Drugs may shut down several EBV induced diseases

maryb

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Anyone know if any trials were ever started following this study?
Drugs May Shut Down Several Epstein-Barr Virus-Induced Diseases
The same virus that causes relatively mild mononucleosis, the "kissing disease," can also cause severe mono as well as several potentially deadly kinds of cancer.

Now researchers think they can kiss a stealthy form of Epstein-Barr virus (EBV) goodbye - or at least shut it down enough to successfully treat several of the dangerous diseases it causes.

Using a class of drugs being clinically tested to treat other kinds of cancer, researchers at the University of Wisconsin School of Medicine and Public Health found that the drugs were the first to stop the latent form of EBV infection from causing disease.

The drugs, Hsp90 inhibitors, prevented human EBV-related tumors from growing in mice, protected immune cells from transforming into tumors and killed established tumor cells at low, non-toxic doses.

Until now, there have been no effective drugs for treating latent EBV infection in any of the EBV-associated diseases, which in addition to mono include a subset of stomach cancers, certain types of nose-throat cancer and lymph node cancers such as lymphoproliferative disease, says lead author Shannon C. Kenney, MD.

"This discovery suggests a new way of treating patients with severe mononucleosis, which in rare circumstances can be fatal, and patients with EBV-driven cancers, particularly immuno-compromised AIDS and transplant patients," says Kenney, an infectious disease expert at UW Hospital and Clinics.

The study appears in the current (Jan. 25, 2010) Proceedings of the National Academy of Sciences.

Kenney, also a professor of oncology at the McArdle Laboratory for Cancer Research and of medicine, has studied EBV for nearly 30 years. Most of her work has focused on the form of EBV that actively produces infection, but recently she turned to the so-called latent form.

"The latent infection form actually is not so latent," says Kenney, a member of the UW Carbone Cancer Center. "This is the form of EBV that is most closely associated with cancer development."

Latently infected cells express transforming viral proteins that can change normal cells into cancer cells. One key viral protein, EBNA-1, is required for EBV to live long-term in host cells. Many scientists and drug companies are looking for ways to block this viral protein, expressed in every EBV-infected cell.

Kenney and her team had been using Hsp90 (heat shock protein 90) inhibitors as they studied the infectious form of EBV.

"Normal cells can survive when treated with Hsp90 inhibitors," Kenney says. "In contrast, Hsp90 inhibitors are toxic to certain types of cancer cells, which often are more dependent upon high levels of Hsp90."

After they discovered that EBNA-1 itself must have Hsp90 in order to function in cells, the Wisconsin researchers conducted three different experiments to see what the effect of exposing EBV-infected cells to Hsp90 inhibitors would be.

In all three experiments, the results showed a dramatic reduction in EBNA-1-related activity. The drugs killed EBV-induced tumor cells in one experiment, halted the growth of EBV-induced tumors in mice in another and protected normal immune cells from becoming transformed to tumor cells in the third.

And while the drugs were highly toxic to EBV-infected cells, they had very little effect on normal cells at the doses used in the experiments.

The researchers found the underlying explanation to be that EBNA-1 could not be processed - synthesized and translated - to any degree when Hsp90 inhibitors were present.

Kenney expects the inhibitors-geldanamycin, 17-AAG and 17-DMAG-may be useful for most but not all kinds of EBV-induced cancers as well as severe mono.

In fact, the drugs may be even more widely useful, says Kenney, because clinicians are seeing that people older than age 70 are getting certain forms of EBV-induced cancers more frequently.

"There also is tantalizing early evidence that EBV may contribute to auto-immune diseases such as lupus and multiple sclerosis," she says.

And what about the possibilities for standard mono?

"The majority of healthy humans will get over mono with no treatment after a month or two," says Kenney. "But Hsp90 inhibitors could potentially help, in terms of getting people back to school or work sooner. Clinical trials will need to be performed in patients to determine if these drugs are useful in severe mononucleosis."

Co-authors on the paper include Xiaoping Sun, Elizabeth A. Barlow, Shidong Ma, Stacy R. Hagemeier, Sarah J. Duellman and Richard R. Burgess from the McArdle Laboratory for Cancer Research as well as Judy Tellman and Rajiv Khanna from the Australian Centre for Vaccine Development and Tumour Immunology Laboratory at the Clive Berghofer Cancer Research Centre, Queensland Institute of Medical Research.


Date Published: 01/25/2010
 

Bob

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Interesting thanks Mary.

I've just done a quick search on google and found the following info...

The only company with an Hsp90 inhibitor and a MEK inhibitor in clinical testing is Novartis (NVS).
http://seekingalpha.com/article/710461-synta-the-signal-looks-real
Myrexis' oncology program included the Hsp90 inhibitor MPC-3100 and the cancer metabolism inhibitor MPC-8640, neither of which have progressed past phase I trials.
http://seekingalpha.com/article/729461-despite-myrexis-appeal-as-a-value-investment-more-to-consider
Additional Pipeline Update: Retaspimycin HCl Infinity also announced today that its Phase 2, randomized, double-blind, placebo-controlled trial of retaspimycin hydrochloride (HCl) in combination with docetaxel in patients with non-small cell lung cancer (NSCLC) is enrolling ahead of schedule. Infinity now anticipates completing enrollment in this trial this Fall and expects to report data from the trial in the first half of 2013. Retaspimycin HCl is an intravenously administered, potent and selective heat shock protein 90 (Hsp90) inhibitor.
http://www.marketwatch.com/story/in...-faah-and-early-discovery-programs-2012-07-18
CHIARA Study Aiming For Clear Signal In ALK+
The separate CHIARA Phase II study of ganetespib, as monotherapy, in ALK-positive NSCLC, gives Synta two registration directed strategies in NSCLC, confirming ganetespib’s position as the most advanced Hsp90 inhibitor.
http://www.forexpros.com/analysis/synta-pharma:-galaxy-interim-results-128464
 

August59

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This very interesting and may eventually help a subset of PWC. There seems to be a growing list of evidence that EBV is involved either directly or indirectly in a few diseases. Especially the latent version of the virus that doesn't always kill the cell it infects, but instead keeps it alive and I believe virtually undetecable since the body does not produce antibodies to it because it doesn't know it's there. I would be willing to bet it can work synergistically with other viruses or at least it may help propogate other viruses.
 

Ema

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I found this once looking for EBV and adrenal insufficiency and wondered if that was somehow related...still don't know the answer though!

From Wikipedia:

Interaction with steroid receptor
Schematic diagram of the translocation of the glucocorticoid receptor (GR) from the cytoplasm into the nucleus assisted by Hsp90 (90).[48] In the cytoplasm, GR is complexed with Hsp90 and the immunophilin FKBP51 (51). Binding of hormone to GR causes a conformational change in the complex, which results in exchange of FKBP51 for FKBP52 (52). FKBP52 in turn binds the dynein (dyn) motor protein that attaches to the cytoskeleton and transports the GR complex into the nucleus. Once in the nucleus, the complex disassembles releasing GR, which dimerizes and binds to DNA where it facilitates transcription of DNA into mRNA.

The glucocorticoid receptor (GR) is the most thoroughly studied example of a steroid receptor whose function is crucially dependent on interactions with Hsp90.[49][50] In the absence of the steroid hormone cortisol, GR resides in the cytosol complexed with several chaperone proteins including Hsp90 (see figure to the right). These chaperones maintain the GR in a state capable of binding hormone. A second role of Hsp90 is to bind immunophilins (e.g., FKBP52) that attach the GR complex to the dynein protein trafficking pathway, which translocates the activated receptor from the cytoplasm into the nucleus.[51] Once in the nucleus, the GR dimerizes and binds to specific sequences of DNA and thereby upregulates the expression of GR responsive genes. Hsp90 is also required for the proper functioning of several other steroid receptors, including those responsible for the binding of aldosterone,[52]androgen,[53] estrogen,[54] and progesterone.[55]
 

maryb

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Thanks for all the info Bob. August59 I agree, think that is definitely the case as far as my illness is concerned. I have tested at 4 of my really bad phases (eg bedbound) for active EBV, the rest of the time when I am just ill and limping through life is when I believe the virus is latent and doing greater harm.
 

Daffodil

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will we need thsi hps90 drug for the rest of our lives? will it be IV? $$$$$$$ :(

only in phase 2.....blahh