Fast-forward 10, maybe 20 years. A pathologist receives a patient sample. What does she do? Perhaps first, she runs a complete cancer genome and transcriptome on the tissue. Then she drops the codes into a supercomputer, reverse engineers the signaling pathways, and simulates the effects of different drugs to see which are most beneficial. According to Mark Boguski, HMS associate professor of pathology at Beth Israel Deaconess Medical Center and a research associate at the HMS Center for Biomedical Informatics, “This is personalized cancer medicine circa 2020.”
Boguski painted this picture, one based on the idea that the experimental platform of the future will be in silico models rather than animal models, at the first annual Beth Israel Deaconess Medical Center Cancer Symposium, titled “Defining New Frontiers to Eradicate Cancer.” Sponsored by the center, the symposium drew speakers from around the world for a three-day collaborative conversation about cutting-edge research.
The spirit of the conference meshed well with HMS goals, according to HMS dean Jeffrey Flier in his opening remarks. “There is still some competition between the hospitals,” he said, “but one goal is to make some of those competitive factors diminish and to support the science and the welfare of our patients through collaboration.”
The dialogue began on Oct. 22 with a keynote address from Nobel laureate Phillip Sharp, Institute Professor at MIT. Sharp launched a discussion of targeted cancer therapy beyond the kinome by zooming in on the role of microRNAs in cancer. MicroRNAs, single strands of RNA transcribed from genomic DNA, downregulate gene expression. “Over half of all messages are regulated by microRNAs,” said Sharp.
Normally, microRNAs suppress growth and proliferation of cells, especially quiescent tissue-building cells. When microRNA regulation does not function properly, these cells may begin cancerous growth and proliferation. Sharp cited studies of small-cell lung cancer and prostate cancer as evidence. “MicroRNAs are part of the picture of the development of cancer,” he said, suggesting that it may be possible to restore regulation by targeting microRNA binding sites.
Daniel Tenen, HMS professor of medicine at BID, followed later in the week with another frontier for targeted therapy. He suggested that lineage-specific transcription factors act as tumor suppressors because they regulate two aspects of cell differentiation: they suppress proliferation and induce differentiation. “Transcription factors that induce differentiation are important in cancer,” he said. “If you don’t control proliferation, the cell may go on to produce tumors.”
Some existing drugs already target transcription factors, but more work needs to be done to understand how transcription factor pathways are disrupted in cancer and to develop drugs that target these pathways, said Tenen. “This work emphasizes the idea that in the future we should be thinking about pathways in cancer, not just tissue type.”
In addition to searching for ways to end cancer, several speakers presented their research into how cancer begins. “Cancer occurs in a series of steps,” said Craig Thompson, professor of medicine at the University of Pennsylvania. “The question has always been, which one is first?”
Thompson presented a hypothesis that “mutations in the fuel-signaling pathway”—which regulates energy intake and storage—“induce cancer because they give a cell a way to survive and mutagenize.” Cells with a single oncogene tend to die, he said, but a cell with a single metabolic mutation may survive with a glut of energy. That excess energy can produce metabolites that alter the cell’s signaling in a way that may increase the rate of DNA mutations. The work points to possible new therapies that target cell metabolism.
Raghu Kalluri, HMS professor of medicine at BID, looks at tumor genesis slightly differently by distinguishing tumors from cancer. He noted that 35 percent of people over 40 years of age have dormant tumors, only a fraction of which progress into cancer. “Most people ask: How does cancer progress into a lethal disease?” said Kalluri. “My question is: Why does cancer not progress to a lethal stage in most people?” Kalluri’s work suggests that the microenvironment of a tumor—the immune system, surrounding cells and their secretions, and even microbes—has an influence over the progression of these tumors.
On the technology front, Todd Golub, HMS associate professor of pediatrics at the Dana–Farber Cancer Institute, presented a novel method for doing gene-expression profiling of formalin-fixed, paraffin-embedded tissue samples, the routine means of tissue collection in clinical settings outside of major research hospitals. Until now, profiling only worked on frozen tissue samples. The new method led him to discover a gene expression signature in liver tissue adjacent to tumors that predicts patient survival and cancer recurrence.
Another new tool, a microfluidic chip that sorts and captures circulating tumor cells (CTCs) that have escaped into the bloodstream, was presented by Daniel Haber, the Kurt J. Isselbacher/Peter D. Schwartz professor of medicine and director of the Cancer Center at Massachusetts General Hospital. To use the tool, researchers flow a few milliliters of blood through the device. The chip captures tumor cells in a network of microscopic posts coated with antibodies. The cells are then stained and counted and can be analyzed at the molecular level.
The noninvasive tool may someday provide early cancer diagnosis and help monitor disease progression. It may also identify molecular markers that guide therapy.
In addition to new targets, new triggers, and new technologies, cancer researchers are also investigating new ways to translate cancer research to the clinic. Pier Paolo Pandolfi, HMS professor of medicine at BID, described a methodology called the “coclinical trial” in which both humans and mouse models of human cancer undergo the same clinical trial simultaneously. Mice add information that can be used to improve drug testing, singly or in combination, or to identify candidate patients.
The talks, together, reinforce Pandolfi’s opening remarks. “We can cure cancer,” he said. “We are enthusiastic that we can do it, provided we have the right tools and the right approach.”
