Tumor Ecology, Not Tumor Biology

During the first years of this millennium as the newly discovered field of anti-angiogenesis was reaching a fevered pitch, I had the opportunity to attend an AACR Special Symposium, held at Whistler Resort in British Columbia. While there I attended a symposium by Dr. Rakesh Jain. Dr. Jain a long-time colleague of Judah Folkman, MD,  at Harvard University presented his observations on tumor vascularity and its implications for therapy. Despite the prevailing belief that tumor angiogenesis was a linear phenomenon, from cessation of blood supply – and thereby nutrients and oxygen – to the death of cancer, Dr. Jain provided compelling evidence to the contrary.

Every so often I read an article, hear a lecture, or attend a symposium that changes the way I think. Dr. Jain’s presentation that year was just that type of lecture. In the span of an hour he described the dynamics of blood flow through the network of disorganized tumor blood vessels. He showed that anti-angiogenic factors actually “pruned” the blood supply and returned normal flow. He went on to point out that most of the experiments being reported at that time by other investigators had short windows of observation during which the effects of Bevacizumab could be captured, photomicrographed and published to great acclaim in the most prestigious journals. But there was a fly in the ointment. Bevacizumab by itself had a miniscule response rate. Indeed, in the absence of chemotherapy, it was single digits.

Jain, an engineer by training, developed a novel tissue “window” method that enabled him to explore the temporal sequence of cellular response to VEGF therapy. He found that it all wasn’t as simple or tidy as it had seemed. The short-term control of vasculature was followed by revascularization. Cells deprived of oxygen and nutrients devolved into more stem cell-like phenotypes. Therapies based on an incomplete understanding of angiogenesis might, in his opinion, be adding to the problem.

As the years have gone on I’ve carried the insights from that lecture with me. At a subsequent AACR presentation by Napoleon Ferrara, PhD, many years later, Dr. Ferrara, who developed Bevacizumab, reminded his audience that VEGF was originally known as VPF (vascular permeability factor). Perhaps this aspect of the VEGF effects were responsible for its minimal single agent activity, yet profound combinatorial effect.

With this as a backdrop, I sat among 15,000 medical oncologists at the plenary session lecture where Dr Jain presented his work and I delighted in the possibility (however slight) that his message of experimental analysis and systems biology would sink in.

Cancer is not a cell, it is a system. Tumor cells are but a small portion of the process. Carcinogenesis may represent a response to cellular stress, some of which, we as “therapists” may inflict. The indiscriminate use of cytotoxic agents and antivascular drugs may, in some circumstances, be more harmful than helpful to our patients.

What is the appropriate dose of Bevacizumab? How should it be given? In what sequence with radiation or chemotherapy? With what drugs or targeted agents? Are low doses better than high doses? Is the effect of VGEF inhibition a driver of response or an epiphenomenon? What about the fibroblast matrix, lymphatic vessels, infiltrating monocytes, T-cells, B-cells and neutrophils? Dr. Jain elegantly outlined the complexities of the human tumor microenvironment.

It was with more than a small amount of satisfaction, that I realized how quite correct our approach to this disease has been over the years. It is not just the cancer cell that is important, but the tumor as a whole. Cancer cells are just part of the problem. Using native state microspheroids replete with vasculature, cytokines, stromal elements and tumor cells; we feel that we are now poised to advance the growing use of effective targeted therapies in ever-expanding ways.