By Dario C. Altieri, MD
Professor and Chair of Cancer Biology, University of Massachusetts Medical School
Director, UMass Memorial Cancer Center
December 2003
With the opening of the Research Corner, we would like to provide a forum for brief and timely updates on new research breakthroughs in pancreatic cancer.
The idea is to offer a lay perspective on new discoveries, new findings and new conceptual openings relevant to the understanding and the potential treatment of the disease. We will focus on experimental studies that have appeared in the most thoroughly scrutinized, authoritative scientific literature, and we will try to distill their significance, analyze their impact on our understanding of the disease and anticipate how they may or will change potential new treatment options in the near future.
At times, the Research Corner will discuss studies that do not immediately deal with pancreatic cancer but have the likelihood of being of general significance and impact for this disease.
Although this is not a chat room, we hope that the information provided will be of help to disseminate our expanding knowledge of how pancreatic cancer originates, progresses and may be hopefully cured in the future.
Determining how a tumor arises and identifying what makes it grow are obviously key questions in experimental oncology. The hope is to identify the "Achilles' heel" of that particular tumor so that with this knowledge in hand, it may be possible to tailor new "smart drugs" that target the weak point and eliminate the cancer cells without damaging the normal tissues.
For pancreatic cancer, identifying what makes the cancer grow has proven frustratingly elusive. Now, two research papers published back-to-back in the British journal Nature may provide some unambiguous clues of potential great importance (Berman et al. Nature 425:846, 2003; Thayer et al., Nature 425:851, 2003).
The main conclusion of the two papers is that pancreatic cancer, or at least a large proportion of it, originates from activation of a single signaling pathway, dubbed, somewhat creatively, Hedgehog. Not only activation of the Hedgehog signals was invariably found in specimens isolated from pancreatic cancer patients, but was also required to maintain the growth of the tumor in vitro or in laboratory animals, in vivo. Moreover, an inhibitor of Hedgehog signaling that had been known for a while to researchers interested in mechanisms of embryogenesis and development, resulted in strong anti-cancer activity, at least in some of the pancreatic cancer cell types examined.
But what is Hedgehog signaling, and why is this important for pancreatic cancer?
Hedgehog signaling takes its name from a family of genes that were originally found in the fly. For many years, researchers have used the fly as a relatively simple model to find out how genes work and, among other things, how modifications in their function can generate cancer cells. Differently from more complex organisms like humans or even laboratory animals, flies can be quickly and relatively simply manipulated in their genetic content so that the function of specific genes can be tested in relatively clear-cut "loss of function" studies. In the fly, Hedgehog signaling proved essential to determine the fate of important cells during development, and to specify a sort of blueprint that ensures proper development of the embryo.
As it often happens, it turns out that Hedgehog signaling is also conserved and utilized in human cells, and potentially very important for a class of cells that are important in sculpting our organs during development but also throughout adult life. These cells are the so-called "stem cells" that have recently attracted so much attention for their ability to self-renew, and to provide potential new therapeutic prospects for various human diseases. It was also known that abnormally elevated Hedgehog signaling was found in some types of human cancers, including pancreatic cancer. However, what was unclear was whether this finding was a passenger (an occasional abnormality in profoundly deranged tumor cells) or a driver (a key signal required for tumor formation) in the onset of the tumor.
At the very least, the two papers in Nature provide a conclusive answer on this matter. Hedgehog signaling is a driver of pancreatic cancer in humans, and in some cases (approximately half of the tumor cell types examined) it seems to be the only driver. Understanding how Hedgehog activation drives the disease will clearly require further studies, but it is likely to involve both increased proliferation and enhanced survival of pancreatic cancer cells. And, importantly, the diseased cells retain their need for this stimulus even in the advanced stages of the cancer.
In trying to understand how tumors work, we are constantly confronted with the extraordinary complexity of tumor cells: cells that in most cases carry a plethora of genetic modifications affecting many signaling pathways. In addition to the conceptual complexity, this makes finding that "Achilles' heel" the more difficult to identify and exploit.
Now, somewhat as a surprise, pancreatic cancer, or at least some types of pancreatic cancers, join the restricted group of tumors that are driven by a single genetic modification, in this case Hedgehog signaling. This does not make the disease any less dreadful. But it makes it suitable to therapeutic intervention with the aim of dismantling the driver and killing the tumor.
Cyclopamine, the Hedgehog inhibitor that blocked pancreatic cancer growth in one of the two studies published in Nature is far too toxic to be a drug in humans. But its anti-tumor effects are relevant because they prove the principle. The hope is that these results may pave the way for the design and creation of better, more effective and less toxic antagonists of Hedgehog signaling, suitable for testing in cancer patients.
How far are we from that point? Probably far, but it's gratifying to see already emerging a host of potential antagonists of Hedgehog signaling to target what seems to be a central "Achilles' heel" of pancreatic cancer.
December 2003
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