His M marker is now 0.1, as of 2-14-08. Since cyclopamine attacks the mm stem cell, and eliminating the mm stem cell may stop the cancer completely, this patient may be on a curative treatment. Will report later. Dr P

Hi, I am wondering if the researcher who put the myeloma patient on cyclopamine to start a trail would be interested in having another myeloma patient on this trial too. If so, I would be interested. My email address is mjt8@mjosolutions.com