Looking Beyond the Academic Walls for Cancer Care

At the recent Society for Integrative Oncology meeting in Cleveland, Ohio, I had the opportunity as an invited lecturer, to sit in on many informative presentations. As I listened to these investigators, who have developed clinical therapy programs combining traditional chemotherapies with dietary, lifestyle and herbal remedies, I felt a sense of shared frustration. Here, after all, were dedicated therapists using available non-toxic interventions to improve outcomes, yet the major academic centers continue to turn a blind eye to their contributions. Instead they are required to meet stringent research criteria that those within conventional therapy might be unable to meet.

I then realized that cancer patients must step outside the confines of usual and customary referral patterns and treatment programs to obtain the best outcome for themselves. I was favorably impressed by the dedication of the many investigators and feel convinced that the application of natural products, supportive measures, dietary and lifestyle modifications, and the judicious use of chemotherapeutics will indeed lead the way to a better future in oncology.

As I often say to my patients, “No one is more interested in saving your life than you.”

Paradigm Shifts

Scientific dogma in all disciplines is slow to change.

I am again reminded of this by the recent publication of a book by Dava Sobel, “A More Perfect Heaven: How Copernicus Revolutionized the Cosmos” about the life and times of Nicolaus Copernicus. I use the term “dogma” intentionally, for Copernicus lived in the tumultuous times of the Protestant religious movement. Thus, his revolutionary concept of a heliocentric (sun-centered) solar system clashed with both scientific and religious dogmas.

Copernicus himself, a polymath, was a linguist, astronomer and a physician. His original observations in 1514 so conflicted with existing thinking regarding the geocentric solar system, that his treatise on the topic wasn’t published until 1543 – just a year before he died.

Copernicus, Galileo and Giordano Bruno — who himself was burned at the stake in 1600 for having the temerity to suggest that there might be other solar systems in the universe — were all victims of prevailing thinking that would not and could not yield to the burgeoning new understanding contained within Copernicus’s carefully constructed view of the cosmos.

These experiences are instructive, for they shine the light of day upon dogma in contemporary science and medicine. Failed attempts to utilize human tissue for the study of tumor biology led to an entire generation of cancer researchers to erroneously dismiss this profoundly important field of endeavor. No amount of data or cogent scientific argument could dissuade these authorities from their “dogmatic” position that human tissue could not predict cancer response. When one colleague in the field compiled all of the existing data and showed in an analysis that patients who received assay-sensitive drugs responded statistically, significantly more often than those who received assay-resistant drugs (p= 0.00000001) it had absolutely no impact on the “experts” opinions.

Perhaps today, 500 years later, we can learn something from Copernicus and his experience with scientific dogma.

An Ounce of Prevention

Colorectal cancer is among the leading causes of cancer death in the United States. While most patients develop this disease over a period of decades, associated with an accumulation of genetic mutations (elegantly described by Burt Vogelstein, PhD at Johns Hopkins), a small percentage of patients have a genetic predisposition for this cancer. Among these are those people that carry the familial adenomatous polyp syndrome (FAPS) and those who carry mismatch repair mutations know as Lynch syndrome.

It is the latter group who are the subject of a report in the October issue of the English journal Lancet. In this study, known as the CAPP2 trial, patients with Lynch syndrome received either placebo or 600mg of aspirin per day (the equivalent of two tablets). The results reveal a statistically significant reduction of colon cancer that clearly favored the aspirin group.

To put this in perspective, this dramatic improvement in the highest risk population didn’t come about as the result of a new signal transduction inhibitor or a monoclonal antibody. Instead, it came from the simple administration of one of mankind’s earliest medicinal substances. I applaud these English investigators in conducting this study of 861 patients.

What is most laudatory is that the intervention, while highly effective, is so inexpensive. In an era of proprietary medications and the promotion of expensive new interventions, it is indeed refreshing to read the results of a well-conducted study using an intervention available to all.

Data generated more than two decades ago established the benefit of non-steroidal anti-inflammatory drugs like aspirin for the prevention of colorectal cancer. It is gratifying that this simple intervention has additional scientific support both for those with high-risk predisposition, as well as other patients at risk for this relatively common, yet potentially lethal, malignancy.

What Exactly are the Targets of Targeted Therapy?

The term “targeted therapy” has entered common parlance. Like personalized medicine, targeted therapy is a generic description of drugs and combinations that inhibit specific cancer-related pathways. I am impressed by how quickly esoteric phenomena like the downstream signal in the insulin factor pathway have entered the lexicon of medical oncologists. With the advent of temsirolimus and everolimus, both rapamycin derivatives that target mTOR, we now have at our disposal agents that are every bit a part of the therapy repertoire. Unlike erlotinib that targets a specific tyrosine kinase, mTOR is a complex and multifaceted target.

There are actually two separate forms of mTOR, TORC1 and TORC2, and they sit at a critical point in cellular determination. Stimulated by the insulin growth pathway, cells must decide whether they will grow in size or divide. The mTOR proteins participate in this process by regulating protein synthesis and glucose uptake among other functions. In turn, the mTOR pathway is regulated by numerous other factors like AMP kinase and AKT. The current crop of mTOR inhibitors all target TORC1.

New classes of compounds are being developed that inhibit both TORC1 and TORC2. More interesting are the compounds that influence upstream signaling, including phosphoinositol kinase (PI3K) and AKT. What we are coming to learn, however, is that these are not targets but collections of targets. Indeed, the PI3K inhibitors themselves have influence on one, two or all of the distinct classes of phosphoinositol kinases.

Most of the studies to date have used compounds that affect all the classes equally (pan-inhibitors). Pharmaceutical companies are now developing highly selective inhibitors of this fundamental pathway. In addition, duel inhibitors that target both PI3K and mTOR are in clinical trials. What we are coming to realize is the complexity of these pathways. What may prove more vexing still is their redundancy. One well-established by-product of successful inhibition of mTOR (principally TORC1) is the upstream activity of AKT via a feedback loop. This has the undesirable affect of redoubling mTOR stimulation through the very pharmacological manipulation that was designed to inhibit it. Again, an unintended consequence of a well laid plan.

To unravel the complexities and redundancies of these processes, we have utilized the primary culture platform. It enables us to examine the end result of signal inhibition and dissect disease specific profiles. Using this approach we can partner with collaborators to define the specific operative pathways in each disease entity.

Biological complexity is the hallmark of life. We ignore it at our peril.