Heat Shock Protein 90 [HSP90]

New study below [1] [2].

Heat shock proteins [HSPs] are a response to heat, among other things.  For example, HSP90 is commonly produced during radiation therapy & cause radioresistance.

HSP90 is known as a chaperone protein.  One of its clients is the androgen receptor [AR].  As such, it is protective of AR.  It accompaies AR when it translocates to the nucleus of the cell.

Current treatment strategies target AR fairly directly, via androgen deprivation or AR antagonists.  HSP90 inhibition is a more subtle approach, which might also synergize well with other treatments.

The new study is of great interest because of the focus on the AR variant AR-V7 which is resistant to current therapies.

"We demonstrate that AR-V7 and full-length AR (AR-FL) were depleted upon inhibition of HSP90. However, the mechanisms underlying AR-V7 depletion differed from those for AR-FL. Whereas HSP90 inhibition destabilized AR-FL and induced its proteasomal degradation, AR-V7 protein exhibited higher stability than AR-FL and did not require HSP90 chaperone activity. Instead, HSP90 inhibition resulted in the reduction of AR-V7 mRNA levels but did not affect total AR transcript levels, indicating that HSP90 inhibition disrupted AR-V7 splicing."  

HSP90 has been studied for about 25 years.  There have been two PCa clinical trials of HSP90 inhibitors:

a) clinicaltrials.gov/ct2/show...

"A Study of HSP90 Inhibitor AT13387 Alone or in Combination With Abiraterone Acetate"

b) clinicaltrials.gov/ct2/show...

"Hsp90 Inhibitor STA-9090 in Treating Patients With Metastatic Hormone-Resistant Prostate Cancer Previously Treated With Docetaxel-Based Chemotherapy"

I can't find published results for either trial.

-Patrick

[1] cancerres.aacrjournals.org/...

Second-Generation HSP90 Inhibitor Onalespib Blocks mRNA Splicing of Androgen Receptor Variant 7 in Prostate Cancer Cells

Roberta Ferraldeschi1,2, Jonathan Welti1, Marissa V. Powers1, Wei Yuan1, Tomoko Smyth3, George Seed1, Ruth Riisnaes1, Somaieh Hedayat1, Hannah Wang1, Mateus Crespo1, Daniel Nava Rodrigues1, Ines Figueiredo1, Susana Miranda1, Suzanne Carreira1, John F. Lyons3, Swee Sharp1, Stephen R. Plymate4,5, Gerhardt Attard1,2, Nicola Wallis3, Paul Workman1, and Johann S. de Bono1,2,*

+ Author Affiliations

1Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom.

2Prostate Cancer Targeted Therapies Group, Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom.

3Astex Pharmaceuticals, Cambridge, United Kingdom.

4Department of Medicine, University of Washington School of Medicine and GRECC at VAPSHCS Seattle, Washington.

5Department of Urology, University of Washington School of Medicine and GRECC at VAPSHCS Seattle, Washington.

↵*Corresponding Author:

Johann S. de Bono, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom. Phone: 44-20-8722-4028; Fax: 44-20-8642-7979; E-mail: Johann.de-bono@icr.ac.uk

Abstract

Resistance to available hormone therapies in prostate cancer has been associated with alternative splicing of androgen receptor (AR) and specifically, the expression of truncated and constitutively active AR variant 7 (AR-V7). The transcriptional activity of steroid receptors, including AR, is dependent on interactions with the HSP90 chaperone machinery, but it is unclear whether HSP90 modulates the activity or expression of AR variants. Here, we investigated the effects of HSP90 inhibition on AR-V7 in prostate cancer cell lines endogenously expressing this variant. We demonstrate that AR-V7 and full-length AR (AR-FL) were depleted upon inhibition of HSP90. However, the mechanisms underlying AR-V7 depletion differed from those for AR-FL. Whereas HSP90 inhibition destabilized AR-FL and induced its proteasomal degradation, AR-V7 protein exhibited higher stability than AR-FL and did not require HSP90 chaperone activity. Instead, HSP90 inhibition resulted in the reduction of AR-V7 mRNA levels but did not affect total AR transcript levels, indicating that HSP90 inhibition disrupted AR-V7 splicing. Bioinformatic analyses of transcriptome-wide RNA sequencing data confirmed that the second-generation HSP90 inhibitor onalespib altered the splicing of at least 557 genes in prostate cancer cells, including AR. These findings indicate that the effects of HSP90 inhibition on mRNA splicing may prove beneficial in prostate cancers expressing AR-V7, supporting further clinical investigation of HSP90 inhibitors in malignancies no longer responsive to androgen deprivation. Cancer Res; 76(9); 2731–42. ©2016 AACR.

[2] sciencedaily.com/releases/2...

New cancer drugs could treat lethal resistant prostate cancers

Date:

May 1, 2016

Source:

Institute of Cancer Research

Summary:

Men with aggressive prostate cancer that has stopped responding to conventional treatment could potentially benefit from a new class of cancer drug designed to overcome drug resistance, a new study suggests. Researchers found that the drugs, called Hsp90 inhibitors, specifically target and inactivate a mechanism commonly used by prostate cancer cells to evade the effects of standard treatment.

Men with aggressive prostate cancer that has stopped responding to conventional treatment could potentially benefit from a new class of cancer drug designed to overcome drug resistance, a new study suggests.

Researchers found that the drugs, called Hsp90 inhibitors, specifically target and inactivate a mechanism commonly used by prostate cancer cells to evade the effects of standard treatment.

The findings provide vital information about the role of Hsp90 in drug-resistant prostate cancers, and open up potential new routes to cancer treatment based on blocking this or related proteins.

A team at The Institute of Cancer Research, London, found that Hsp90 inhibitors countered the effect of malfunctions in the androgen receptor, which often occur in resistance to hormone treatments.

The research suggests that Hsp90 inhibitors could be effective in prostate cancers that have become resistant to treatment and started spreading round the body.

The study is published in the journal Cancer Research, and was mainly funded by the Wellcome Trust.

Hsp90 inhibitors are among several innovative new types of treatment designed to attack cancer indirectly, by destabilising multiple different proteins required for the growth and survival of cancer cells.

By destroying several cancer signals at once, they are designed to make it hard for cancers to escape the effects of treatment, giving them promise as potential 'resistance-busting' drugs.

The new research found that on top of their known effects on cancer, Hsp90 inhibition also blocked production of abnormal forms of the androgen receptor, stripping cancer cells of their defences against hormone treatments.

Prostate tumours rely on male hormones called androgens to grow and spread, and blocking androgen receptors can be an effective treatment.

However, cancer cells often generate abnormal forms of the androgen receptor that can be switched on all the time without the need for androgen hormone stimulation.

Researchers investigated the effect of Hsp90 inhibition on human cancer cells that produced the most common androgen receptor variant, called AR-V7. They grew the cancer cells in the lab and injected them into mice.

The researchers showed that Hsp90 inhibition reduced production of AR-V7 through a new and unexpected mechanism of action -- by changing the way that messenger RNA molecules carrying the code for AR-V7 are processed.

Hsp90 inhibition also reduced the levels of the normal androgen receptor, and other important prostate cancer molecules called AKT and GR.

Study co-leader Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, said:

"We call Hsp90 inhibitors 'network drugs' because they tackle several of the signals that are hijacked in cancer all at once, across a network rather than just a single signalling pathway. These drugs can hit cancer harder than those targeting only one protein, and look promising for preventing or overcoming drug resistance.

"Our study has found that Hsp90 inhibition can specifically stop resistance to hormone treatments in prostate cancer, through a completely new mechanism of action involving the processing of messenger RNA.

"It's an exciting discovery which adds a string to the bow of these cancer drugs, and means they could work against prostate cancers that have otherwise stopped responding to treatment."

Study co-leader Professor Johann de Bono, Professor of Experimental Cancer Medicine at The Institute of Cancer Research, London, said:

"We have demonstrated for the first time that Hsp90 inhibitors can block the production of the most common abnormal androgen receptors that cause many prostate cancers to stop responding to current treatments.

"These drugs are already in clinical trials for several types of cancer, and I am excited that our work suggests they could also benefit men with prostate cancer who have otherwise run out of treatment options."

5 Replies

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  • Patrick,

    Thank You for this, I wonder if these drugs are available now or in the future?

    Drugs that would stop hormone resistance would be a huge step in advanced prostate Cancer! The Author Johann De Bono from England was the one who first developed zytiga I believe, or at least the first clinical investigator.

    Dan

  • Hi Dan,

    de Bono has an impressive resume:

    icr.ac.uk/our-research/rese...

    His name is on 130 PubMed papers with a match for <PCa & the Royal Marsden hospital>.  The latest, from April 23, sheds light on the emergence of  AR-V7:

    sciencedirect.com/science/a...

    I remember reading studies 10+ years ago that basically found the AR to be normal at diagnosis, & for amplification, etc, & mutation to be a feature of ADT failure.  i.e. treatment itself selects for changes that resist treatment.

    Therefore it was a surprise to me that AR-V7 could be found at an early stage, albeit at inconsequential levels.  But here we read:

    "... the first evidence that nuclear AR-V7 expression increases with emerging CRPC ..."

    which would be reassuring if we could find a way to change treatment direction before CRPC happens, rather than as a response to it.  Hence my interest in rapid alternation between castration & high-normal testosterone.

    -Patrick

  • Patrick,

             Dr. De bonos resume and work is very impressive, Especially considering he has only been at it for 13 or so years with 300 peer reviewed studies.And responsible for 2 of the 4 new prostate Cancer therapies . He is a good one to follow , and if I was in the UK I would want him for my Doctor. I have a feeling he may be the one to cure this disease.

    Dr. Bob Leibowitz has done studies on Testosterone replacement in Prostate Cancer.

    Dan

  • The (b) trial you mentioned achieved a median of 1.9 months with no disease progression. I found these limited results at clinical trials.gov.

  • Thanks for noticing that.  

    In this small trial, progression-free survival ranged from 1.7 to 2.7 months.  Doesn't sound very encouraging, but these men with metastatic CRPC had already gone through Docetaxel.

    In the trial, the drug name is "STA-9090".  No papers on PubMed for that name.  Just searched instead for "Ganetespib" & found the study paper:

    ncbi.nlm.nih.gov/pubmed/265...

    "Only 2 patients achieved {progression-free survival} PFS > 4 months."

    "Conclusions Ganetespib demonstrated minimal clinical activity in men with mCRPC. The true 6-month PFS rate was, at most, 0.20. Possible reasons for this include selection of a heavily pretreated patient population and lack of agent potency in patients with mCRPC."

    -Patrick

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