Humans evolved around their food supply. The foods we eat, the herbs we consume, our sources of nutrition, indeed everything that makes it possible for us to meet our caloric needs can be traced through evolution. A new study examining the enzyme amylase has now traced the origin of this carbohydrate metabolizing enzyme through 47 different species. Amylase, critical for the digestion of carbohydrates, hydrolyzes starch into sugars. It is found in the pancreas and in some species in the saliva. The authors examined duplication of the amylase gene which allows for multiple copies to produce more of the enzyme, allowing carbohydrates to be consumed in the diet and shows how evolution drives adaptation. Species that live in close proximity to humans develop higher levels of amylase.
In fact, wild dogs have virtually no amylase, while domesticated species have high quantities of amylase in their saliva. Thus, adaptation to the human diet through table scraps drove the production of amylase. Monkeys that store food in their cheeks have large quantities of amylase, while mountain lions have none. But what has this got to do with cancer?
Possibly quite a lot. Investigators in the UK have begun to apply evolutionary principles to cancer therapy. Under Dr. Charles Swanton the clinical trial TRACERx (Tracking Cancer Evolution through Therapy) is using liquid biopsies to examine how cancer cells evolve and become resistant to therapy. The similarity between the amylase study and cancer are interesting. For one, amylase levels reflect a specific environmental pressure that provides an advantage to species with higher levels. Secondly, the evolutionary process is relatively rapid, as the domestication of dogs and the infestation of rats and mice in the human environment is historically comparatively recent. Thirdly, the adaptation is not driven by mutations, per se, but instead up-regulation of an existing normal gene. If we consider cancer adaptation to the stressors that we call therapy, we can imagine that the process of evolution is accelerated as cells divide and live comparatively short periods of time compared to dogs and humans that proliferate comparatively slowly and live a rather long time. By condensing evolutionary adaptation, cancers can outdo our best therapies quickly. In oncology, patients who show brilliant responses to initial therapy, breast cancer to estrogen withdrawal or prostate cancer to androgen deprivation, generally become resistant within two or three years as selective pressures lead to an outgrowth of resistant clones. What are the lessons?
Among them is the growing thought that cancer therapy should not be continuous but instead episodic or intermittent. This may offer the opportunity to avoid selective pressures.
This approach has been utilized successfully in prostate cancer and may apply in other diseases. Unfortunately, most oncologists are afraid to find out, as removing therapy could result in progression even death. At least that is a very real fear. Where the principle has been applied, however, it has shown some early signs of success. Among them is the use of chemotherapy in diseases like small cell cancer and even non-small cell cancer of the lung for defined periods of time with cessation or low-dose maintenance as the subsequent treatment. One widely used approach in colon cancer is dubbed OPTIMOX which stops patient treatments after FOLFOX and observes them until recurrence, only then reinstating treatments. Survivals have been similar with improved tolerance for those patients who stop active treatment. There are several questions that remain unanswered. For the amylase study, did amylase arise first and animals then seek starch or did the accessibility of starch render the expression of amylase an evolutionary advantage? Similarly, for those patients with relatively indolent cancers, does the introduction of therapy, particularly mutagenic chemotherapy set in motion the very process of resistance that we seek to avoid? The field of evolutionary biology will provide extraordinary insights into cancer once we begin to apply its principles. Scientists around the world are beginning to take new looks at the way we think about and treat cancer. It will be refreshing to get the input of physicists, mathematicians, and biochemists in a field that has been uniformly managed by genomic scientists. The future could be bright, maybe even sweet, as we move in these new directions.