Startup develops late-stage prostate cancer therapy that could increase patient survival rates

Below is a press releases from last week [1].

{A cell/mouse study was actually published in 2015 [2].}

Cholesterol accumulation is something that occurs in tumor cells, a fact that was noted a hundred years ago. In PCa, the accumulation is associated with aggressiveness. Enough reason, I think, to consider a statin, regardless of what one's LDL status is.

Cholesterol is of particular significance in PCa, since treatments mostly entail depriving the cancer of androgens, & cholesterol is the starting point for steroidogenesis. Not only can PCa cells use their cholesterol to make androgen, but the cells are also capable of making cholesterol.

Examination of the Wiki-pages for Zytiga & Xtandi informs one that the drugs are used to treat metastatic castration-resistant prostate cancer. i.e. first we close the largest barn door, then we move on to the next & so on. Dr. Myers has spoken against the sequential approach, claiming that successful treatments for other forms of cancer all require more that one drug.

In any event, I tend to think of the cholesterol problem as being the last ADT barn door. When all other doors have been closed, the cells will synthesize cholesterol & find a pathway to create androgen.

The Purdue University technology licensed by Resarci Therapeutics targets cholesterol metabolism.

""We target the aberrant cholesterol metabolism using an inhibitor of cholesterol esterification enzyme ACAT-1, named avasimibe. Avasimibe selectively kills cancer cells by preventing the cholesteryl ester accumulation and inducing free cholesterol related toxicity in cancer cells.""

"... the company has demonstrated the ability of the inhibitor avasimibe to overcome the resistance to hormone therapy in mouse models and is looking to further improve their product in future trials."

Unfortunately, while cholesterol synthesis & metabolism may be the final ADT barn door, treatment may select for androgen receptor mutations that do not require androgen binding - e.g. AR-V7. i,e, where castration becomes irrelevant.

The press release is a bit misleading:

"Resarci Therapeutics has developed a new therapeutic strategy by targeting the cholesterol metabolism instead of the androgen pathway."

& yet they claim that the treatment can "overcome the resistance to hormone therapy", which suggests that they don't see ADT going away.

However, in the published study:

"In cell lines of human prostate, pancreatic, lung, and colon cancer, avasimin significantly reduced cholesteryl ester storage in lipid droplets and elevated intracellular free cholesterol levels, which led to apoptosis and suppression of proliferation."

Which makes it clear that they view the drug as having potential for all solid tumors that accumulate cholesterol. If that works, we might finally move out of the Huggins castration era.

In fact, back in May, it was touted as a treatment for pancreatic cancer [3].

-Patrick

[1] medicalxpress.com/news/2016...

Startup develops late-stage prostate cancer therapy that could increase patient survival rates

October 13, 2016

Startup develops late-stage prostate cancer therapy that could increase patient survival rates

Junjie Li, a postdoc research fellow in the Weldon School of Biomedical Engineering, retrieves a sample that will be tested for research related to the development of an alternative therapy for late-stage prostate cancer patients who may …more

A biomedical startup that licensed a Purdue University technology has developed a late-stage prostate cancer therapy that could provide an alternative to current hormone therapies that are known to develop resistance after prolonged use.

Ji-Xin Cheng, a professor in Purdue's Weldon School of Biomedical Engineering; Junjie Li, a postdoc research fellow in the Weldon School of Biomedical Engineering; and Timothy L. Ratliff, a professor in Purdue's College of Veterinary Medicine and director of the Purdue University Center for Cancer Research, co-founded Resarci Therapeutics LLC to further develop the technology.

Cheng said that resistance to current hormone therapies is one of the biggest challenges patients face in treatment.

"Hormone therapies have a goal to reduce male hormones, called androgens, in the body, or to stop them from affecting prostate cancer cells," he said. "Almost 100 percent of cancer patients will eventually develop a resistance to hormone therapies. Every year in the United States around 32,000 new cancer cases become resistant, lessening the likelihood of survival."

Resarci Therapeutics has developed a new therapeutic strategy by targeting the cholesterol metabolism instead of the androgen pathway.

"By targeting the cholesterol metabolism, which is specific to cancer cells and independent of the hormone signaling pathway, we are able to eliminate the hormone resistance," Li said. "We target the aberrant cholesterol metabolism using an inhibitor of cholesterol esterification enzyme ACAT-1, named avasimibe. Avasimibe selectively kills cancer cells by preventing the cholesteryl ester accumulation and inducing free cholesterol related toxicity in cancer cells."

Ratliff said the company has demonstrated the ability of the inhibitor avasimibe to overcome the resistance to hormone therapy in mouse models and is looking to further improve their product in future trials.

"We want to improve the formulation of our product, test it in preclinical settings and launch an early-stage clinical trial," he said. "We are applying for funding from NIH and other agencies but are also looking for investors or potential partnerships with pharmaceutical companies."

[2] ncbi.nlm.nih.gov/pubmed/?te...

ACS Nano. 2015 Mar 24;9(3):2420-32. doi: 10.1021/nn504025a. Epub 2015 Feb 16.

Avasimibe encapsulated in human serum albumin blocks cholesterol esterification for selective cancer treatment.

Lee SS1, Li J1, Tai JN1, Ratliff TL1, Park K1, Cheng JX1.

Author information

Abstract

Undesirable side effects remain a significant challenge in cancer chemotherapy. Here we report a strategy for cancer-selective chemotherapy by blocking acyl-CoA cholesterol acyltransferase-1 (ACAT-1)-mediated cholesterol esterification. To efficiently block cholesterol esterification in cancer in vivo, we developed a systemically injectable nanoformulation of avasimibe (a potent ACAT-1 inhibitor), called avasimin. In cell lines of human prostate, pancreatic, lung, and colon cancer, avasimin significantly reduced cholesteryl ester storage in lipid droplets and elevated intracellular free cholesterol levels, which led to apoptosis and suppression of proliferation. In xenograft models of prostate cancer and colon cancer, intravenous administration of avasimin caused the concentration of avasimibe in tumors to be 4-fold higher than the IC50 value. Systemic treatment of avasimin notably suppressed tumor growth in mice and extended the length of survival time. No adverse effects of avasimin to normal cells and organs were observed. Together, this study provides an effective approach for selective cancer chemotherapy by targeting altered cholesterol metabolism of cancer cells.

KEYWORDS:

ACAT-1 inhibitor; avasimibe; cancer; cholesterol; cholesteryl ester; human serum albumin

PMID: 25662106 DOI: 10.1021/nn504025a

[PubMed - indexed for MEDLINE]

[3] medicalxpress.com/news/2016...

26 Replies

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  • Patrick, thank you for saving your useful research to this page for all current members and for members in the future.

  • Patrick,

    THe science looks promising and logical. Thank you for reporting something, in the future that maybe a cutting-edge protocol.

    Rich

  • Sounded interesting, but I got lost after awhile.

  • But thanks though.

  • Thank you Patrick.

    Very useful and promising information.

    I wish to quote below from page 503 of Dr.Patrick Walsh's book Guide to Surviving Prostate Cancer :

    "Recent studies suggest that in men with castration-resistant prostate cancer, cancer cells can still synthesize hormones from cholesterol and steroids in the blood stream to make the tumor grow again. But by blocking the production of these hormones with drugs like abireteron ( Zytiga ), we can stop the cancer from growing - and in many cases cause it to regress."

    Sisira

  • Sisira (and Patrick by implication)

    That quote from Walsh is unexpected. Possibly outdated?

    One sees V7 cells post abi/enza. And that seems to result in the neuro-endocrine variant. (?)

  • Oh, patric was talking about "avasimibe", not abi/enza.

  • Your scientific knowledge amazes me. We're you ever trained in the sciences or did you learn along your journey. I have a lot to learn. Thank you to all for big great teachers. Love this post. It was nice to see a new press release and gives so much hope at the rate at which info is coming out. Ty xo

  • Don't worry, still I have time to lay aside Dr.Patrick Walsh's golden book before it becomes outdated ( Not in this century! ).

    The copy I have in my hand is the Third Edition published in 2012 and my quote came from it.

    I was not in the least excited by the news of this drug Avasimibe ( inhibitor of enzyme ACAT-1 ) blown out of the trumpet of yet another multinational drug company prematurely, whilst undergoing the process of trials with mouse models. Even if they mange to complete all their trials successfully and get the approval to introduce the drug into the market, it will only be added to the list of hormone theraputic drugs like Abiraterone ( Zytiga - well established ). This cholesterol theory in HRPC is years old as has been spoken of in the article itself. But I am quite sure about one thing - The drug company will fix a world record price for the new drug claiming its ability to close the "last barn door" - One and the only drug!

    Ironically, it is admitted in the same article that still it won't be the end of the story. Then what?! The nasty cells that do not require androgen binding, the cells that don't give a damn to hormone. From the day we contract PCa, though in very small number these are the cells that grow silently being hormone insensitive ( AR-V7 ). Finally they overpower everything ( unless they are destroyed ) and put an end to our life.

    This is where I fully appreciate and respect what Dr.Walsh has emphasized over and over in his book that the need of the hour is not to depend too much on palliative hormone therapy ( still widely practiced ) which has not changed fundamentally over the last fifty years and buy time, instead, invest on efforts to develop cytotoxic drugs which can be targeted for the killing of these nasty cells, with the minimal collateral damage. To begin with Prostatectomy and Radiation are two such gold standard curative treatments. ( Not applicable to everybody due to pathological factors ) but both protocols have seen vast innovative changes/development over the years. So are the chemotheraputic drugs when administered strategically with proper discrimination.

    To be frank with you I am on Hormone Therapy ( Zoladex ) for the last 21 months after undergoing RP and IMRT ( Don't laugh at me being on ADT! ). My PSA ever since treatment remains at 0.00ng/ml (Yesterday I got the latest). I am eagerly waiting to go for the "kill" using Docetaxel, no sooner I see my first biochemical failure, without buying time with further ADT protocols just for the sake of quality of life, because I want to destroy the nasty ones before they launch their attack on me. Hope I will be somewhere, with more time to live!

    Thanks for picking up my response to the above news item posted by Patrick.

    Best regards,

    Sisira

  • Martin,

    My reply to your above comment accidentally fell under Daddyishealing's reply.

    Sisira

  • o o i see. I didnt read it but I will go back now

    I am not familiar with that book or that doctor either actually. Let me read all that before I comment more.

  • o o k Martin, you read my reply leisurely.

    For your kind information here is a little on Dr.Patrick Walsh :

    "Patrick C. Walsh MD, University Distinguished Service Professor of Urology and Chairman Emeritus at the Brady Urological Institute at Johns Hopkins which position he held over a very long period of time, is a world renowned urologist and surgeon, best known for pioneering the anatomic approach to Radical Prostatectomy and also its nerve-sparing modality. He has won many a world awards and written several priceless books and also presented numerous research papers at international urological forums. He held the chairmanship of several important urological associations too.

    He is simply a legend and the foremost authority on prostate cancer America has ever produced!

    You may ask any Urologist in your country about him.

    Sisira

  • Cool. I never heard of him.

    I will be going to the "Diamond Jim" Brady Institute at Johns Hopkins next week as it happens. Donald Coffee is also at the Brady Institute at JH, although he is in his 80's now.

  • Yes I completely agree with his line of thinking:

    ---

    that the need of the hour is not to depend too much on palliative hormone therapy ( still widely practiced ) which has not changed fundamentally over the last fifty years and only buys time. Instead, we should invest on efforts to ... kill these nasty cells, with the minimal collateral damage

  • Well maybe with this exception: that "all out war" is probably not appropriate. The more likely path is to co--exist with prostate cancer. We should try to prop up our normal prostate cells, and even possibly even prop-up the non-metastatic cancer ones, since it may well be that most men develop some micro prostate cancer in their 20's and what the reason is for that has hardly been examined or considered.

    ---

    There is evidence that metastasis is the body's attempt to evict cancer cells from the prostate, shall we anthropomorphise and say in an attempt to clean-up the problem, There is no question that tumor associated macrophages assist in the mesenchymal transition.

  • Wow! You are going to Brady Institute at Johns Hopkins next week. Please tell them there is a guy in Sri Lanka who worships Dr.Walsh!

    I really appreciate your rather philosophical expression of avoiding "all out war " with the prostate cancer. My problem is I am really scared to sleep with this lethal enemy and such a nasty monster! It is inside me, unseen and there is no way to communicate to decide which is better - PEACE or WAR?

    Regards,

    Sisira

  • I am going for Plerixifor. (!) yes.

  • Great research. Never knew there were so many promising studies that give so much relavant insight to present treatments and what will be the best phase 1 2 and 3 clinical trials to fast ttract. Also helps decide which schools thought sequencing or combining drugs in any particular case . Reserve your arsenal or go for the kill?

  • Patrick will respond later---Have an early Bible study.

    Nalakrats

  • Patrick - you said (but I cant seem to find it) that you got your doctor treat you with BAT by talking a long time to him. Do you think he is open to using that on me, or do you know other places that are using that? I see a trial in progress, post enzalutimide, but I don't want to wait till I fail enz to begin. That gives the cancer much too much time to diverge genetically.

  • The discussions with my doctors were to bring them on board in terms of (a) being willing to support my approach & (b) writing the prescriptions. Ideally, one would be under the care of someone driving the therapy you believe in, rather than being in a supporting role.

    I'd need to go out of state for that. For BAT itself, there is Denmeade at Johns Hopkins. Then there is Morgentaler (Department of Urology, Harvard Medical School, Brookline, Massachusetts). "Dr. Bob" Leibowitz (Compassionate Oncology Medical Group, LA) has used high-dose testosterone for many years - but not rapid cycling. Maybe there are others.

    -Patrick

  • Very interesting--thanks, Patrick.

    Roughly how many years does it take from this point to FDA approval, assuming all goes well in the clinical trials?

    Neal

  • People used to say >10 years, but the FDA has fast-tracked PCa drugs.

    fda.gov/forpatients/approva...

    e.g. Zytiga:

    "The application was reviewed under the FDA’s priority review program, which provides for an expedited six-month review for drugs that may offer major advances in treatment, or provide a treatment when no adequate therapy exists. Zytiga is being approved ahead of the product’s June 20, 2011 regulatory goal date."

    The trick is to show significant benefit in mCRPC cases that have failed every treatment. After that, it gets used in less dire cases without specific FDA approval.

    -Patrick

  • Where can I go and who do I contact to get on a list for a trial study?

    Dennis

  • No idea what the plans are, but Mr Cheng might know:

    Email: jcheng@purdue.edu

    -Patrick

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