BREAK THROUGH IN CANCER RESEARCH

BY DR. PIER PAOLO PANDOLFI

“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.”

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.

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.

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 ourgenetically 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.

“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

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.”