GIST Support Wiki

 
Online tutorial of HSP90

LINK

http://www.onclive.com/publications/Oncology-live/2012/April-2012/Targeting-Hsp90-Researchers-Aim-to-Thwart-Chaperones-of-the-Guardian-of-the-Proteome


MARINA - 4/24/2012

The following link above came this morning from Google Alerts. It's a nice tutorial about HSP90 chaperone and its role in cancer cells.

Some quotes:

""The important chaperone function of Hsp90 is hijacked during cancer, so that mutated and overexpressed proteins are protected from misfolding and degradation. This promotes cancer survival in its stressful environment and promotes the ability of cancer cells to tolerate the many genetic alterations associated with cancer.""

""Hsp90 is the only chaperone for which targeted cancer agents have been developed thus far. It is considered an attractive therapeutic target because, unlike targeting individual components of signal transduction pathways, Hsp90 agents have the potential to target multiple oncogenic pathways simultaneously, by enabling the cell to degrade a variety of mutant proteins. Although there are currently no approved Hsp90 agents, there are many in clinical development.""

""A significant problem with many of these inhibitors has been the development of resistance. Recent studies have indicated that Hsp90 inhibition may actually drive a heat shock response (rapid induction of Hsps in response to stress), which increases the cellular levels of prosurvival chaperones, and is likely one of the primary causes of resistance. Currently in preclinical development are carboxy-terminal inhibitors, which do not induce this response and may help overcome resistance. These molecules are based on the coumarin antibiotic novobiocin.""

""The expression of co-chaperones and posttranslational modification of Hsp90 can affect the efficacy of Hsp90 and its inhibitors. Targeting co-chaperones or their interaction with Hsp90 might prove to be a therapeutically beneficial strategy, especially when combined with Hsp90 inhibitors.""

""Hsp90 is subject to several posttranslational modifications, including phosphorylation and acetylation. Studies have shown that Hsp90 function can be impaired by the inhibition of the enzyme histone deacetylase (HDAC). The HDAC inhibitor LBH589 (panobinostat; Novartis) is currently in phase I/II trials and may be a promising combination therapy with Hsp90 inhibitors, to offer a double hit on Hsp90 function."" [[I'll add that SAHA, i.e. Vorinostat, is an HDAC inhibitor already on the market for other cancers.]]


QUESTION:

""My question is that hyperthermia, whatever the cause, could have caused a rapid increase of HSP, which in turn helped to cause normally imperfect, muted proteins in GIST cells to fold properly and caused them to multiply GIST tumor cells rapidly. Is this plausible?""

MARINA ANSWERS

This is a very logical question, but I think the answer is probably "no."

Controlled hyperthermia has been a treatment for cancer cells and it sensitizes them to chemotherapy or radiation.

http://www.cancer.gov/cancertopics/factsheet/Therapy/hyperthermia

""Hyperthermia (also called thermal therapy or thermotherapy) is a type of cancer treatment in which body tissue is exposed to high temperatures (up to 113°F). Research has shown that high temperatures can damage and kill cancer cells, usually with minimal injury to normal tissues ""

Most globular proteins have extremely fragile folded 3-D structures. These 3-D structures are necessary for the protein to have its cellular activity. Mutant proteins can have even more fragile 3-D structures even as they have higher levels of signaling activity.

Very slight perturbations in the solution environment of a protein (temperature, salt levels, pH, etc) can cause a protein to become unfolded and inactive. IN fact, working with purified proteins in the lab is challenging because they can be so labile.

Heat much higher than the organism's normal temperature is usually very destabilizing for the protein's 3-D folded structure conformation. At temperatures just a few degrees above a certain threshold, the protein's 3-D structure unfolds and becomes a tangled mess in an irreversible process.

I'm fairly optimistic that once a certain threshold of heat is reached, the unfolding and denaturation of the 3-D structures of mutant proteins would be faster and more complete than the extent to which a possible induction of HSP90 might counteract the destabilization process.


QUESTION

""Hyperthermia, whatever the cause, could be very dangerous to people with tumors. They, especially cancer patients, should not overexpose to the sun and hydrate properly to maintain their body temperature? Am I wrong?""

MARINA ANSWERS

As endothermic mammals, humans are pretty good a thermal regulation of body temperature. We sweat, pant, drink water when it's hot, we shiver when it is cold. Etc. I think a person's body temperature (minus a fever) is maintained in a fairly narrow window up to a certain point of environmental conditions.

If the core temperature of the body became so high from summer heat as to cause an induction of heat shock proteins, then I bet the person would already be very ill from heat stroke. I don't think summer heat would cause the effect on tumors that you have postulated.


QUESTION


""According to her daughter, her tumor grew very rapidly and gained 2-3kg after experienced hyperthermia, cause of which is unknown. She died shortly afterward."" ""GIST tumor with a high mitotic count... she was directed to hold off Gleevec.""

MARINA ANSWERS


Did she die of hyperthermia or from GIST? By hyperthermia do you mean what we would call a fever, and if it was a fever then did she have an uncontrolled infection? I think having a high mitotic rate and being off of Gleevec could have caused her rapid progression and death. That is the most straightforward explanation


MARINA CONTINUES


In general terms, the expression of chaperones is very inducible by many types of cellular stress triggers. Heat would be one stresser, but it is not the only one. Cancer cells already have high levels of chaperones because of their derranged physiology, their stressful hypoxic enviroment, and high levels of abnormal proteins.

While I do not know this as a fact by any means, I have speculated whether the inducible high capacity of cells to express chaperones might be why so far the results with HSP-90 inhibitors in pts have been less than what seemed possible by cell culture studies in the lab. I've wondered if the cell can simply overwhelm these single agent drugs by synthesizing yet more chaperones. I've considered as an analogy the Disney movie Fantasia in which the sorcerer's apprentice tries to stop a magical broom with buckets of water...and when he welds an axe to hack it back into splinters, the splinters morph into an army of brooms with buckets. Wikipedia says that up to 2% of the total protein in a cell can be various chaperone proteins...that's huge considering there are genes for tens of thousands of proteins possible.

http://www.youtube.com/watch?v=XChxLGnIwCU


Out of curiosity I searched Google for "HSP90 induction humans" because I was wondering what variables have been shown to increase HSP90 in walking breathing humans compared to cell cultures growing in laboratory dishes.

Here's a link to a study by the US army, showing that treadmill exercise and accompanying heat acclimation increases chaperones in normal peripheral blood cells. Please note this is not demonstrating that exercise might increase chaperones in tumors in the body's core tissues, and besides as stated above--cancer cells already have high levels of chaperones because these cells live under stressful conditions caused by their own derrangement. I don't believe we could then argue that cancer patients should not exercise.

http://www.ncbi.nlm.nih.gov/pubmed/17977914

For a patient who had a high mitotic rate GIST, who couldn't tolerate Gleevec, and then had an aggressive progression and an elevated body temperature of unknown origins...we can't conclude much other than it sounds like there were serious problems. It's a very normal and average human reaction to want to know why, and to ruminate over all the causes. I spent three years ruminating over why I got GIST in the first place and blaming all kinds of reasons, sometimes illogical reasons. And I never figured it out.