Curis, P&g, And The Lost Baldness Cure

[pegasus2]

Many of you have heard of this drug before. Famous hair loss researcher Angela Christiano has said that it cured hair loss, but caused skin cancer. The drug in question is a variation of SAG (smoothened agonist). It seems much information on this project has been lost over time. I hope we can piece it together in this thread. People lost interest in it due to the risk of cancer, but if there is ever going to be a pharmacological cure I believe it's going to come from finding a way to safely manipulate this pathway.

The role of the sonic hedgehog (shh) pathway in hair follicle cycling and morphogenesis was revealed in the late 90s. Then in 2005 Curis published this paper that set the hair loss world abuzz:
https://www.sciencedirect.com/science/article/pii/S0022202X15324830

Shortly after publishing that paper Curis partnered with Proctor & Gamble to develop an shh agonist for treating male pattern baldness. They successfully cleared the first of two preclinical milestones with P&G before the partnership was terminated because, "the Hedgehog agonist compounds under development pursuant to the collaboration did not demonstrate an acceptable safety profile". Curis announced that they would seek out another partner for developing the drug, but they either abandoned that idea or were unsuccessful in finding a new partner.

"This first preclinical milestone represents the successful completion of several initial steps toward our goal of bringing a topical Hedgehog agonist into the clinic for the treatment of hair growth disorders," said Daniel R. Passeri, President and Chief Executive Officer of Curis, Inc. "We are pleased by the progress that the joint research team has made, particularly since our collaboration with Procter & Gamble began only five months ago. We are hopeful that this will be the first of several development achievements that will allow Curis and Procter & Gamble to advance a Hedgehog agonist into clinical development and ultimately succeed in providing an effective treatment for hair growth disorders."

https://www.businesswire.com/news/h...hes-Preclinical-Milestone-Hair-Growth-Program


Now this study has recently come out showing that tumors regress considerably with one week treatment of shh inhibitor vismodegib while new hair follicles remain intact:
https://elifesciences.org/articles/46756

What if the shh pathway was activated just long enough for HF morphogenesis to begin, and then vismodegib was applied for a week. Would that be early enough to prevent any tumors from forming in the first place?

I found some interesting posts from a member on this site with the handle "hedgehog_info" who seems to have been connected with Curis. He joined the forum when the partnership with P&G was announced, and then left when the partnership was terminated. His final post:

Yes I believe the 14 day tox study had side effects. The program will revert back to curis to develop if they want to reformulate the topical application. Wouldn't expect them to do this anytime soon.

Here are some other interesting posts that I found:

"P&G uses the same animal strain and got the same results as curis did before they partnered for this program."

"Side effects to this treatment is the real question if the FDA will allow this Hh agonist treatment to work. It will definitly not be an over the couter medication."

"I hope it works too. I honestly have doubts due to cancer risk effects. Not that it won't grow hair."

"The male hormone slowing the hair back down, the immune system attacking " something" about the miniaturizing follicle that eventually causes cell death in the lower follicle. Perhaps hedgehog could be a treatment that has to be applied once a year? "

"When the Hh is turned on it actually prevents the immune system from attacking the cell sorta of like cancer cells aren't seen by the immune system. However, it will be a once applied application and hopefully quick at that. I would guess application's would really depend on how fast your hairs fall back out and doesn't grow back."

"It was orginally going to be used for chemo therapy patients. However, curis along with P&G thought they could bring it to the market for male pattern baldness."

" on the flip side they have done animal experients and have noted these same cells that send the signals when turned on permanately develop BCC and other types of skin cancer.
Curis is trying to turn on this pathway just enough to grow hair but not have patients develop cancer.
I little inside info. Curis was trying to develop another program for stroke

but use a systemic agonist of this pathway and one of the side effects they found was hair growth with a one time application."

"Yes you would have to apply a Hh agonist treatment every few years. However, it really depends on how fast it falls out."

"The pathway is only turned on for a day(or less) in order to start the wave of 2ndry pathways to start the hair growing.
If the pathway is turned on to continuous you will get Basal Cell Carcinoma (skin cancer), or if it turned on more frequently then normal you might get a mole with a long hair sticking out of it."

"Yes if you turn on the pathway to much you could develop a lot of problems. Curis/P&G have not noted any side effects after 1 year of a one time topical application treatment. But there is a big chance for side effects and should not be taken lightly.
For example this is not going to be an over the counter answer to for hair growth. It WILL work for hair growth but we will see what the FDA will say.
Not trying to pessimistic but there are some REAL things to consider. I hope it works and I think P&G developing this says a lot and bodes well for clinical trials.
Agonists of the Wnt pathway probably won't be used for Hair growth unless they are using Embryonic stem cells to create new hair follicles."

"about a year until human trials. Until then P&G are getting the formulation and process development aspects of the drug correct."

"I would say that a Hh agonist treatment for Hair growth would be whenever the hairs shed again."

"New presentation but nothing has changed. It is all up to P&G. They should select a lead molecule in Q1 of 07 and then an IND late in 07."

"Yes that would be a perfect world. I myself work at a biotech company and can saw it costs a lot of money and resources to get a single drug into the first patient. Even then a lot of them fails before reaching the public."

"Go ahead and PM me or send me an email and I will loan you the article.
hedgehog@pathway2curis.com"

"The Wnt pathway along with a few other embryonic pathways help to create a hair follicles from immature cells. So if somebody’s hair follicles died then you would want to create hair follicles this is the route to take. I guess it is sort of like HM but would probably be a lot faster.
The Hh pathway (Wnt’s sister pathway), does not create new hair follicles rather it kicks any hair follicles into the growth phase. Such as in Alopecia. This is what Curis along with P&G are hoping to do. At first they were seeking to develop this treatment for patients with chemotherapy when their hair fell out. However, they both think now that they can develop it for Alopecia and other hair follicle cycling problems.
Both of these pathways when turned on for an extended period of time WILL cause cancer. About 1/3 to ½ of all cancers have these pathways turned on abnormally. I honestly don't think that a topical application will cause a pathway to be turned on continuously but you have to use caution.
It should also be noted that Wyeth pharmaceuticals are developing a Hh agonist for stroke patients. This treatment will use a oral Hh agonist which IMO is more risky then a topical Hh agonist. They have noted side effects in the Oral Hh agonist. The two side effects were abnormal growth in the intestines and hair growth."

"Any body's guess. IND in just under a year. The hair will grow fast but I guess it really depends on how they conduct the clinical trial and how long the FDA wants them to wait to see if any people develop abnormal proliferation."

"Curis product will kick any resting hair follicle into the growth phase. It will be a replacement[to minoxidil] and you probably won't need any other treatment. However, if you have a lot of damage to your hair follicle and it doesn't work well such as maybe a burned victim then you will probably need HM and curis product won;t work. However depending on HM your hairs will probably fall out again and you will need curis's product to kick the HM follicles back into the growth phase.
Regardless of the treatment curis;s product will need to be used every time your hair doesn't go back into the growth phase you have more shedding then growth.
Hope this helps. I don't know that much about HM so i might be wrong on that aspect."

"I believe people with alopecia don't have dead follicles, at least that is what P&G hope.
I would GUESS that people would have to use P&G/Curis treatment every 2-5 years. Their treatment would probably be a 1 time topical application. But this is all a BIG GUESS. All assuming clinical studies go well"

"Hopefully it will be in the clinic in a year and should see results about 10 days after a topical application."

"A few people including P&G seem to think that hair follicle cycling requires a Hh pathway activation to get into the growth. The real problem will be how to stop the side effects."

"There have been a few studies that used a mouse model of hair loss. According to the researchers they said that this animal strain has been extensively studied and characterized for hair cycling, hair loss, hair growth ect... After they applied an agonist (used to turn on the pathway) it grew hair in about 14 days with a one time dose.
They also looked at human scalp and confirmed that we humans also express this pathway when the hair needs to get kicked into the growth phase.
This agonist was going to be first used for people who lost hair due to chemotherapy. However, after curis licensed it to P&G they wanted to develop it for alopecia.
Curis has also stated that neuronal and hair follicles are the most sensitive to pathway activation. Obviously the formulation has to be perfect."

"Well, the pharma companies are betting on a one time application will do the trick. Wyeth is hoping for a one time systemic application (for stroke) and P&G are hoping for a one time topical application. If you have skin cancer and you put this topical stuff on your head it is going to be like adding gasoline to a fire."

"Yes that is the main problem with most of these embryonic pathways. In embryonic development different concentrations of certain proteins will give rise to different types of cells and tissues. For example, high concentrations Hh a gives rise to neuronal tissue, in creation of hair follicles the Higher the concentration of Wnt the more hair follicles develop, however the higher the concentration of Notch less hair follicles are developed.
Also if you don't have the correct concentration of Wnt/notch/Hh to develop hair follicles you will obtain an undesired cell type and thus side effects. My hope that because the Hair follicle is one of the most sensitive types of cells to Hh pathway activation that one could develop a formulation that could potentially develop the target cells. I plan on calling curis in the near future to obtain what exactly the side effects are. IE, undesired proliferation, wrong hair color, hair size, ...ect
The published report from curis didn't report any of these side effects... be interesting to find out."

This drug was apparently tried by four members of one of the private forums more than five years ago. Reportedly they all regrew hair, but I don't know how much. I wonder if anyone here has seen the pictures, or can get in touch with these people? It's been over 5 years now. It would be nice to know if any of them ever developed any tumors. Maybe they are all dead now? As far as I know nobody else has ever tried this drug for hair loss, and for good reason.

 

[Armando Jose]

What if the shh pathway was activated just long enough for HF morphogenesis to begin, and then vismodegib was applied for a week. Would that be early enough to prevent any tumors from forming in the first place?

Very interesting,
I have always thought that you should only use any drug that tries to promote hair growth only for a period of time and not for chronic use. The reason is that human hair is out of sync, and that each phase of the hair cycle can vary its dependence on that drug.

An example is minoxidil/finas sheding/regrowth phases.

Take care and good luck.

 

[S Foote.]

Many of you have heard of this drug before. Famous hair loss researcher Angela Christiano has said that it cured hair loss, but caused skin cancer. The drug in question is a variation of SAG (smoothened agonist). It seems much information on this project has been lost over time. I hope we can piece it together in this thread. People lost interest in it due to the risk of cancer, but if there is ever going to be a pharmacological cure I believe it's going to come from finding a way to safely manipulate this pathway.

The role of the sonic hedgehog (shh) pathway in hair follicle cycling and morphogenesis was revealed in the late 90s. Then in 2005 Curis published this paper that set the hair loss world abuzz:
https://www.sciencedirect.com/science/article/pii/S0022202X15324830

Shortly after publishing that paper Curis partnered with Proctor & Gamble to develop an shh agonist for treating male pattern baldness. They successfully cleared the first of two preclinical milestones with P&G before the partnership was terminated because, "the Hedgehog agonist compounds under development pursuant to the collaboration did not demonstrate an acceptable safety profile". Curis announced that they would seek out another partner for developing the drug, but they either abandoned that idea or were unsuccessful in finding a new partner.


https://www.businesswire.com/news/h...hes-Preclinical-Milestone-Hair-Growth-Program


Now this study has recently come out showing that tumors regress considerably with one week treatment of shh inhibitor vismodegib while new hair follicles remain intact:
https://elifesciences.org/articles/46756

What if the shh pathway was activated just long enough for HF morphogenesis to begin, and then vismodegib was applied for a week. Would that be early enough to prevent any tumors from forming in the first place?

I found some interesting posts from a member on this site with the handle "hedgehog_info" who seems to have been connected with Curis. He joined the forum when the partnership with P&G was announced, and then left when the partnership was terminated. His final post:


Here are some other interesting posts that I found:





This drug was apparently tried by four members of one of the private forums around 2015-2016. Reportedly they all regrew hair, but I don't know how much. I wonder if anyone here has seen the pictures, or can get in touch with these people? It's been close to 5 years now. It would be nice to know if any of them ever developed any tumors. Maybe they are all dead now? they used the drug at a dose of .02% once or twice a week for a short period. As far as I know nobody else has ever tried this drug for hair loss, and for good reason.

I am going to try this myself with just one application and see what happens. I am leaning towards .05%, and doing it one to two days before or after my next wounding session. I don't want to do it the day of and have it go systemic. Aside from avoiding side effects the other problem is getting the dose right. If the dose is too high it acts as an inhibitor rather than an agonist.

There is a major influence upon hair follicle enlargement that is being overlooked in the current research, and explains why some effective treatments like this can grow a lot more hair, but also risk cancer development. All normal cell growth and tissue development is subject to the external resistance based spatial grow controls described here. http://phys.org/news/2014-04-room-tissue-growth-cell-response.html

This consideration is a central concern in tissue engineering where the goal is to grow new tissue in the body. This is why scientists in tissue engineering use scaffolds to negate this external resistance factor, and create the intended size and form of the required new tissue. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2587658/

To encourage new tissue growth is also the goal in hair loss treatments, yet this research consistently fails to take account of this overruling growth control. This is technically grounds for the retraction of many papers that propose hair loss treatments for quote, "Ignoring a process that is known to have a strong influence on the area under study" https://authorservices.wiley.com/Re...-by-step-guide-to-reviewing-a-manuscript.html

The evidence is that this external resistance based growth restricting factor, is the significant mechanism of the miniaturisation of hair follicles in the common cases of hair loss. Foote, J Tissue Sci Eng 2018, 9:1 DOI: 10.4172/2157-7552.1000217 If this is so, any treatment that can enlarge the follicles against this external restriction, will risk uncontrolled cell growth and cancer development. I suggest this is what is happening here.

The primary influence of this growth control upon anagen follicle growth, also explains why the cell based treatments continue to fail when it comes to actual Human trials. You cannot just inject a cocktail of cells, primordiums or whatever, and expect this to grow a large hair follicle against this growth restriction. The accepted science in tissue engineering says otherwise.

The only way to grow large hair follicles that last long term, is to deal with this external resistance factor. There is nothing in the pipeline that is going to do this. The whole focus of hair loss research needs to change.

 

[Throwaway94]

Oh 2005... I was but a wee 10 year old laughing at my dad's bald spot.

There is a major influence upon hair follicle enlargement that is being overlooked in the current research, and explains why some effective treatments like this can grow a lot more hair, but also risk cancer development. All normal cell growth and tissue development is subject to the external resistance based spatial grow controls described here. http://phys.org/news/2014-04-room-tissue-growth-cell-response.html

This consideration is a central concern in tissue engineering where the goal is to grow new tissue in the body. This is why scientists in tissue engineering use scaffolds to negate this external resistance factor, and create the intended size and form of the required new tissue. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2587658/

To encourage new tissue growth is also the goal in hair loss treatments, yet this research consistently fails to take account of this overruling growth control. This is technically grounds for the retraction of many papers that propose hair loss treatments for quote, "Ignoring a process that is known to have a strong influence on the area under study" https://authorservices.wiley.com/Re...-by-step-guide-to-reviewing-a-manuscript.html

The evidence is that this external resistance based growth restricting factor, is the significant mechanism of the miniaturisation of hair follicles in the common cases of hair loss. Foote, J Tissue Sci Eng 2018, 9:1 DOI: 10.4172/2157-7552.1000217 If this is so, any treatment that can enlarge the follicles against this external restriction, will risk uncontrolled cell growth and cancer development. I suggest this is what is happening here.

The primary influence of this growth control upon anagen follicle growth, also explains why the cell based treatments continue to fail when it comes to actual Human trials. You cannot just inject a cocktail of cells, primordiums or whatever, and expect this to grow a large hair follicle against this growth restriction. The accepted science in tissue engineering says otherwise.

The only way to grow large hair follicles that last long term, is to deal with this external resistance factor. There is nothing in the pipeline that is going to do this. The whole focus of hair loss research needs to change.

The idea behind most of these cell based treatments is that they are resistant to the external resistance factor, aka the biopsies are taken from the donor zone. If these cells /primordiums / whatever don't assimilate as planned and retain DHT resistant hair then yeah it's back to the drawing board.

 

[Armando Jose]

This drug

Which drug are you going to try?
The patent
https://patents.google.com/patent/US6683192B2/en

 

[dr75]

Very interesting thread. Please keep us updated.

 

[S Foote.]

Oh 2005... I was but a wee 10 year old laughing at my dad's bald spot.



The idea behind most of these cell based treatments is that they are resistant to the external resistance factor, aka the biopsies are taken from the donor zone. If these cells /primordiums / whatever don't assimilate as planned and retain DHT resistant hair then yeah it's back to the drawing board.

Leaving the question of any significant direct influence of DHT on hair follicles to one side, the fact is that all normal tissue growth can be prevented by a certain degree of external resistance. No "normal" hair follicle growth is immune to this, DHT resistant or not. Only cancer cells can avoid this.

When you factor this into the whole body of data about changes in hair follicle size, it becomes clear that spatial conditions are playing a central role here, and that the hair cycle evolved to use the prevailing tissue pressure conditions to adjust anagen follicle size. This had important purpose in the evolution of hairy mammals. I have uploaded my take on this here.

The Holy grail of hair loss treatment, is to get the miniaturised follicles to significantly re-enlarge. In this regard, I think the immune deficient mouse study here is very important. DOI: https://doi.org/10.1067/mjd.2003.95

This clearly demonstrated that Human miniaturised hair follicles, have the internal ability to significantly re-enlarge given the right external conditions, despite any direct action of Androgens.

 

[HairOnFire]

and that the hair cycle evolved to use the prevailing tissue pressure conditions to adjust anagen follicle size.

A more conventional take: The purpose of hair follicle cycling is to prevent hair from becoming too long. Unchecked growth of hair would be a major hindrance for haired animals. A mouse with 6-inch long hair would be conspicuous, and all that hair would also reduce it's ability to squeeze through very tight spaces. Male lions would trip over their manes. Humans with foot-long eyelashes would have trouble seeing. Etc.

 

[Armando Jose]

More important than follicle cycling in humas is its asynchronocity of scalp hairs, all hairs are renovated withouth loss of personal image. Think about it, what would happen if all humans shed scalp hair at the same time !!!???

OTOH, Mr Foote is very persuasive and he is right regarding spatial conditions and hydrahulic forces surrounding pilosebaceous unit.
"Any secreting gland must have arrangements for an excess of local tissue fluid, as the raw material for the required secretion"
My idea is that sebum have a role, because t s and fluid and it is inestabe passing the time, changing ts rheologcal properties, also its composition and redox state, and can possibly can explain the pattern of hair loss in common baldness,
A paper of Masako Nakamura in J Soc Cosmetic Chem Japan vol 27, nº4 1994

 

[baldingAF]

Yeah but who tryna play with cancer.

Bunch of coritcosteroids are agonist for this
https://www.pnas.org/content/107/20/9323

Heres another research drug:
https://www.ncbi.nlm.nih.gov/pubmed/25341035

 

[baldingAF]

Still goes back to hormones

https://digitalcommons.wustl.edu/cgi/viewcontent.cgi?article=7332&context=open_access_pubs

 

[baldingAF]

Our scalp environment's standard through 17B hydroxysteroid and other dehydrogenases has favored overproduction of androgens, that coupled with sensitivity is my reasoning/theory. This synthesis starts with cholesterol. whether its an increase of certain enzymes, lack of others, influence from serum or something along those lines it comes down to steroidogenic communication and getting the right players involved.

your metaphor is dumb

 

[baldingAF]

Bruh

https://www.google.com/url?sa=i&url=https://www.researchgate.net/figure/A-Schematic-representation-of-the-steroidogenesis-pathway-Steroidogenesis-involves_fig1_334518864&psig=AOvVaw2ehoS1hEgq87yYsDYN0OZr&ust=1585011055320000&source=images&cd=vfe&ved=0CAIQjRxqFwoTCIC8rsKwr-gCFQAAAAAdAAAAABAP


https://www.google.com/url?sa=i&url=https://link.springer.com/chapter/10.1007/978-981-10-7013-6_9&psig=AOvVaw0arf-THrm4x7uhyPmYW9aC&ust=1585011616307000&source=images&cd=vfe&ved=0CAIQjRxqFwoTCNi91NGyr-gCFQAAAAAdAAAAABAe


No sh*t not the cause but if theres more taking away from there being cholestrol, like enzymes turning it down some path to dht or increased inflammation then it makes sense. Your grandpa eating all them eggs supports this silly goose

 

[baldingAF]

but yo daddys daddy and them eggs is huge for the scientific community. kudos Dr.

 

[baldingAF]

lol heres a breakdown for you and im done. daddys daddy = your father's father = your gradfather

him eating eggs = not a damn thing to do with not going bald

your thought process = fuel for MTV

 

[baldingAF]

Goodness gracious. You do know that cholesterol is the precursor to like every major hormone right. all these natural steroid and their effects, including the dht you mentioned, start at cholesterol right. You must know that to have any kind of basis here.

DHT, testosterone, estrogen -> they all come from cholesterol. Sorry for not making it easly understood to the layman, thought I was talking to people that understood more than just what they've been told.

Locally or systemically that chain is influenced by enzymes but they need the precursor(s). To focus on the end and not take the whole picture into account leads to doo doo treatments. Theres a whole system at play, not one or two. So we start at the source and work from there. And according to your reasoning for this post, the absolute source for hormones (CHOLESTEROL) coincides with your theory. But you too busy trying to stand on shoulders than actually learn something- something extra basic at that. you've been labeled.

 

[baldingAF]

*Explains science theory with some science words

Mythical Flying Horse that came in second: you don't know how to communicate cause i don't understand those words

*Explains base concept in laymans terms

Mythical Flying Horse that came in second: You must be on drugs AND LIKE VEGETABLES!!!!! HAHAHA I am the best and my posts are as mythical as my handle on this forum. Can't wait till I can laugh about this with my body pillow of dog the bounty hunter later!! HAHA

 

[baldingAF]

Also its not going to far back cause considering what you posted to start this thread:

https://digitalcommons.wustl.edu/cgi/viewcontent.cgi?article=7332&context=open_access_pubs

so tf? you saying the people who did that study aren't relevant with their findings

 

[baldingAF]

oh gosh thats my bad, i didn't realize you had short terms memory loss and that you forget one fact to make room for another. My apologies. I'll retract the part where cholesterol is the root of all hormones and then the other one that the study directly quotes cholesterol, the root and part of the hormone system, as being the agonist for the receptor you're trying to hit. that ones on me. My bad mr second-rate flying horse, sir

 

[baldingAF]

lol Its like you live on the last few words, incapable of getting the whole exchange.

I def don't know it all, not even close. But even someone comes to me with some ish that I can't outright say is wrong I at least try and learn. Take your own advice and "read some more"

or don't lol idc. you've been labeled