For more than two decades, Scott Lowe has been exploring the genetic changes that sustain cancer cells. Mutations found in human tumors can hint at the cellular pathways that normally keep cancer in check, but the disease is complex: its…
For more than two decades, Scott Lowe has been exploring the genetic changes that sustain cancer cells. Mutations found in human tumors can hint at the cellular pathways that normally keep cancer in check, but the disease is complex: its cells migrate and evolve, and genetic alterations that are crucial in one context may have little effect in another. Lowe's goal is to turn genetic data into knowledge that can point the way toward new therapeutic approaches. Lowe has focused largely on the role of p53, the gene that is altered in human cancer cells more frequently than any other. The p53 protein provides crucial oversight to growing cells: stalling cell division or triggering a type of cell death known as apoptosis in times of stress, ensuring damaged cells do not pass genetic defects on to future generations of cells. Defects in p53 remove these restraints, increasing the likelihood of tumor formation. Lowe began investigating p53 as a graduate student at the Massachusetts Institute of Technology. His early studies revealed how p53 triggers cell death in response to DNA damage and how mutations in the gene can affect a tumor's response to treatment. At Cold Spring Harbor Laboratory, where he set up his own lab in 1995, Lowe developed several research tools that have accelerated the pace of discovery in his own lab and in others. “We know that cancer is way too complicated to study one gene at a time anymore,” he says. He collaborated with colleagues Gregory Hannon and Stephen Elledge to produce small RNA molecules that can selectively shut off any gene in mammalian cells. They have shared their tools widely and used them to identify genetic alterations that cancer cells depend on for growth and survival. Lowe and Hannon have also worked together to develop mouse models in which genes can be shut off and later switched back on, allowing researchers to examine gene function during specific windows of an animal or tumor's development, and as well as to rapidly test the effects of inhibiting different combinations of genes. The tools have helped Lowe's lab shed light on p53's role in both apoptosis and the growth arrest known as senescence, as well as reveal some surprising new functions. Lowe found that the p53 produced by a cell not only prevents that cell from becoming cancerous, but can also stave off tumor development in neighboring cells of different types. His team also found that p53 helps cells maintain their identity: shutting off p53 in liver cells allows the cells to revert to a less specialized cell type that gives rise to both liver tumor and bile duct tumors. Lowe remains dedicated to understanding p53's profound influence, but his team is also using the tools they developed to identify and study other tumor suppressors. They've found that reactivating a tumor suppressor called APC eliminates colorectal tumors, suggesting that drugs targeting APC-regulated pathways might make effective treatments for that cancer. They also discovered that inactivation of a protein called PTEN makes leukemia cells more likely to spread through the body. They then showed that turning PTEN back on kills cancer cells that have disseminated to new organs, but not those that remain in the spleen or bone marrow. These studies are part of a growing emphasis in Lowe's lab on identifying vulnerabilities in cancer cells that might be targeted with new therapies. “We've done years of work trying to develop really robust genetic tools to characterize dependencies that are required to sustain cancers,” he says, crediting oncologists who worked in his Cold Spring Harbor lab with helping him aim those tools at clinically relevant questions. One success, he says, was work he did with Chris Vakoc showing that suppressing a protein called Brd4 has potent anticancer effects in acute myeloid leukemia. Drugs that target Brd4 are now being evaluated in clinical trials. In 2011, Lowe moved his lab to the Memorial Sloan-Kettering Cancer Center, where clinical colleagues and resources are invigorating the clinically focused aspects of his research program. One finding that Lowe is excited about is the discovery that defective p53 spurs metastasis of pancreatic cancer by triggering overproduction of a signaling molecule called PDGFRb. In mice, metastasis can be preventing by blocking PDGFRb signaling. Patients who are diagnosed with pancreatic cancer before it metastasizes might benefit from drugs that block PDGFRb, Lowe says, adding that PDGFRb is a target of the FDA-approved drug Gleevec. With hundreds of different cancer-associated genes and a variety of circumstances shifting the effects of those genes, Lowe's quest for understanding requires creativity and persistence. Ultimately, he says, his team aims to support personalized medicine by identifying not just potential drug targets, but also the contexts and combinations in which they are most important.