Rumination 11. Nothing Ventured, Nothing Gained

Rumination 11. Nothing Ventured, Nothing Gained

by

Thomas P. Vogl

January 24, 2008

It has been an interesting start to 2008. On January 4th I met with Dr. Geoffrey Shapiro who went over with me in some detail the four phase 1 clinical trials he was currently conducting. We agreed that the trial of AZD1152, an aurora B kinase inhibitor, was the best match for me. My reasons for the choice are: the optimum dose had already been established; only the most minimal side effects have been observed in 30 patients; in the one melanoma patient on which the drug has been tried, extended remission has been observed. We agreed to start the study on January 14th.

On January 8th, I went out to Columbia, MO to spend a day with Dr. John Viator to learn how to prepare samples for his experimental test for melanocytes circulating in the blood (there are not supposed to be any). As I knew beforehand, the protocol is very straightforward and the necessary reagents are easy to obtain. I had already bought the centrifuge and the reagents, tubes, and pipettes all arrived last week. I will make the first dry run next week and send samples to John every six to eight weeks for him to run. I really enjoyed my visit because his experiments are so interesting and it is a rare pleasure these days to be able to give my gray matter a really good workout. To top it all off, he has a delightful family with two great kids. What more could one want?

The immediately past week has been an exhausting one. I spent the entire week, from early Monday (getting there through a snow storm) until Saturday morning in Boston, getting prepped for and receiving the first cycle of AZD1152 "chemotherapy". I put that in quotes, because AZD1252 is one of a new class of drugs that is quite different from the classic anti-cancer drugs, both in mechanism of action and in the image of side effects that the term chemotherapy evokes. AZD1152 works not by arresting cell division but by inhibiting the kinase responsible for arranging the chromosomes in proper alignment. Consequently, the daughter cells are either destroyed by normal p53 at subsequent checkpoints in mitosis or, in the absence (or inactivity) of p53 will be destroyed upon initiating the next cycle of division (because of their polyploidy). Experiments have demonstrated that the effect is much greater on cancer cells than on normal cells that also divide rapidly (mucosal, gut lining, and hair follicle cells) but the reason for this delightful effect are unclear. Details below.

On Monday lab tests (which were normal) and another PET scan that demonstrated some increase in the size of the liver tumors and the lymph node in my chest, as well as a new, small, lesion in my sacrum (the bone at the base of the spine). Clearly, it is time to try something to slow the progress of the disease.

Tuesday was devoted to installing a port. This was a minor surgical procedure, under sedation (not anesthesia), requiring three small incisions, two in my right shoulder and one in my neck, that runs a line (tube) from a small bulb resident under my skin below my clavicle up to my jugular vein and down into the right atrium of my heart. Now that it is in place, any drugs that I need infused, including the AZD1152, can be injected through my skin into the bulb. The procedure went very smoothly. The PA (physician assistant) who did it told me he usually does four a day. The sedation does leave one woozy and exhausted for the rest of the day so I spent the day in my room except for a sojourn to an excellent Vietnamese Pho restaurant for a very restoring bowl of noodle soup.

Wednesday and Thursday each were 13 hour days (7:00 am to 8:00 pm) in the CRC (Clinical Research Center) starting with EKGs and blood samples, a two hour infusion of the drug through the port, and blood samples every couple of hours for the rest of the day. The CRC nurses are knowledgeable, delightful, helpful, and busy. I got a lot of reading done in the comfortable recliner chair in which I spent my days. Katherine's iPod provided lovely classical background music for my reading. I also had a brief but informative chat with Dr. Shapiro who was on his way to Amsterdam for a meeting on AZD1152.

Friday was a short day in the CRC. One more EKG and a blood draw. The drug company requires that the EKGs be done on their machine which incorporates software that interprets the traces. Unfortunately, the interpreting software leaves something to be desired and kept reporting that I have a right bundle branch block, sometime first and sometimes second degree. Of course, I have no such thing, which had to be confirmed by a hospital EKG machine which requires different pads glued to me. I am reasonably sure that the problem is my normal bradycardia (slow heart rate) which confused the software's interpretation algorithm. Unfortunately for me – I wanted to go home – I had to stay over until Saturday for one last blood sample. Then I could dash to the airport and arrived back on island at 11:40.

Yesterday (Wednesday) I went back to Boston for a blood draw and a 'how are you feeling'. The chemistry came back disgustingly normal, including the white cell count which is the real issue (leukopenia is a known possible side effect which I happy to avoid).

Since this is a rumination, I feel free to discourse at random.  I have been looking for an opportunity to bring some stray thoughts in, but it has not presented itself.  Since I think it is important, I'll stick it in here. As most of you know, I am, and always have been, the opposite of a hypochondriac (hyperchondriac does not sound right and the spell checker doesn't recognize it). None the less, I find myself considering (worrying is too strong a word, at least so far) whether every twinge or ache, which I most certainly have cheerfully ignored in the past, may not be symptomatic of a new or enlarged lesion. So far, it has never been, but I cannot prevent the thought from crossing my mind. I would not be surprised that to a greater or lesser degree it happens to everyone in my situation. It is probably just egotism (or a better understanding of pathophysiology), but I feel that I panic far less than most people in my situation. I can notice the reaction in me, but (so far) I can brush it off within a couple of minutes with the help of a few deep breaths and a little objective analysis.

While on the subject of stray ruminations, although the realization did not hit me until several days later, having the port in place is amazingly reassuring and calming,. As I told one of the nurses in the CRC, having the port in was nearly as good as moving to Oregon. With a port, the problems with potassium induced pain that brought on the execution by lethal injection cases now before the Supreme Court go away, because it is potassium in the peripheral veins that cause the excruciating pain; directly to the heart avoids the issue. An air embolism would do as well as potassium. Even though I knew of the Oregon studies that demonstrated that the suicide rate in Oregon among terminal patients decreased after the passage of the Death with Dignity law (http://egov.oregon.gov/DHS/ph/pas/docs/year8.pdf), it was amazing to me how reassuring and anxiety relieving it is to know that, de facto, I retain control of my life. I am confident that I will actually live longer knowing that I have control. It avoids (as they have found in Oregon) seeking to terminate life sooner for fear of not having the control when it is ultimately needed. You have to be there to appreciate it. So, please, I ask you, dear reader, for your own sake when you get to that point in your life, make every effort to pass a Death with Dignity law in your own state now, before it is too late for you. (End of sermon.)

What follows deals with the details of AZD1152. Readers uninterested in scientific esoterica, can stop reading here.

AZD1152 is a small molecule (relative to the size of proteins and other biologic molecules) that suppresses the activity of aurora B kinase. A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them (phosphorylation). Phosphorylation usually results in a functional change of the target protein.Two aurora kinases, A and B, control two critical stages of cell division (mitosis): Aurora A is essential for the assembly of the spindles and centromere maturation and separation; aurora B is active for chromosome alignment, segregation, and movement as they separate. [See V. M. Bolanos-Garcia. Aurora kinases, Int. J. Biochem & Cell Biol. 37: 1572 (2005) and M. Carmena & W. Earnshaw. The Cellular Geography of Aurora Kinases, Nature Rev., Molec. Cell. Biol. 4: 842 (2003).]

Because errors in mitosis provide a source of genetic instability that is typically associated with tumorigenesis, and aurora A has been identified as a bona vide oncogene, and aurora kinases are over expressed in a number of tumors,  aurora kinase inhibition make an interesting target for anticancer therapy. [See N. Keen & S. Taylor. Aurora-kinase Inhibitors as Anticancer Agents, Nature Rev. Cancer 4: 927 (2004) and R. Carvajal et al. Aurora Kinases: New Targets for Cancer Therapy, Clin. Cancer Res. 12:6869 (2006).] The paper by Keen is exceptionally lucid and well written.

The specifics of AZD1152 pharmacodynamics is described by Wilinson et al. AZD1152, A Selective Inhibitor of Aurora B Kinase, Inhibits Human Tumor Xenografts Groeth By Inducing Apoptosis, Clin. Cancer res. 13:3682 (2007); by Evans et al. The Selective Aurora B Kinase Inhibitor AZD1152 Is A Potential new Treatment for Multiple Myeloma, Brit. J. of Haematology doi:10.1111/j. 1365-2141 2007.06913.x (11 Sept. 2007); and by Yang et al. AZD1152, A Novel And Selective Aurora B Inhibitor, Induces Growth Arrest, Apoptosis, and Sensitization For Tubulin Depolymerizing Agent Or Topoisomerase II Inhibitor In Human Acute Leukemia Cells in vivo And in vitro, Blood 110: 2034 (2007)].

A reference that Dr. Artemis Simopoulos sent to me [Xia et al. Melanoma Growth is Reduced in Fat-1 Transgenic Mice: Impact of Omega-6/Omega-3 essential Fatty Acids, PNAS 103:12499 (15 Aug 2006).] made me decide that increasing my omega-3 intake may help and cannot hurt. From the abstract:

"The results showed a dramatic reduction of melanoma formation and growth in fat-1 transgenic mice. The level of n-3 fatty acids and their metabolite prostaglandin E3 (PGE3) were much higher (but the n-6_n-3 ratio is much lower) in the tumor and surrounding tissues of fat-1 mice than that of WT animals. The phosphatase and tensin homologue deleted on the chromosome 10 (PTEN) gene was significantly up-regulated in the fat-1 mice. In vitro experiments showed that addition of the n-3 fatty acid eicosapentaenoic acid or PGE3 inhibited the growth of B16 cell line and increased the expression of PTEN, which could be partially attenuated by inhibition of PGE3 production, suggesting that PGE3 may act as an antitumor mediator. These data demonstrate an anticancer (antimelanoma) effect of n-3 fatty acids through, at least in part, activation of PTEN pathway mediated by PGE3."

Two interesting articles hot off the press:

Schatton et al. Identification of Cells Initiating Human Melanomas, Nature 451: 345 (17 Jan 2008) describes the greater specific tumorigenic capacity of ABCB5 positive cells compared to ABCB5 negative cells. While they do not classify these cells as stem-cells, the theory that there is a subpopulation of malignant cells that solely have the ability to metastasize has received a significant boost.

Bundscherer et al. Antiproliferative and Proapototic Effects of Rapamycin and Celecoxib in Malignant Melanoma Cell Lines. Oncology Reports 19: 547 (2008). According to this paper, celecoxib's action is independent of COX2 expression by the tumor and nor does it induce cell cycle arrest. Consequently, it would appear that it does not interfere with the action of AZD1152. This makes me give serious consideration to increasing my celecoxib (Celebrex) intake.