Rumination 19 Waiting for Godot

By

Thomas P. Vogl

December 12, 2008

My scans three days ago showed that I was ‘stable’. That is, some tumors grew, some decreased in size or metabolic activity. The current experimental therapy that I am on (SCH727965, a Cdk inhibitor) will continue. Since I only have to go to Boston every three weeks for eight hours of infusion, and my body has become acclimated to the drug to the point where I am only uncomfortable for about 12 hours after the infusion, the current regimen exceeds my ground rule that any therapy may interfere with my life no more than 10% of my time. Getting scanned every six weeks (which takes me to Boston for an extra day – not a serious imposition) does not bother me until about two days prior, when I really want to see the radiology report now, not in three days. Unrealistic, but true. I would be remiss in failing to mention that occasional brief periods of free-floating anxiety are, not surprisingly, inevitable.

Why, then, the title of this Rumination? Because being stable is perpetually waiting for the other shoe to drop. I am also waiting to hear the results (in several weeks) of the genetic analysis of my tumor, an analysis that I give a ten percent chance of providing therapeutically relevant information. An finally, waiting for the for the breakthrough in understanding cancer as described below.

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I admit to getting older, and in six months, when I reach my 80th birthday, I will admit to actually being old; until then, I am still middle aged. You may have observed that old people like to reminisce. I have noticed in me a tendency to do likewise. Now that I do reminisce occasionally, I realize that the reason for doing so is quite different from what I had imagined it to be. I have discovered that the reason is that the perceptions of younger people about current events and their relation to historical events about which they have only read or heard about, are very different from the perceptions of those who have lived through those 'historical' events, such as WWII.

Why do I bring this up? Because scientists have the same problem in relating current events to similar historical situations, that may not be perceived as similar by those who have not lived through them. In the early 1950's, as a young scientist, I was aware of, but not personally involved in, the exciting and mystifying research coming out of the 'atom smashing' experiments being conducted on the then novel cyclotrons. Not a week would pass without another paper describing a huge variety of 'hadrons' each with a different energy. The theoreticians were busily engaged in cataloging and numerology trying to discern a pattern in these energy levels. This proliferation of particles prompted Wolfgang Pauli to remark: "Had I foreseen this, I would have gone into botany". It took eight more years until 1961, with the introduction of the quark model, that the mess of particles began to be straightened out, eventually leading to what is now called the standard model in the 1970's.

The graybeards of the time reminisced about the 1880s and 90's when, shortly after the discovery of absorption lines in the solar spectrum, emission spectroscopy produced reams of data about the spectral lines emitted by heated elements and the theoreticians all did numerology on the wavelengths and intensities of all the lines. This continued until 1900 when Max Plank proposed quantization, leading to quantum theory that offered a sound theoretical model/explanation, and all the spectroscopic lines and their interrelationships fell into place.

Despite the overwhelming similarities between the situation in the 1890's and 1950's, very few young physicists in the 1950’s believed that it would take a novel theory to resolve the problem nor that it would take close to 20 years. They had not lived, as physicists, through the 1890's.

As a graybeard, I submit that the situation in cancer research is history repeating itself. Not a week passes by that there is not at least one paper published that details half a dozen or more novel genes associated with this cancer or that disease*. Shades of the 1950's! Cataloging genes, and the associated numerology, is no more going give us fundamental insight into cancer that it did to spectral lines or hadrons. Now, as then, most active researches do not believe a new theory will be needed. I am willing to bet they are wrong; been there, done that, which is very different from reading about it in history books.

That said, I hasten to add that cataloging and numerology may produce clinically important results without necessarily shedding any light on theoretical approaches. A shining and exciting example of just this sort of fruitful analysis is a paper by K. S. Garman, et al., A Genomic Approach to Colon Cancer Risk Stratification Yields Biologic Insights Into Therapeutic Opportunity [PNAS 105: 19431-36 (December 8, 2008)]. The title does not do justice to their accomplishment. They used a Bayesian binary regression to develop a 50 gene signature that effectively distinguishes between early stage, cleanly resected, colon cancer patients with low and with high risk of disease re-occurrence. The model was successfully tested on two independent cohorts of patients (two different cohorts from the patients used to develop the model). In the process they also show that Cox-2 inhibition and PI3Kinase inhibition may well be more effective that the currently standard chemotherapy with 5-fluorouracil and oxaliplatin.

There are significant grounds for long-term optimism. I am cheered by the comment by W. D. Faulkes, in 'Inherited Susceptibility to Common Cancers’, NEJM 395:2143 (November 13, 2008) page 2150, that:

The identification of high-risk cancer susceptibility genes means that physicians and persons at risk must understand the implications of the risk

of genetic cancer; this identification has resulted in the blossoming of cancer genetics as a clinical subspecialty. Genetic counselors and other health specialists with expertise in cancer risk assessment are qualified to offer the kinds of services needed by persons with or at risk for hereditary

cancer.

Genetic testing for the highly penetrant genes listed in Table 1 is widely available (see www.genetests.org for a list of testing laboratories. Despite the apparent simplicity of the genetic tests themselves, interpretation, particularly of unclassified variants, can be much more difficult. Such complexities, including genetic sites of low impact or genetic variants of unknown significance, warrant appropriate pretest and post-test counseling for persons who undergo genetic testing. (Emphasis added by me.)

I predict that the much needed novel theoretical understanding of cancer will come out of the clinical sub-specialty of cancer genetics that studies cancer commonalities across organ systems.

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* A single day’s catch from Medical Research News, 8 December 2008:

Scientists find 12 new genes with potential as drug targets
http://www.news-medical.net/?id=43866
Scientists have identified 12 new genes that are somewhat strange bedfellows: Some link gallstones and blood cholesterol levels, others link melatonin and sleep patterns to small increases in glucose levels and larger jumps in the risk of diabetes.

Discovery of 11 new gene sites that influence cholesterol or triglyceride levels
http://www.news-medical.net/?id=43882
An international research team has identified 11 novel locations in the human genome where common variations appear to influence cholesterol or triglyceride levels, bringing the total number of lipid-associated genes to 30.

Discovery of six novel genetic variants associated with lipid levels
http://www.news-medical.net/?id=43884
A new study presages a real aim of genetics: to look at whole populations to in order determine the significance of individual genetic variants for individual health.

Discovery of gene that protects against lung cancer
http://www.news-medical.net/?id=43667
A study led by researchers at The University of Nottingham has identified a gene that protects the body from lung cancer.