For the vast majority of patients, a diagnosis of cancer triggers fundamentally the same course of therapy as it has for the past 40 to 50 years: surgery (when possible), followed by treatment with noxious chemotherapeutic agents. Certainly, there has been steady improvement in the effectiveness of these therapies and accordingly in the prognoses associated with many cancers. Yet all too often cancer remains a death sentence, forewarning patients to brace for a course of therapy that can be both profoundly difficult and profoundly ineffective in the long term.
The dire situation in the clinic contrasts starkly with the spectacular advances made in the laboratory over the same 50-year period. Geneticists, cell biologists, biochemists, immunologists, and molecular biologists have provided a treasure trove of information concerning the origins of cancer, the signaling pathways responsible for the growth and maintenance of cancer cells, and the body’s response (and lack of response) to tumors. But most of these conceptual insights have not provided the type of breakthroughs in cancer care that scientists and society at large so deeply crave. Why?
The reasons are complex, with the first being that cancer itself is complex. It is not a single disorder; and even within a specific type or subtype of cancer, there is incredible individual and even cell-to-cell variation. Cancer cells are capable of microevolution on a rapid scale, with adaptation to chemotherapeutics being driven by both genetic and epigenetic mechanisms.
Second, except in those relatively rare cases in which a cancer is driven by a specific mutation, multiple changes in gene expression and cell biology conspire to endow tumors to live as a coherent community of unwanted residents within the larger community of normal tissues and organs. As a result, it is extremely unlikely that any single drug or drug target ever will be a fully effective approach to therapy.
Third (and this is by no means a complete list), but arguably most important, it is exceedingly difficult to study cancer in the only organism that really matters: the human cancer patient. The extraordinary insights we have achieved come predominantly from the study of worms, flies, and mice. The identification of mutations and other genetic abnormalities leading to cancer has, of course, been accomplished by brilliant studies of human populations, but these have provided information that is largely descriptive and correlative: It is difficult to test the hypotheses and complex predictions set up by these observations.
I mention all this not for the sake of instilling a sense of despair — far from it. In fact, we find ourselves at a time of exceptional change in our understanding of cancer in humans. Biotech and biopharma companies now are beginning to generate a completely new set of agents that fall into the broad category of “targeted therapies,” the existence of which is owed to decades of work understanding cancer mechanisms. While conventional chemotherapeutics represent broad spectrum anti-mitotics or cytotoxics (which kill normal cells almost as effectively as cancer cells), targeted therapies address features far more selective to cancer cells. Sometimes, these can be mutant or normal gene products made only in certain cancers, but more frequently, they are proteins or pathways on which cancer cells rely far more heavily than normal cells. Several of these are already in the clinic, some already approved for use. Their effectiveness may appear modest at times, but in general, targeted therapies seem to have a far higher therapeutic index, i.e., they exert their benefit without as many off-target side effects.
The advent of targeted agents is not the end of the story, however. Monotherapy seems less and less likely to comprise an effective approach to cancer. As a result, we need to understand how the new targeted agents should be combined and administered, which brings us back to the primacy of the research enterprise. We need to devote time, attention, resources, and rewards to the study of human cancer in human patients. What happens at the cellular level when we inhibit PI-3-kinase in conjunction with blocking angiogenesis in ovarian cancer? Might it have been better to inhibit Akt in conjunction with PARP? Or to deliver a potent cytotoxic drug conjugated to an antibody vehicle that selectively targets the cancer cells? Such questions are easy to pose but difficult to answer. Assays like “progression-free survival” or “tumor shrinkage” are crude, slow, and not very helpful for elucidating the mechanisms underlying a given treatment regimen. What we need are biochemical and functional tools to assay the effects of our attempts to treat patients, in real time and with minimally invasive methods. Such data will greatly enhance our efforts to understand the fundamental cell biology and development of cancer in the only organism where it really matters. It is from this information that, in my view, the true breakthroughs in cancer therapy will emerge.
This is our challenge. It is a grand and an exciting one, not only scientifically but also because of the extraordinary benefit to society that will come from our eventual success.