HMI-115 PRLR antibody: The Most Promising Treatment Ever

pegasus2

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Edit: This comes up over and over again so I'm pinning it to the top. These are quotes from two studies explaining why your prolactin levels have nothing to do with hair loss.

dopamine, known as an inhibitor of PRL pituitary secretions, has no effect on PRL or PRL-R expression in human HFs
We also show that the catagen-promoting activity of PRL is independent of the hypothalamus-pituitary-adrenal axis and systemic hormone levels. It applies to HFs of a mammalian species with mosaic and seasonally independent HF cycling




HMI-115 is a monoclonal antibody for the PRLR(prolactin receptor). It was licensed by Bayer to Hopemed Inc. It is currently in clinical trials for endometriosis and androgenetic alopecia. In early 2022 the company received FDA approval to conduct a phase II trial in the US for Androgenetic Alopecia, and soon after they received approval to begin a 6 month phase I trial in Australia that should demonstrate efficacy. The Australian trial is currently recruiting. The company has said that they hope to have it on the market by 2024, but that will be a difficult target to meet. They originally planned to move straight into a phase II trial for Androgenetic Alopecia since they had already completed a phase I for endometriosis. The FDA approved that, but Australia did not. The phase II trial now appears to be on hold until the Phase I in Australia is completed. They are currently conducting a phase II in endometriosis.

Most of the information we have about the treatment comes from this patent. The patent details a trial conducted in stumptailed macaques. This is the best available model for human male pattern baldness. Stumptailed macaques have androgenetic alopecia like humans. They go bald when they hit puberty, and finasteride prevents this. All treatments that have been tested on both humans and macaques have similar efficacy in both, so that's a very good sign that this drug will work in humans too. What makes this treatment so promising is the amount of hair that the macaques regrew in this trial, and the quality of that hair. No other treatment has come close to growing this much hair in stumptailed macaques. Not even the combination of finasteride and minoxidil could come close. Additionally, the results last longer than other treatments. The macaques were injected subcutaneously with the antibody once every two weeks for 28 weeks, after which they had nearly full regrowth. Even after 4 years without treatment the macaques were still well above baseline. Other trials measure hair weight or the number of vellus hairs regrown. These measurements on the graphs below represent "thick terminal hairs", and you can see by the trichoscope image that miniaturized hairs returned to full thickness. Additionally, results did not plateau during the treatment period, so if treatment were continued for longer than 6 months they very likely would have had even more regrowth.

image0.jpgTAHC.JPGmmexport1630326630242-png.png

From the patent:
Based on hair diameters, the number of vellus and terminal hairs per cm2 was determined. Both measurements (hair diameters and count) were performed using Datinf TrichoScan Smart Software in semi-automated manner with manual curating. For consistency reasons each region was analyzed by the same observer over time. The obtained data showed an increased terminal hair count in the previously bald region in 9 out of 11 monkeys. The increase in hair count ranged from 50 - 220 hairs/cm2 in responder monkeys (see figure 2B). The effect was observed in male and female monkeys. Younger animals responded better than seniles ones. No plateau of efficacy was reached in 6 months of treatment with the antibody mat3. Best effects with regard to increase of absolute numbers of terminal hairs as well as with regard to percentage increase was observed in previously bald areas, i.e. such areas where vellus hairs were dominating before treatment. Such areas had initially been considered the most difficult to treat since baldness of these areas was preexisting for decades in some of the monkeys. Six months after ceasing the treatment, no further increase of hair diameters or increase of terminal hairs has been observed. However, there was also only a marginal (insignificant) drop from the level reached at the end of the study. The proportion of terminal hairs was significantly higher than before start of treatment 12 months ago, i.e. a long lasting effect of treatment was observed.
5 out of 11 monkeys were >25 years of age and were considered particularly difficult to treat. However, three of those responded to compound treatment. Notably, completely bald scalp areas responded best. The PRLR antibody mat3 showed more efficacy and was effective following a more convenient regime (s.c. twice per month) than the only two approved medications for M/FPHL (minoxidil (topical, daily), and finasteride (oral, once daily, men only). (See example 4 and figures 2-3)).
25 years of age for a macaque is equivalent to ~66 years of age in a human. The drug worked on three of these animals, and on all 6 of the younger ones.

There were no apparent safety or tolerability signals during or after 6 month treatment.
It could be demonstrated that there was a robust and visible efficacy in bald and transition areas.

How did we get to this point? The antibody was developed by Bioinvent, and licensed to Bayer in 2008. Some years later Bayer finally got around to developing the drug for endometriosis. They conducted a phase I trial that was published in 2018. During the preclinical work for this trial it was noticed that the drug increased hair growth in mice. Bayer, however, was not interested in pursuing a drug for male pattern baldness. They had begun an initiative to focus on women's health issues. Fortunately for us Rui-Ping Xiao was already working with Bayer on another project as head of the IMM primate center in Beijing. She asked Bayer if she could test the drug on bald, stumptailed macaques, and they agreed. When the results came in she formed Hopemed Inc., and purchased the global rights to the drug from Bayer in 2019.

I will post some links to interviews. Unfortunately some are no longer available or have been revised.

7332.png
https://enmobile.prnasia.com/releas...apabilities-of-global-innovation-317537.shtml

The team behind the financially strong start-up Hope Medicine was so impressed by the preclinical data that they submitted an offer to Bayer. This was apparently so good that it successfully outpaced other interested parties and the option to pursue the program internally at Bayer. As it became known in April, the German pharmaceutical company will receive an upfront payment from Hope Medicine as well as further payments upon reaching certain development stages and a share of sales.

“The surprising hair growth caused by treatment with the active ingredient was observed in preclinical experiments with mice: in animals with artificially increased prolactin levels, shaved areas grew closed again within two weeks.”
https://transkript.de/news/haariges-geschaeft.html
On a schedule, HMI-115, which treats lymphatic fibroids, is first expected to be approved for sale in 2024 and its Core Pipeline when asked about the impact of the new crown outbreak, Xiao Ruiping admitted that its research process is still on schedule
 
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pegasus2

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Potential indications for HMI-115 antibody include male and female alopecia, endometriosis, and other chronic diseases. At present, the HMI-115 antibody has completed a phase I clinical study in Germany, showing good safety, tolerability and pharmacokinetic properties. In the preclinical efficacy evaluation experiment, HMI-115 also showed a good therapeutic effect. Especially in the treatment experiment of the spontaneous alopecia model-the red-faced monkey, the hair in the alopecia area regenerates, the hairline is significantly moved forward, and the proportion of terminal hair in the alopecia area has nearly doubled, while the proportion of the non-alopecia area and trunk terminal hair is not See obvious changes.What is even more exciting is that the curative effect lasts until four years after the drug is discontinued without relapse, which is significantly better than the existing treatment methods. This research is the result of close cooperation between Bayer and Peking University Institute of Molecular Medicine scientists , and it is expected to relieve the suffering of hair loss patients in the future.
Heqirui Medicine announced that it has reached a cooperation with Parexel on the Sino-European clinical research project of HMI-115 antibody, which is of great significance for the smooth start of the Phase II clinical study of HMI-115. This strategic partnership will promote the process of the global multi-center clinical program of new HMI-115 antibody drugs, and promote the early launch of this monoclonal antibody with great market potential. Bring the Gospel.
https://www-njbpv-cn.translate.goog...zh-CN&_x_tr_tl=en&_x_tr_hl=en-US&_x_tr_pto=sc



HMI. 115, a prolactin anti-receptor antibody, has passed animal experiments and Phase I clinical studies in humans. Array and will participate in Phase II trials on multiple indications in 2021. I am pleased to enroll in this perfect superior prospective team, I am committed and motivated to facilitate the company’s built-in global Phase II clinical studies in Europe, the United States and China, and to advance strategic plans for the structure of a pipeline of high quality projects in the future.
For HMI-115, the company is planned to launch a globally integrated phase II clinical study in Europe, the United States and China in 2021. At the same time, in response to unmet clinical needs, HopeMed established a diversified pipeline through License-in and independent research and development of dual-drive models. In addition to HMI-115, based on Professor Xiao's breakthrough research at the IMM, the target drug, MG53 will be introduced from Peking University, which showed a good therapeutic effect on diabetes and diabetic foot animal models.
https://en.prnasia.com/releases/apa...of-research-clinical-development-302551.shtml

https://www.biospace.com/article/re...body-directed-against-prolactin-prl-receptor/

https://newjournal.net/2020/12/14/h...irector-of-clinical-research-and-development/

HMI. 115, a prolactin anti-receptor antibody, has passed animal experiments and Phase I clinical studies in humans. Array and will participate in Phase II trials on multiple indications in 2021. I am pleased to enroll in this perfect superior prospective team, I am committed and motivated to facilitate the company’s built-in global Phase II clinical studies in Europe, the United States and China, and to advance strategic plans for the structure of a pipeline of high quality projects in the future.

For HMI-115, the company is planned to launch a globally integrated phase II clinical study in Europe, the United States and China in 2021. At the same time, in response to unmet clinical needs, HopeMed established a diversified pipeline through License-in and independent research and development of dual-drive models. In addition to HMI-115, based on Professor Xiao's breakthrough research at the IMM, the target drug, MG53 will be introduced from Peking University, which showed a good therapeutic effect on diabetes and diabetic foot animal models.

https://en.prnasia.com/releases/apa...of-research-clinical-development-302551.shtml

https://c.m.163.com/news/a/FHNU61BF05349AL5.html
 
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HopeMedicine is an innovative biopharmaceutical company based on Professor Xiao Ruiping and his team from the School of Future Technology of Peking University, based on decades of research results in the field of translational medicine. At present, the company has completed the B round of financing, signed a global exclusive license agreement with Bayer for the development and industrialization of the monoclonal antibody HMI-115 targeting the prolactin receptor (PRLR), and is developing and industrializing multiple indications worldwide change. This antibody has the function of promoting hair growth and has a therapeutic effect on hair loss. It has shown excellent characteristics in animal models and human safety, and has obtained the approval of the US FDA Phase II clinical trial. In the near future, the US Phase II clinical trial will be launched. The patient was enrolled. In addition, Herqirui has also carried out the R&D and industrialization of more high-end innovative drugs through the dual-drive model of license-in (authorized introduction) and independent research and development.

Qirui Medicine (Hope Medicine, referred to as "Heqi
Rui") is a company dedicated to source innovation and science
1-driven innovative drug research and development company with its headquarters in China
Located in Nanjing, and has R&D bases and offices in Shanghai and Beijing at the same time
Office. The establishment of the company is based on the Future Institute of Technology of Peking University.
Professor Ruiping and his team's deep understanding in the field of translational medicine research
And decades of research results. Heqirui is based on outstanding scientific research
Based on the goal of improving the quality of life, it targets threats to human health.
Common diseases and major diseases, committed to research, development and commercialization.
Innovative medicine.
and
Recently, Heqirui announced the appointment of members of the company's board of directors and the original
President and head of Clinical research and Development Henri, Nico, Duz (Henri
Nico Doods) became CEO. He will promote and practice public
The company's strategic goals ensure more clinical milestones in the future
Achieve, and lead the company towards "becoming science-driven and focusing on the future".
A global biopharmaceutical innovation R&D company that follows science and technology and pioneering new drugs
Industry"keeps moving forward.
Before joining Heqirui, Duz worked for Bollinger Langer Henkel.
Senior vice president, with more than 30 years of experience in pharmaceutical research and development, covering the heart
In the fields of blood vessels, nerves, and respiration, he has participated in more than 15 projects.
R&D projects that have entered the clinical stage.
Duz said: "Heqirui has an excellent team and a strong
Global intellectual property rights, and also has world-class clinical R&D partners
Partner and expert network support. I am very honored to be the head of the company
As chief executive officer, I will work hard to accelerate the company's current clinical research.
Research the progress of the project, focus on research and development, and formulate the company's future
Various strategic development plans, in order to realize Heqirui's becoming a global
Biopharmaceutical companies, for the benefit of more patients' vision, make the most
Great effort. "
Xiao Ruiping, chairman and founder of Heqirui, said: "As
Senior scientists and top experts in the global pharmaceutical industry, Duz does not
Only in the field of scientific research and development, it has achieved great results, and what is even more valuable is,
He has excellent business development and management experience in the industry. Made
As the founder of the company, I am very grateful to Duz for his letter to the company and me.
Ren, be able to accept such a heavy responsibility. At the same time, Duz serves as the chief
The executive officer is an important chapter in the company's history and symbolizes the company's leadership.
The guidance level has reached a new strategic height. Hope to be led by Duz
Under the management of the company, the company can smoothly move towards more research and development milestones.
God. "
The CEO will lead all employees of the company to continue to this goal
Move forward firmly. "Heqirui co-founder, president and Chief operating officer
The official class is telling the truth.
In the first half of 2021, Heqirui announced the completion of a scale of 56 million
Series B financing in U.S. dollars. This round of financing was funded by Qiming Venture Capital and Yuanyi Investment
Jointly led the investment, Honghui Capital and Innovation Workshop followed, and the old shareholder Bi Xin
The capital continues to be blessed, and Haoyue Capital serves as the exclusive financial adviser. This
The round of investment will be for the upcoming international multi-center clinical trial of Heqirui
The second phase of MRCT research and product line construction provide strong
support. IEE
"Duz's appointment has further strengthened He Qirui's leadership,
It will also bring a new atmosphere to the team. Heqirui is based on the source of China's innovation
New, the goal is to become a global biopharmaceutical company, and Duz serves as
Editor of this article: Li Qian, contact email: 157720740@qq.com
The 9th issue of 2021 will be processed 17
http://www.njbpv.cn/index.php?m=content&c=index&a=show&catid=14&id=5606
 

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Guide: Xiao Ruiping has been working in the field of translational medicine for many years, and she is also one of the pioneers of translational medicine
In June, Bayer, a multinational drugmaker, announced that it would launch a Bayer-MassConnect Asia program with the Massachusetts Biotechnology Commission to train pharmaceutical start-ups in Asia, particularly in China, to accelerate the development of treatments to address unmet medical needs
this move undoubtedly reveals the changes in the domestic pharmaceutical innovation environment In the view of Xiao Ruiping, co-founder of Rui, the attention of multinational pharmaceutical companies to Chinese pharmaceutical companies is inevitable for China's pharmaceutical industry to flourish
Looking back at Bayer's past drug development experience, a turnaround has largely highlighted the relationship with its global licensing agreement with Bayer in April 2019 " Bayer, which was one of the first multinationals to enter China at the time, never authorized its IP to local drug companies We are the first Chinese pharmaceutical company to receive Bayer's exclusive global rights) Xiao Ruiping said of the signing
Based on the results of animal tests, Xiao Ruiping decided that the monoantipod has a good drug-based foundation and application prospects, so he urged its cooperation with Bayer, said he is confident that the drug "fix into positive results."
before, Xiao Ruiping has been working in the field of translational medicine for many years, she is also one of the pioneers of translational medicine

Whether it's a senior research fellow at the NIH (National Institutes of Health), a deputy editor of NEJM (New England Journal of Medicine), founding director of the Institute of Molecular Medicine at Peking University, and co-founder of Rui, Xiao's identity has always revolved around the different stages of translational medicine practice Why do have such a mind about translational medicine? To answer this question, you need to go back to Xiao Ruiping's overseas study and work experience Time to the starting point, even she did not expect, overseas this stay is more than 20 years Professor Xiao Ruiping, director of the Institute of Molecular Medicine at Peking University and founder of Rui Medicine, from quantitative change to qualitative change for more than 20 years in 1988, Xiao Ruiping received a master's degree in medicine from Tongji Medical University and entered Peking University for a doctorate In the same year, she traveled to the United States, first to the University of Puerto Rico University of Medicine to do research, and then in 1990 to the NIH for postdoctoral research, which led to the forefront of biomedical research like fish and water - this is the intuitive feeling that environmental change brings to Xiao Ruiping
"I especially like to deal with people, then suddenly feel that there are a lot of good people around, we have different cultures, skills, personality, and be able to like a rainbow to complement each other, I feel that their spiritual life and the pursuit of knowledge and other aspects are very helpful."

2003, she was promoted to NIH Senior Fellow, the highest academic title of NIH, and a tenured position, and in 2006 she was awarded the NIH's first Consultant Fellow of Female Scientists, the United States and the NIH are particularly warm and friendly to young people who are interested in scientific research, "as long as you work hard you can pursue a wonderful scientific life." In the case of NIH alone, its institutional and funding systems are huge, with each research institute and research centre with its own planning office for independent strategic planning 2003, the NIH, aware of the importance and urgency of translating scientific research results into practical applications, proposed the "NIHroadmap for medical research" for the 21st century, providing a concrete guide and layout for the development of global biomedicine

To further optimize resource allocation, NIH also launched the organization-wide strategic plan NIH-Wide Strategic Plan, Fiscal Years 2016-2020: Turning DiscoveryInto Health, in 2015, to continue to drive the translation of basic research into clinical practice to address new challenges to human health
"I think the best thing about this 20 years has been that I've had a sense of mass change in my life." Xiao Ruiping recalled. Although the educational environment received in China is not bad, but from high school to college experience can not answer her biggest confusion: "I learn a body, in the end why?" What should I do to make my life truly valuable? Sometimes, the domestic study can easily become 'self-entertainment', one exam after another seems to be very full, but to the top of the school, this inner emptiness will be released Therefore, after entering Peking University, Xiao Ruiping came up with the idea of going abroad, hoping to learn about the whole story to the western origin of modern medicine more than 20 years of studying in NIH, with the academic background of medicine and molecular biology, Xiao Ruiping has long been engaged in cardiovascular disease drug target research, found the important role of beta 2 epinephrine receptors, presided over the development of a new class of new drug R, R-Fenoteandand and other beta 2 epinephrine receptor agonists, overturning the current concept of the widespread use of heart failure treatment beta 1 epinephrine receptor blocker, proposed beta 2 epinephrine receptor for better treatment, and beta 2 epinephrine receptor sedatives

After the target confirmation, small molecule drug synthesis, drug screening, animal experiments, technology transformation, until participating in clinical trials of this drug development complete route NIH this study and research experience so that Xiao Ruiping's scientific literacy and outlook on life have been "quality" changes: on the one hand, the study environment to the origin of scientific problems, so that its basic ability to think and solve problems to be improved, more able to grasp the essence of things; the "First Global Conference on Frontier Synoping in Biomedicine" Professor Xiao Ruiping in the conference report
and its Rui: The Last Kilometer of Sprint Translational Medicine and its Rui yu Xiao Ruiping, is a new chapter in the life of medicine
In the course of the interview, Xiao Ruiping clearly expressed his devotion to entrepreneurship To some extent, it is understood that this spirit is linked to the idea of how to translate scientific results into products. 2010, seven years after winning the NIH's top academic title, Mr Xiao decided to step down from his tenure and return home to "do something meaningful." This coincided with the year (2003) in which Xiao Ruiping became a senior NIH researcher and NIH announced "Roadmap" March 2004, Peking University approved the establishment of the Institute of Molecular Medicine, headed by Xiao Ruiping "I learned about China's national conditions and the prevalence of chronic disease in China, and put enormous pressure on health care With all this in mind, you can slowly figure out what I'm going to do "Actually, I've been asking myself for decades: What can I do? What do I want to do? Is it necessary for the country to do something, is it contributing to humanity? Back in China, this sense of certainty is becoming more and more clear " what makes Xiao Ruiping sure is that "the future of translational medicine in China" has become a key question to be answered As we all know, molecular biology is mainly studied in the molecular level of the basic theory, but medicine is different, the latter span is very large

The transformation from molecule to medicine also means that the difficulties that need to be overcome vary "For example, there's a genetic disease in the clinic, and I've found the genes that cause it, and I've modeled a mouse to test the relationship between disease and genes, from molecule to medicine," explains Xiao Ruiping Then from the clinical metatype, and can return to a specific molecule, which is actually forward, reverse through Beyond that, medicine is not just about diagnosis, not just knowing the mechanism of the disease, you've got to solve the problem in the end, which involves small molecule drugs, antibodies, vaccines, or devices, and in short, implements them into a product "
adheretod to the concept of "transformational medicine", Xiao Ruiping finally contributed to the birth of his Rui "The article is written again well, can not return to disease treatment, still can not solve the problem, will not benefit patients." Therefore, there needs to be a bridge between the transformational medicine
Shaw added that it is not only focused on results transformation, but also focused on the development of global First-in-Class drugs
And to improve the success rate of First-in-Class drug research and development is based on its one-stop translational medicine platform
and its one-stop translational medicine platform It is worth mentioning that, with its Rui-Beijing University Joint Non-Human Primate (NHP) Research Center has been the first Domestic University AAALAC international authoritative certification, also has the world's only rhesus monkey functional genomics database

It was with the latter that it completed the functional validation of the monoantithing resistance to Bayer's targeted prolactin (PRL) receptors - a drug that effectively promotes the growth of the hair of elderly redmas, and after six months of treatment, the number of hairs in the hair loss area nearly doubled, even in areas that had previously been nearly completely bald, and the effect continued for more than four years after the drug was discontinued - which led Bayer to transfer its development interest in the drug

" hair loss is just one of its indications, and the new target PRLR of HMI-115 antibody selection has many potential developments, such as endometriosis, lymphosarin disease and other autoimmune diseases Xiao Ruiping revealed that the above indications have completed the development of clinical Phase I , in addition, it has also developed innovative pipelines in various fields such as diabetic foot (DFU), rheumatoid arthritis (RA), and has been validated by the NHP platform for First-in-Class drugs On a schedule, HMI-115, which treats lymphatic fibroids, is first expected to be approved for sale in 2024 and its Core Pipeline when asked about the impact of the new crown outbreak, Xiao Ruiping admitted that its research process is still on schedule "But it is true that there are a lot of small companies in the impact of the outbreak, the capital chain broke, and ultimately can not go down What's interesting is that these small companies are lying in tigers and dragons, and there are a lot of people with international experience to join them, which is an unexpected gain Xiao Ruiping shared currently, and its Swiss to promote b round of financing Mr Xiao believes that adequate funding is essential Capital ensures that companies get through the storm and attract talent, which will ultimately accelerate the progress of research and development and product transformation interlaced "reason", the scientist's AB face for many researchers, starta a company is a threshold, and in the face of this new crown outbreak, "looking for money" becomes another need to break through the fence But this confusion has not been revealed in Xiao Ruiping "," to be honest, the process has been more of a surprise Xiao Ruiping further responded, "I think people have to be exposed to new things every day if they want to grow." If I were always in this scientific work, doing what I was particularly good at, I would not be able to acquire new knowledge, new skills, new horizons

I feel to do financing and management, all of a sudden gave me a new world and scenery in fact, this mentality has become routine long before he stayed in the United States A little attention can be found that the domestic mainstream view of a scientific researcher's portrayal of the image, it is difficult to put on Xiao Ruiping: on the one hand, she believes in the "10,000-hour law", this kind of effort and investment is essential for scientific research;

if you want to talk about the things that he will miss most when he returns home, it's probably one of the things that friends often meet in the yard
"When the sun sets, I chat with two or three friends in my backyard with a glass of wine, for two or three hours, and even when it's completely dark, I think it's really a kind of peace that money and status can't buy, a completely relaxing peace." There's always a lot of inspiration at that time, and it's going to be a very clear picture of things like your research The process is not a time-wasting as it seems, but a high degree of refinement, Mr Xiao said of course, contact with new things is not entirely comfortable, which also faces a number of challenges, become neJM deputy editor-in-chief is an example In Xiao Ruiping's own words, this is equivalent to "another PhD and a full-time clinical study." For a long time after 2013, Shaw had to travel frequently to meetings and sometimes to Boston for training, and the workload was so great that it even once influenced the idea of creation and the idea of rui , driven by Xiao Ruiping, was officially released in 2016 Chinese electronic weekly NEJM Medical Frontiers
This also means that not only Chinese scholars can keep pace with the latest and most important developments in medical innovation in the world, but also help to promote outstanding local clinical research results out of China and enhance the international voice of Chinese medical research
In July this year, at the 2nd Global Conference on Frontier Technology and Policy and Regulation in Biomedicine, NEJM Medical Frontiers will also sign a field contract with the same idea to jointly help the development of pharmaceutical innovation in China NEJM's resume is good for the creation of new drugs
"When I see cutting-edge research methods in the world, I'm more confident as a pharmaceutical company, and I know what the highest international standards are, and it's better to be able to practice it and transformitmedicine." Xiao Ruiping added
when asked about the time balance between doing research and starting a business, Mr Xiao said the two were interlaced
Scientific research has a clear time node, but entrepreneurship needs to be strictly limited, development cycle, clinical time, team building these are "hard goals", management should be more compact
Xiao Ruiping's final answer was philosophical: "The goal is the starting point, but it is also the end." The final acceptance of the work is your goal, you reach the goal did not, this is the key to the problem
https://topic.echemi.com/a/xiao-rui...ilometer-of-translational-medicine_87591.html
 

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The stumptailed macaque has been used for decades to study male pattern baldness. They bald on the top of their head like we do when they hit puberty and DHT levels rise. When hairs are transplanted from the balding area to a non-balding area they continue to miniaturize, just like humans. When hairs are transplanted from non-balding areas to the bald areas they continue to grow and cycle normally, just like when humans get hair transplants. That is why this is the gold-standard for testing hair loss treatments. Mice do not suffer androgen-induced hair loss so it's difficult to test drugs on them. That is why you hear a lot about drugs growing hair in mice that just will not work in humans.

Baldness was induced by long-term injections of testosterone. Baldness in these animals is pre-determined, and only those parts of the scalp that normally become bald are affected by androgen even when transplanted in foreign sites. In vitro studies of the metabolism of testosterone by hair follicles and by the epidermis showed the same regional and age variation. The rate of total metabolism of testosterone was higher in frontal than in occipital areas, and was higher in younger than in adult animals. The ratio of metabolites to unmetabolized testosterone was higher in the frontal area. The amount of 5α-dihydrotestosterone was highest in the frontal scalp of young animals.

Studies of Common Baldness of the Stump-Tailed Macaque


Inhibition of Hair Growth by Testosterone in the Presence of Dermal Papilla Cells from the Frontal Bald Scalp of the Postpubertal Stumptailed Macaque

Effect of Latanoprost on Hair Growth in the Bald Scalp of the Stump-tailed Macacque: A Pilot Study



The RU58841 macaque trial is here. It was the best performing drug on macaques until now. Anagen follicles increased 103% with RU, but most of them were just vellus hairs. In contrast, the number of terminal hairs increased 107% with HMI. In the RU trial, growth of vellus follicles to terminal size was only 26%, and those terminal hairs don't seem to be as thick.

In the main finasteride study they only measured hair weights and length. Hair length before treatment for each group were "7.3 +- 3.2 and 7.5 +- 4.1 mg hair/in2, respectively, for 2 months of growth." The control group saw an increase in hair weight of 32% vs 55% for the finasteride group. That is an increase of 2.3 and 4.13 mg/in2, respectively. That is .36 and .64 mg/cm2, respectively. An average human hair weights .2-.4mg at 6 inches length. Let's split the difference and call it .3mg/6in, and we have .05mg per in. I think it's safe to assume macaque hairs are about the same weight. They let the macaque hairs grow for 2 months before weighing them. Hair grows at a rate of about an inch per 2 months. So, one terminal hair would weigh about .05mg. Again, the increase in hair weights was .36 and .64 mg/cm2 for the v and f groups, respectively. Ignoring vellus hairs, that represents 7.2 and 12.8 terminal hairs. Of course the entire increase was not terminal hairs, and for the placebo group it was mostly vellus hairs. We can probably assume that in the finasteride group the increase in terminal hairs was no more than (12.8-7.2)=5.6 hairs/cm2. However, for argument's sake let's fantasize that the entire hair weight change was due to an increase in terminal hairs. In that case we have a terminal hair count increase of 7.2 in the control group, 12.8 in the finasteride group, and 113 in the HMI-115 group.

From this same finasteride study:

Screenshot_20211115-025744_Drive.jpg

The same is true across the board. The results of every trial in macaques that is public has correlated with human trials for the same treatment. We don't have human trial data from RU, but the person who conducted the trial has said that the results of the human phase II were great. Unfortunately that drug had patent issues and was dropped due to limited market potential when the company was bought out by a larger company. These past results don't guarantee that HMI-115 will perform as well in humans, but it is very promising.


graph.JPG
Results of finasteride, min, and finasteride+minoxidil in stumptailed macaques
 
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Now you might be asking, are there other ways we can inhibit prolactin to grow hair? Unfortunately not. Dopamine agonists inhibit pituitary prolactin, but that does little for hair growth because the hair follicle produces its own prolactin, and this is regulated separately. There are other prolactin receptor antagonists(none on the market), but they are not as potent as HMI-115. HMI-115 is the first and only PRLR antagonist to mimic the PRLR knockout phenotype in mice.

dopamine, known as an inhibitor of PRL pituitary secretions, has no effect on PRL or PRL-R expression in human HFs

Hormonal Effects on Hair Follicles

We also show that the catagen-promoting activity of PRL is independent of the hypothalamus-pituitary-adrenal axis and systemic hormone levels. It applies to HFs of a mammalian species with mosaic and seasonally independent HF cycling
zjh0020667440003.jpg

Human Scalp Hair Follicles Are Both a Target and a Source of Prolactin, which Serves as an Autocrine and/or Paracrine Promoter of Apoptosis-Driven Hair Follicle Regression

The double weakness of PRL core-based antagonists involves their lower binding affinity compared to hPRL (~ 10 fold) and their short half-life in vivo (< 1 h) due to rapid renal clearance (their 23 kDa size is below the renal glomerular cut-off). By inserting mutations within the competent binding site 1, a high affinity version of G129R-hPRL was recently developed and validated in cell-based assays [19]. Others coupled G129R-hPRL to albumin binding peptides, which was shown to improve pharmacokinetics in vivo; this however was at the expense of its potency (decreased by 5-fold in vitro) [20]. We recently developed a long half-life prototype of Del1-9-G129R-hPRL
The prolactin receptor as a therapeutic target in human diseases: browsing new potential indications

Addition of an alternative promoter through Telogen Effluvium insertion in primates may also have led to specialized functions of PRL in the human immune system. A point of controversy is that there are many indications for a role of PRL in the human immune system, whereas PRL or PRL–R knockout mice are not immune deficient.(2,36) It could be that, in primates, local PRL, produced in the immune system under the control of the alternative upstream promoter has a special, cytokine–like, function

primate (for instance Rhesus monkey) models will be indispensable to gain a better insight into the role of human extrapituitary PRL expression.
neither the classical pituitary PRL inhibitor, dopamine, nor corticotropin-releasing hormone significantly modulated PRL IR in HFs or skin respectively....This study identifies substance P, TNFα and IFNγ as novel modulators of PRL and PRLR expression in human skin, and suggests that intracutaneous PRL expression is not under dopaminergic control. Given the importance of PRL in human hair growth regulation and its possible role in the pathogenesis of several common skin diseases, targeting intracutaneous PRL production via these newly identified regulatory pathways may point towards novel therapeutic options for inflammatory dermatoses.

Tumour Necrosis Factor Alpha, Interferon Gamma and Substance P Are Novel Modulators of Extrapituitary Prolactin Expression in Human Skin


It's interesting to note that primates are the only animals with a unique promoter for ePRL, and they are also the only animals that develop androgenetic alopecia, despite hair follicles being highly conserved across species. Prolactin is also the mechanism by which other mammals go through seasonal shedding.
 
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It's been known for two decades that Prolactin may play a role in Androgenetic Alopecia, but it was difficult to test without a suitable PRLR antagonist, and it wasn't regarded as being of great importance. Given the macaque results it seems it's more directly responsible than previously thought. There is substantial evidence for prolactin's role in male pattern baldness, though nothing definitive due to the lack of effective PRLR antagonists.
PRL receptors, expressed in HFs, are functional and that human skin and human scalp HFs are both direct targets and sources of PRL. Our data suggest that PRL acts as an autocrine hair growth modulator with catagen-promoting functions and that the hair growth-inhibitory effects of PRL demonstrated here may underlie the as yet ill-understood hair loss in patients with hyperprolactinemia.
our study shows that human anagen scalp HFs are very sensitive for inhibitory PRL-R-mediated signals. This is clinically relevant, because it provides a reasonable mechanism to explain the, as yet ill-understood, telogen effluvium associated with hyperprolactinemia.25 It also points to novel therapeutic strategies for the management of stress-related and hormonal hair loss in men and women,60 eg, by use of recently developed PRL-R antagonists

Prolactin and Its Receptor Are Expressed in Murine Hair Follicle Epithelium, Show Hair Cycle-Dependent Expression, and Induce Catagen

These data support the intriguing concept that PRL is generated locally in the hair follicle epithelium and acts directly in an autocrine or paracrine manner to modulate the hair cycle.
With the development of the inner root sheath (IRS) during early anagen (anagen III), PRL immunoreactivity could be detected in the inner layer of the proximal ORS and the IRS (Figure 1B) . During later anagen stages (IV to VI), PRL staining extended with hair shaft elongation and could be seen in a restricted area that included the inner layer of the proximal two-thirds of the ORS and lower IRS

Prolactin Signaling Influences the Timing Mechanism of the Hair Follicle: Analysis of Hair Growth Cycles in Prolactin Receptor Knockout Mice


Both PRLR and PRL transcripts in mouse skin have been demonstrated, and PRLR has been localized to the hair follicle. These receptors do not appear to have an essential function in follicle morphogenesis during embryonic development. However, disruption of this hormone axis shortens the quiescent phase of the hair follicle. PRL, directly or indirectly, appears to be inhibitory to the growth processes of the murine hair follicle by delaying the proliferative processes involved in the reactivation of follicles from telogen to anagen.
hairlengthprl.JPG
PRLR null mice grew significantly longer and thicker hair, with premature anagen entry and delayed catagen.
Only full inactivation of the PRLR enlarged hair shafts. Also from this you can see that silencing the PRLR enlarges male follicles more than female. This aligns with the hair counts from the macaque study that found males responded better than females to the PRLR antibody, and studies showing that catagen genes are downregulated by prolactin in human female frontotemporal hair, and that blocking prolactin causes apoptosis in those hairs while adding prolactin elongates them. This is the opposite of what has been observed in human male scalp follicles. This might partially explain the different patterns in female and male pattern hair loss. Women don't usually recede, and this is the best explanation for why. PRLR antagonism will likely only work on the vertex in women while working everywhere in men.

The prolactin receptor shows a significantly stronger expression in the ORS, the IRS and the keratinocytes of the matrix in anagen hair follicles. In catagen III, the immunoreactivity for prolactin is more intense than during the growth phase. Prolactin receptor is discovered in catagen hair follicles in keratinocytes of the ORS and the matrix....The human hair follicles were treated with prolactin and measured for six days. Prolactin-treated hair follicles showed a significantly shorter hair shaft lengthening than the hair follicles of the control group. While most of the hair follicles in the control group were still in the anagen, most of the hair follicles in the prolactin group were already at the stage of hair follicle regression. Immunohistological staining (Ki-67, TUNEL) also showed that in the test group there was a significantly reduced number of proliferating keratinocytes in the matrix cells of the hair bulbs and that at the same time the number of apoptotic nuclei in the hair follicle increased. Prolactin not only causes a significant inhibition of hair shaft production,31 ].These data support the hypothesis that prolactin has direct local inhibitory effects on human hair follicles and that prolactin receptor antagonists may be effective therapeutic agents for prolactin-induced androgenetic alopecia in the future.
New Findings in the Treatment of Alopecia: The Influence of Prolactin, Retinoids and Transforming Growth Factor-β on Hair Growth

Also notable in the context of Androgenetic Alopecia is the observation of sex- and location-dependent hair growth regulatory effects for PRL in studies of human ex vivo HFs.While PRL promoted hair growth/hair shaft elongation in HFs derived from female frontotemporal scalp, PRL treatment of isolated male occipital scalp HFs resulted in premature catagen induction and thus the inhibition of hair growth.[77] This observation has been further substantiated on a molecular level, since PRL treatment resulted in sex‐ and site‐specific differences in gene expression.[77] Furthermore, analyses of plucked HFs from male frontal and occipital scalp revealed differential expression for several microRNAs (miRNAs) that target PRL signalling.[64] Together, these findings suggest that PRL action may contribute to the observed differences in Androgenetic Alopecia susceptibility between frontal and occipital HFs and the resulting characteristic hair loss pattern. Though PRL has a reported stimulatory effect on HF stem cell-associated keratins located in the outer root sheath in HF cultures of isolated female HFs [78], it is tempting to speculate—especially given the reported sexual dimorphism of PRL action on the HF—that PRL might have an inhibitory effect on stem cell function in male HFs, which could result in the stalled growth observed in miniaturized Androgenetic Alopecia HFs.

exd14130-fig-0001-m.jpg
PRL has been recognized as a potent (seasonal) hair cycle regulator in mammals and extensive research has been conducted into its effects on human hair growth.[70-73] The gene that encodes PRL is located on chr. 6p22.3 and lies within 500 kb of an Androgenetic Alopecia risk locus on the same chromosomal band (lead variant: rs6935891; P = 3.0 × 10−39, β = −0.05, SE = 0.004).[12, 24] Given the fact that PRL and its receptor are expressed in human HFs and that their paracrine and autocrine effects on hair cycle control and hair growth are well recognized, PRL represents a promising candidate gene for the hair growth defects observed in Androgenetic Alopecia-affected HFs. Moreover, PRL stimulates adrenal androgen production and elevated PRL levels have been reported to be accompanied by hirsutism and hair loss from the scalp, which resembles the pattern observed in Androgenetic Alopecia.

Hormonal regulation in male androgenetic alopecia—Sex hormones and beyond: Evidence from recent genetic studies


At least in certain blood cells PRLR expression increases in adulthood as GHR expression decreases. This coincides with the time when men start losing their hair. Additionally, newborns have extremely high levels of serum prolactin, 100-300ng/ml, well beyond hyperprolactinema levels of 20ng/ml. This could be why newborns lose hair in the male pattern baldness pattern, and lends some credibility to the theory that PRLR expression is responsible for the hair loss pattern found in Androgenetic Alopecia. Prolactin levels return to normal in the weeks to months before babies regrow their hair.
PRLRAGE.JPGprlnewborn.JPG

We confirmed this role by showing that re-entry to anagen was advanced when circulating prolactin secretion was suppressed with BRC, but delayed when mice were treated with exogenous prolactin
We therefore speculate that prolactin may exert its effects on follicle cycling by modulating the migration of precursor cells in the outer root heath. This could be achieved by regulating cell adhesion factors such as the cadherins (Sultan et al. 2005) or by Stat3-responsive factors
(Kira et al. 2002), both of which are necessary for continuous hair cycling (Sano et al. 1999, Young et al. 2003). Such inhibition of migration would deprive the germinal matrix of cells with proliferative potential, thereby either extending the telogen phase or terminating anagen.
Cyclosporine A is well-known as a highly potent hair growth promoter. In responders it is more potent than minoxidil, and its effects may be mediated by downregulation of the PRLR.
Although the mechanism of its action within the hair follicle is unclear, CsA is known to complex with cyclophillins, which interact directly with the PRLR and its signal transduction factors. These molecules have propyl isomerase activity that induces structural changes within the PRLR intracellular domain and, along with further interactions with JAK2 (cyclophillin A) (Syed et al. 2003) and Stat5 and protein inhibitor of activated stat (PIAS) (cyclophillin B) (Rycyzyn & Clevenger 2002), are able to potentiate prolactin-induced gene transcription. Therefore, follicle stimulatory actions of CsA, which possibly arise from decreased PRLR signal transduction, are consistent with the inhibitory nature of prolactin reported here.

csa.JPGcsa2.JPG
Prolactin delays hair regrowth in mice
Topical cyclosporine in male pattern alopecia


In this study, we identified genetic changes associated with SC activation following administration of CSA, a robust activator of follicular SCs. Gene expression profiling revealed a novel molecular interplay between Nfatc1 and Prlr, implicating Prl signaling as a regulator of SC activity in the hair. Using pharmacological and genetic experiments in mice, we revealed that Prl signaling and Nfatc1 expression are required for the abrogation of hair growth during pregnancy. Furthermore, we demonstrated that direct administration of Prl promotes HF quiescence. Finally, we showed that Prl signaling activates Jak/Stat5 signaling in follicular SCs to maintain their dormancy. Our findings unveil a novel CN–Nfatc1–Prlr–Stat5 pathway that governs skin SC quiescence downstream from a systemic hormone.

Calcineurin/Nfatc1 signaling links skin stem cell quiescence to hormonal signaling during pregnancy and lactation

 
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In regards to safety the phase I trial for HMI-115 in women found no serious adverse events. There is another drug which antagonizes the PRLR. Unfortunately it is not as potent as HMI-115, and probably ineffective against hair loss. The literature for this drug talks a little about the potential side effects of inhibiting the PRLR. This is what it concludes:

a relevant question is whether blocking the PRLR by SMI-6 would cause undesirable side effects in treated BC patients. We think not. Indeed, cabergoline, a potent suppressor of pituitary PRL release, has been chronically prescribed to thousands of patients with hyperprolactinemia with minimal ill effects [47]. On the contrary, all known adverse effects of PRL result from its overproduction, which can cause infertility in women, impotence in men, and aggravation of autoimmune diseases [4]. The only potential caveat is that women with BC who have an infant, will not produce breast milk while treated with a PRLR-blocking drug. However, breast feeding in patients with BC is clearly not a recommended practice.


Although PRL has been shown to be involved in a wide spectrum of biological functions, including immune responses, metabolic functions or bone formation / turn-over (5), it is viewed as a modulator, rather than a key regulator of these functions. Therefore, no major problem of toxicity is anticipated, although we should remain vigilant since many of the actions attributed to PRL have been identified and studied using animal models. Reproductive performance appears to be the physiological function that is the most sensitive to abnormal PRL levels, since both hyper- and hypoprolactinemia lead to fertility problems. In the current state of the art, no other major function should be significantly altered following administration of PRLR antagonists.

Development and Potential Clinical Uses of Human Prolactin Receptor Antagonists


Mice with a targeted disruption of the prolactin (PRL) receptor gene were used to study the physiological role of PRL in the control of the male reproductive function. Fertility parameters as well as body and reproductive organ weights (epididymis and testes) were unaffected in PRL receptor knockout mice. Testicular histology and sperm reserves were also normal. Compared with wild-type animals, [PRLR] knockout mice had no significant difference in basal plasma LH, FSH, and testosterone levels, and the weight of seminal vesicles and prostate was unaffected. Moreover, no alteration was detected in human chorionic gonadotropin-induced testosterone levels. It is concluded that the absence of PRL signaling is not detrimental to male testicular function and to fertility in the mouse.
Male Reproductive Function Is Not Affected in Prolactin Receptor-Deficient Mice
 
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14 genes were found upregulated in frontal vs vertex scalp. At least 10 of them are upregulated by PRLR signaling, and 2 others induce prolactin secretion. Many of these genes are also upregulated by Wnt inhibition.

frvsvtx.png

An analysis of gene expression data involving examination of signaling pathways activation reveals new insights into the mechanism of action of minoxidil topical foam in men with androgenetic alopecia


There is a probable role for PRLR in the pathogenesis of alopecia areata, independent of serum prolactin. Two additional studies found similar results, but two others found significantly increased serum prolactin levels in patients with AA. They all found a role for prolactin signaling in AA. From this study:
a significant positive correlation was found between the prolactin receptor and the SALT[severity of alopecia] score
AA.jpg

Do Prolactin and its Receptor Play a Role in Alopecia Areata?

PRLREXP.jpg


In mice the PRLR is not expressed in the matrix, while in humans it's expressed in the matrix only during catagen. This is important because the prolactin seems to function as a Wnt inhibitor in the HF, and Wnt signaling is required in the matrix to maintain anagen. In the ORS and IRS Wnt signaling interferes with the differentiation that builds the hair shaft. Aberrant PRLR signaling in the matrix would result in shorter anagen phases and a smaller hair follicle.
 
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There's always been a paradox in DHT-theory of male pattern baldness that suggested the existence of a coregulator. Androgens are always proliferative except in the hair follicle on the scalp. They are even proliferative in body hair. Why do they cause hair loss on the scalp but hair growth everywhere else? Why does DHT promote prostate growth while promoting apotosis and stem cell quiescence in the hair follicle? While DHT always has a proliferative effect on stem cell proliferation(even in balding scalp hair follicles under hypoxia), prolactin has tissue-specific effects on stem cells. In the prostate it is proliferative, while in hair follicles it promotes stem cell quiescence.

Depending on the tissue, prolactin can either maintain stem cell quiescence or, in contrast, promote stem/progenitor cell expansion and push their progeny towards differentiation.

Patient matched DPC from balding and occipital scalp were cultured at atmospheric (21%) or physiologically normal (2%) O2. At 21% O2 DPC showed flattened morphology and a significant reduction in mobility, population doubling, increased levels of ROS and senescence associated β-Gal activity and increased expression of p16INK4a and pRB. Balding DPC secreted higher levels of the negative hair growth regulators TGF-β1 and -β2 in response to H2O2 but not cell culture associated oxidative stress. Balding DPC had higher levels of catalase and total glutathione but appear to be less able to handle oxidative stress compared to occipital DPC. These in vitro findings suggest there may be a role for oxidative stress in the pathogenesis of Androgenetic Alopecia both in relation to cell senescence and migration but also secretion of known hair follicle inhibitory factors....ODPC[occipital] and BDPC[balding] were more proliferative (P < 0.001 for both ODPC and BDPC) and had reduced levels of senescence when cultured at 2% O2 versus 21% O2 (Figure 2). However, BDPC underwent fewer PD than ODPC under both oxygen conditions (12 vs. 16 PD at 2% O2 (P < 0.001) and 5 vs. 9 PD at 21% O2 P < 0.001) (Figure 2a, 2b) furthermore, senescence was significantly higher in BDPC at 21% O2 than ODPC (P < 0.001) (Figure 2c). There was no significant difference in senescence between ODPC and BDPC at 2% O2....DHT stimulated TGF-β secretion from DPCs only at 21% O2, suggesting that oxidative stress is an essential component of androgen response in Androgenetic Alopecia. In addition, our observation that at 2% oxygen DHT had significantly reduced TGF-β1 secretion in ODPCs and BDPCs.

Oxidative stress-associated senescence in dermal papilla cells of men with androgenetic alopecia

Minireview: Prolactin Regulation of Adult Stem Cells

Now we've established that Prl has a significant role in hair follicle cycling, enforcing stem cell quiescence, promoting premature catagen entry and delayed anagen. It is differentially expressed between balding and non-balding hair follicles, and genetically-associated with Androgenetic Alopecia. Where then does DHT come into play. DHT has been shown to upregulate extrapituitary prolactin, providing an explanation for the DHT paradox.
Increasing evidence demonstrates the presence of ePRL, as well as its receptors, in male reproductive organs. ePRL mRNA was detected in the dorsal and lateral prostate of rats using Northern blotting and in situ hybridization. Immunostaining localized the protein to secretory granules of the apical cytoplasm of epithelial cells. Expression within the prostate was activated by testosterone, with castrated rats producing no ePRL whereas treatment with exogenous testosterone restored its production.

Minireview: Extrapituitary Prolactin: An Update on the Distribution, Regulation, and Functions


In addition to the increased Prl production induced by DHT the binding affinity with the PRLR is strongly upregulated by higher oxygen levels

The dissociation rate constant for hPRL is strongly dependent on pH, with an approximate 500-fold increase over the pH range of 8-6

The Kinetics of Binding Human Prolactin, but Not Growth Hormone, to the Prolactin Receptor Vary over a Physiologic pH Range

At least in sheep, lower O2 levels reduced intracellular pH significantly. A slightly lower pH level can strongly upregulate prolactin signaling. Together with other findings this suggests that high levels of AR signaling induces an upward shift in intracellular pH which upregulates the PRLR, forcing stem cell quiescence.
hypoxiaph.JPG


Intracellular pH changes induced by hypoxia and anoxia in isolated sheep heart Purkinje fibres

Here it is found that the AR upregulates PRLR in breast cancer cells. It doesn't seem like a stretch to assume this is happening in hair follicles as well.
PRLR binding activity was increased approximately 2-fold by treatment for 24 hr with 10 nM R1881, TEST, DHT, MPA and ORG 2058.

Androgen regulation of prolactin-receptor gene expression in MCF-7 and MDA-MB-453 human breast cancer cells


Evidence of a Prl autocrine loop in breast cancer.
Proof of an autocrine/paracrine loop for PRL within normal and malignant human breast tissues requires that the following three criteria be met: (1) PRL must be synthesized and secreted within mammary tissues; (2) the receptor for PRL (PRLR) must be present within these tissues; and, (3) proliferative responses to autocrine/paracrine PRL must be demonstrated. These criteria have now been fulfilled in several laboratories. With the demonstration of a PRL autocrine/paracrine loop in mammary glands, the basis for the ineffective treatment of human breast cancer by prior endocrine-based anti-somatolactogenic therapies is evident. These findings provide the precedent for novel therapeutic strategies aimed at interrupting the stimulation of breast cancer growth by PRL at both endocrine and autocrine/paracrine levels.

Prolactin as an Autocrine/Paracrine Factor in Breast Tissue


Once upregulated by DHT this Prl signaling loop remains active even after the AR is silenced. This must contribute to the lack of hair regrowth seen from castration and AR antagonists despite complete cessation of further hair loss. Cells that have not yet been affected are spared when androgens are blockaded, but in cells in which Prl is already upregulated this loop must be interrupted before hair can grow thicker and longer again. This is where HMI-115 should be superior to AR antagonists and 5-alpha reductase inhibitors.
 

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I have a lot more data to compile here, but it will have to wait. Next I will explore the mechanisms downstream of the PRLR.
 
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