Profiles in Cancer Research
Dr. Pier Paolo Pandolfi
Director of Research for the Cancer Center
and Director of the Cancer Genetics Program
at Beth Israel Deaconess Medical Center
As an undergraduate student at the University of Rome in the early 1980s, Pier Paolo Pandolfi studied philosophy and appeared to be heading into the family business––his parents were both University professors of literature (French and Russian). Approaching his senior year, however, he suddenly realized that he wanted to be a scientist and transferred to the medical school. “My parents weren’t thrilled, to say the least,” he said, “but at least I was still at the University of Rome.”
At least for a while. But then he left Rome a few years later to finish medical school at the much smaller University of Perugia, in a beautiful town 100 miles away in the countryside. His parents, he joked, “were tearing their hair out for a while.”
These hairpin turns on the road to where he is today could be seen as the vagaries of youth, but looking back over his career in cancer research, he admits these abrupt changes in direction may be a character trait.
“At a certain point I can get distracted and even bored if I’m only working on one single thing. If you do that in science 24/7 for 10 years, you become an utmost authority,” he observed. “That is not me, I’m afraid. I need to follow many leads simultaneously and jump from one to the other, maybe until I drop dead of exhaustion. But, meanwhile, it’s tremendously exciting.
“Cancer is a complex disease. The ability to make connections between various disciplines is an essential component of cutting-edge cancer research,” Dr. Pandolfi explained. “This ability to make unexpected connections is perhaps our distinctive trait as a research team.”
Dr. Pandolfi’s colleagues see him as a brilliant cancer researcher who has already done a career’s worth of work and whose prolific laboratory at Beth Israel Deaconess Medical Center, continues to make important discoveries. Two of his breakthroughs may never have happened had he stayed in Rome.
Finding the APL Gene
Acute promyelocytic leukemia (APL) is a fast-growing blood cancer that affects both children and adults. In the late 1980s, only one in four patients survived.
During this era of ambitious gene-hunting expeditions, Pandolfi applied to work with Dr. Pier Giuseppe Pelicci, a prominent geneticist who had recently returned from the United States and was looking for APL-causing genes. When Pandolfi arrived in Perugia he met and began working with another young researcher, Letizia Longo, and within a year they were first authors on a paper that identified and described the identification of the primary gene driving APL. They also fell in love.
“Call it luck, determination, fate, whatever you will,” said Dr. Pandolfi, “but if I hadn’t quit Rome for Perugia, I certainly wouldn’t have discovered the [promyelocytic leukemia] gene , and I probably would not have met my wife.”
Having cloned the APL gene, the newlyweds headed to the University of London to continue working on the disease using what was then the new rage in molecular biology—the knockout mouse. Researchers inactivate specific genes in these animals to learn more about the role those genes might play in cancer and other diseases. The challenge before them was not trivial, said Dr. Pandolfi, because no mouse had ever naturally developed APL.
Dr. Pier Paolo Pandolfi discusses his involvement in identifying the primary gene that causes acute promyelocytic leukemia, and his continued work on the disease using mouse models—research that has led to improved survival for patients with the disease. (Video produced and edited by Sarah Curry)
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Pioneering the Knockout and Transgenic Models
In parallel with his research on APL, Dr. Pandolfi was developing other interesting ideas and results on gene expression. He had not even finished his Ph.D. when researchers at Memorial Sloan-Kettering Cancer Center (MSKCC) recognized his potential and brought him to New York, gave him his own lab, and made him an assistant professor.
In those early days, most people trying to eliminate genes in a mouse were developmental biologists studying the role of specific genes in embryogenesis, according to Dr. Pandolfi. “But MSKCC was ahead of the curve, looking hard at how this new approach could be applied to cancer,” he said. “The turning point for us came when Dr. Raymond Warrell, head of the clinical leukemia program, kept coming back to our lab meetings and began to believe in the results we were having with our genetically engineered mice.”
These genetically engineered mice faithfully developed APL in a manner very close to the way that people do, something Dr. Pandolfi refers to as “phenocopying” the disease. Even better, the mice mimicked how humans responded to specific drugs.
Dr. Pandolfi’s mouse-engineering expertise brought him into contact with many people who were interested in this approach; one that is now being used to study other forms of cancer, such as breast, prostate, and lung. Then-NCI Director Dr. Richard Klausner asked him to join a group that eventually formed the Mouse Models of Human Cancers Consortium (MMHCC).
Dr. Cheryl Marks, program director of the MMHCC, calls Dr. Pandolfi’s body of work on APL “profound." Over the course of 15 years, using his evolving expertise with the mouse, "Pier Paolo has been a driving force in saving the lives of countless patients and raising the APL cure rate to more than 90 percent,” she remarked.
“He’s energetic, incredibly inquisitive, and a lot of fun—at times exuberant, always passionate about helping patients,” she said. “But he’s also a powerfully convincing scientist, backing his observations with clear-cut, well-designed experimental data, and able to bring others around to his views by force of a compelling vision. And he has an uncanny ability to discover connections that many people miss.”
Exploring a Pathway
This portrait of Dr. Pandolfi as a keen observer and dogged researcher is reinforced by a colleague and director of the cancer center at Beth Israel Deaconess Medical Center, Dr. Lewis Cantley, whose biochemistry lab studies cell signaling, including the role of PTEN in cancer development. In the late 1990s, Dr. Cantley was in New York to talk about his latest grant on prostate cancer, and—knowing that the PTEN gene was down-regulated in some 70 percent of cancer patients—started a conversation with the young assistant professor who had been trying to engineer a PTEN mouse model.
“From the first, I was impressed by his openness, willingness to share unpublished data, and his enthusiasm,” remembered Dr. Cantley. “We agreed to use his PTEN knockout mice, and I’ve been collaborating with him ever since.” At a meeting on mouse models held in Bethesda, MD, last month, which Dr. Pandolfi organized, Dr. Cantley spoke about the progress his lab has made using these PTEN knockout mice to test drugs that inhibit the PI3 kinase pathway in prostate cancer.
“The problem is that cancer is not one but many diseases,” explained Dr. Pandolfi. “We are curing APL because it has only six subtypes, and we found a drug combination for each one. But prostate cancer looks like it has five to 10 times that many subtypes. This is certainly the case for any major cancer type.” His lab has engineered more than two dozen animals that they hope will successfully phenotype those prostate cancer subtypes.
Exploding the “Junk” Paradigm
This summer in the journal Nature, Dr. Pandolfi published findings that could have tremendously important implications for the central dogma of molecular biology.
Genes make messenger RNAs (mRNAs), mRNAs make proteins, and the proteins within and around a cell determine its fate. However, only 2 percent of the human genome consists of protein-coding genes, and for many years much of the rest was labeled “junk.”
Then it was discovered that another type of RNA, microRNAs (miRNAs), can bind to certain mRNAs and disrupt their ability to produce proteins. “We’ve learned over the last few years that miRNAs can have a significant impact on which genes are expressed and blocked, and thus on the development of cancer,” said Dr. Pandolfi.
His lab has now found that some RNAs that encode for proteins, as well as some that do not, can bind to and regulate miRNAs.
“We call them competitive endogenous RNAs, or ceRNAs, and they can regulate whether PTEN and other important cancer genes are turned up or down,” said Dr. Pandolfi. “This is quite simply a radical change of perspective on how genes operate, and I think the real breakthrough is that we can use it to predict how specific genes function.”
Dr. Cantley said that this is typical of Dr. Pandolfi’s vision as a scientist. “ceRNA makes a lot of sense now that we see it, but nobody else was thinking about it,” he explained. “Pier Paolo dove into it and showed how it worked and opened up an entire area of regulation that everybody had missed.”
“We’re astonished,” said Dr. Pandolfi. “It’s a new, largely unexplored dimension of cell biology, and it never occurred to me that I would live through such a transformative phase in biology and cancer research.”