Up Island Eggs
Rumination 22: If at First You Don't Succeed
posted Friday, 1 May 2009
Rumination 22. If at First You Don't Succeed
By
Thomas P. Vogl
May 1, 2009
By
Thomas P. Vogl
May 1, 2009
I have now been on my new drug, AUY922, an Hsp90 inhibitor by Novartis, for almost eight weeks of weekly infusions. A CT scan last week showed that I was stable (no progression of disease) and that there were hints that the vascularization (blood vessels) at the periphery of the tumors was decreasing. However, a PET scan a week later showed that the many liver metastases were continuing their slow growth and some lab measures of liver function are deteriorating. I hasten to add that my liver is not enlarged and that I continue to be asymptomatic.
So, yesterday, after a lengthy and most helpful consultations with Drs. Geoffrey Shapiro, Bruno Bastos and Andrew Wolanski, with a telephone consult with Dr. Frank Hodi thrown in for good measure, we decided to take me off the AUY922 trial. Since any new trial would have to wait a month wash-out period before I could be started on it, and there was no Phase I trial that seemed obviously appropriate, the collective decision was a trial of Sutent (www.sutent.com/), an FDA approved drug for renal cell carcinoma and gastrointestinal stroma tumors, and thus immediately available by prescription rather than through a study. Its use for melanoma would be off label (not a big deal - done all the time) and there have been recent reports that it is effective in 20% of uveal melanoma patients, which for anti-cancer drugs is a huge success rate. Scans in eight weeks will see whether it is working. One of the major fringe benefits of the new regimen is that I have to go to Boston only once a month for a checkup and can monitor my own blood pressure and have labs drawn locally. Hurray! Only time will tell how well I tolerate Sutent and whether it works on me.
So, at this point I am off any Phase I trial and therefore no longer being treated in DFCI's CRC (Clinical Research Center). I cannot part from the CRC without expressing my thanks and profound admiration for the entire staff of the CRC, singling out DeeDee (Demetra) McDonald, Susan Coggeshall-Aikey, Moira Pevear, and Caroline Charron because they were responsible for my care and worked such wonders to make a difficult time much easier.
The AUY922 study design, particularly the first five weeks, is very hard on the patient. In those five weeks I spent three long weekends (Thursday afternoon through Monday morning) in Boston. Starting early in the morning on Friday (which is why I had to arrive Thursday afternoon) eight hours of hourly EKGs, each in triplicate, as well as a bizarre schedule of blood draws that had three hour intervals followed by one hour intervals. The rest of the weekend I had to go in for just 30 minutes each mornings for the EKGs and a blood draw. The blood draw was to measure drug levels and therefore could not be done locally. What really galled was that the four day weekend rigmarole was required with the fourth (last) infusion of the first cycle and, a week later, with the first infusion of the second cycle - as if anything will change between the fourth and fifth infusion a week apart! Thereafter I could have gone to Boston once a week in the morning and come back that afternoon except once every eight weeks for scans. No getting around it, March was hard on both of us and we are just now recovered.
No drug is without side effects and AUY922 is no exception. These new small molecule anti-cancer drugs, just like the older drugs, work on relatively small differences between normal and malignant cells, usually differences in speed of reproduction. That is why so many anti-cancer drugs have side effects such as hair loss (hair grows quickly), gastrointestinal problems (the lining of the intestine reproduces rapidly) etc. Which is why I now have only one third of the hair I had two years ago.
Hsp90 is one of a class of chaperone proteins, whose normal job is to help other proteins acquire and maintain the shape required for those proteins to do their jobs. Chaperone proteins work by being in physical contact with other proteins. Hsp90 can also enable cancer cells to survive and even thrive despite genetic defects which would normally cause such cells to die. Thus, blocking the function of HSP90 and related chaperone proteins may cause cancer cells to die. Of course, treating with a combination of drugs acting differently toward the same end is more effective that a single drug but that research is not supported because it is not in the interest of a drug company seeking a blockbuster for their own drug.
Some of the side effects of AUY922 (and probably other drugs with HSp90 as the target) are, at least to me, fascinating. Probably not as fascinating to you, dear reader, than to me and a subset of the scientific community. So I will deal with it below the break. Suffice it to say that they are annoying but tolerable by my definition of not interfering excessively with my normal activities.
********************************************************************************************************
Hsp90 is ubiquitous in the body and comprises 1-2% of total proteins in most tissues under non-stress conditions. To oversimplify, its function is to regulate protein folding, since misfolded proteins cannot execute their intended function. Tumor cells have an extraordinary reliance on Hsp90 which complrises as much as 4-6% of total proteins in tumor cells [L. Yanyan et al., New developments in Hsp90 inhibitors as anti-cancer therapeutics: clinical perspective and more potential. Drug Resistance Updates, 12 (1-2): 17-27 (February-April 2009)]. Thus Hsp90 inhibitor, like so many other old and new anti-cancer drugs, relies on relatively subtle differences between normal and cancer cells for its effectiveness. It is, therefore, not surprising that side effects abound; rather, it is surprising that for these new drugs they are so few and relatively mild.
One of the known (among many unknown) clients of Hsp90 is rhodopsin, one of the five photosensitive 'opsins' in the eye. Rhodopsin is the active pigment in the rod cells of the retina that are responsible for night vision. Three other opsins are responsible for color vision in the cone cells. The fifth opsin is melanopsin, which serves to control the size of the pupil in response to light as well as providing a signal to the pituitary gland to help regulate circadian rhythms.
To summarize my symptoms, they are (1) markedly reduced night vision, particularly on days 1 and 2 (the day of the infusion is day 0) that recovers substantially by day 4; (2) A marked decrease in my ability to adapt to changes in illumination level, particularly noticeable when going from well lit to poorly lit areas, as evidenced by my perception that areas that I used to consider adequately lit now appear quite dark (particularly when I come in from a well lit area); that Katherine observes that under these condition my pupils are 'tiny'; the effect diminishes far more slowly than (1); and (3) when I first wake up in the early dawn light, both the off-white (in the direction of orange) wall in our bedroom as well as the cloudy sky have a distinct green cast.
Effect (1) can be explained by the known rhodopsin requirement for Hsp90; (2) could be explained by a similar, yet undocumented, requirement of melanopsin for Hsp90; a possible relationship is that both of these opsins are Vitamin A derivatives; (3) still lacks a cogent explanation - under photopic (day-time) conditions I have never observed any derangements of color balance. It is difficult to imagine that AUY922 acts so uniformly across three different opsins that the color balance remains unaffected and if the effect were due to such a derangement it would not vanish promptly as soon as photopic vision is restored. It is noteworthy, but not explanatory, that the peak in spectral sensitivity of rhodopsin is in the yellow-green, just about the color I observe.
The collected Ruminations may be found at http://upislandeggs.com/Ruminations.htm
and my e-mail addresses at the bottom of the page at http://upislandeggs.com/
comments (5)
1. GeorgeJJL left...
Saturday, 2 May 2009 9:17 am
I wonder if bilberry extract might help with your night vision side
effects. I am not a doctor and this is not medical advise. It is just meant
as food for thought.
2. Tom left...
Saturday, 2 May 2009 10:27 am
Nothing is off the table. Right now I'm giving Sutent a chance and if that
does not work I am leaning toward one of the vaccine/immune system
boosters; which one still TBD.
3. Georgejjl left...
Saturday, 9 May 2009 5:42 pm
You might be interested in the video at the following URL site
http://app2.capitalreach.com/esp1204/servlet/tc?cn=aacr&c=10165&s=20385&e=9
605&&
4. Tom left...
Sunday, 10 May 2009 7:22 am
George, Thanks for the link. If the Sutent I am currently on does not work
(I'll find out at the end of June) The Aurora A inhibitor was a;ready high
on my list. I have already had some success, six month stability, with an
Aurora B inhibitor.
5. George left...
Tuesday, 2 June 2009 6:57 am
Tom,