Cancer: Understand, Treat, Defeat

Kara Kelly, M.D., with a patient, Gabriella Apostle
Kara Kelly, M.D., with a patient, Gabriella Apostle
JUST A YEAR AGO, PEDIATRIC ONCOLOGIST KARA KELLY, M.D., associate professor of clinical pediatrics, might have raised her eyebrows in disbelief at the thought of giving drugs designed to treat Alzheimer's disease to her young patients. By now, it's become one of the more unusual details about her new clinical trial for patients with acute lymphoblastic leukemia (ALL).
What's not unusual is the rationale behind the trial (and yes, there is a good reason for giving experimental Alzheimer's drugs to children with cancer). The ALL trial is just one of a growing number of clinical trials in children (and adults) that are testing new "smart drugs": targeted therapies designed to home in on specific targets within tumor cells while leaving normal cells unscathed.
It's also a prime example of how molecular biologists at Herbert Irving Comprehensive Cancer Center are increasingly moving their own laboratory discoveries into clinical trials run by Columbia oncologists. The research that led to the new ALL trial was conducted by a new Columbia recruit, Adolfo Ferrando, M.D., Ph.D., assistant professor of pediatrics and pathology, last year when he was a postdoc at the Dana Farber Cancer Institute in collaboration with Dr. Jon Aster's group at Brigham and Women's Hospital in Boston.
Expect to hear about more and more such trials in the next few years as the HICCC grows under the new direction of Riccardo Dalla-Favera, M.D., the Percy and Joanne Uris Professor of Genetics and Development and of Pathology. "Our highest priority is designing the center to bring basic and clinical science together," Dr. Dalla-Favera says. "We must create an environment where scientists plan their research to have an impact on therapy and where doctors are prepared and eager to move new drugs and new approaches into the clinic. This is the quickest way to improve therapies."
To help create that environment, over the next five years the HICCC will recruit five to six new faculty who have translational research expertise.
They and other cancer investigators will soon move into the just completed Irving Cancer Research Center, a nine-story building dedicated solely to cancer research.
"This building is of particular importance as it marks the start of what I believe will be a new era in the history of the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center and New York- Presbyterian," Dr. Dalla-Favera says.
"We're expanding the cancer center as we face a historic moment in cancer research. In the last 20 years enormous progress has been made in understanding how cancer develops. Many of the genes involved have been identified, and we're beginning to design more selective cancer drugs based on those genetic defects. The impact of new therapies is just starting to be felt, but a much bigger impact is expected in the next five to 10 years."
The National Cancer Institute at the NIH will be investing major resources in this effort through comprehensive cancer centers like Columbia's.
"We are facing exciting times in oncology and our contributions should be second to none," says Dr. Dalla-Favera.

Treating T Cell Leukemia With Alzheimer's Drugs
The treatment of childhood cancer may be the war on cancer's best success story to date. For acute lymphoblastic leukemia, the most common type, five-year survival rates have steadily risen from less than 30 percent in the 1970s to approximately 80 percent today. Burkitt's lymphoma, which used to have the worst prognosis of all childhood cancers, now has the best with a 90 percent survival rate.
The success is partly due to pediatric oncology's spectacular record of multi-center clinical trials, says Michael Weiner, M.D. professor of pediatrics and chief of pediatric oncology. "Unlike adult oncology, the vast majority of children are entered into studies run by a cooperative group of many institutions. It has been the record of entering children into randomized controlled studies and basing trials on the best evidence of the science at the time that has gotten us to where we are today."
The chemotherapy now used for T cell leukemia, one type of ALL, works by interfering with the cell's DNA to stop cancer growth or kill the cancer cells and includes agents that have been used against malignancies for 30 to 40 years. But not everyone is cured, a situation researchers are trying to change by turning to new "smart bomb" therapies that home in on a specific abnormality in pediatric cancer cells.
"Right now for T cell leukemia, which accounts for 20 to 25 percent of ALL cases, about 20 percent of patients relapse and then the prognosis is very poor, even after a stem cell transplant," says Dr. Kelly. "The new drug we're testing is different. It really exploits a mutation that is a driving force behind T cell leukemia."
That mutation, in a gene called NOTCH1, was originally thought to play a role in only a small minority of T cell leukemia cases. Notch signaling tells normal stem cells in the blood to turn into T cells, but in approximately 1 percent of T-ALL patients, a chromosomal translocation leads to an overactive Notch, too many T cells, and leukemia.
But just last year, reporting in the Oct. 8, 2004, issue of Science, Dr. Ferrando found that Notch is much more important. Of the nearly 100 T-ALL patients the investigators looked at, more than 50 percent harbored other activating NOTCH1 mutations in their leukemic cells. In an instant, the findings changed the way researchers viewed T-ALL. "We now think T-ALL is a Notch-driven disease," says Dr. Ferrando.
At the same instant, the cancer research also crossed paths with research on Alzheimer's disease. Experimental Alzheimer's drugs that were designed to inhibit the formation of beta amyloid coincidentally also inhibit Notch.
"We were very lucky in identifying mutations in NOTCH1 because it let us bypass many steps between finding a target and developing a potential drug," Dr. Ferrando says. "Notch inhibitors have already gone through some clinical testing, and that allowed us to get into clinical trials very quickly."
(Incidentally, the study of Notch originated at Columbia in 1917, when Thomas Hunt Morgan first described a strain of Drosophila with "notched" wings).
The trial using Alzheimer's drugs first opened at Dana Farber in early 2005 for adults before it was opened to all patients with relapsed or refractory T-ALL and expanded to other sites, including Columbia, which is the only institution in the New York metropolitan area enrolling patients.
Now set up in his own lab in the Irving Cancer Research Center, Dr. Ferrando is searching for ways to extend his remarkable discovery. "We want to know how the activation of Notch leads to leukemia. Finding the downstream effectors may help us find an even more universal therapeutic target that will help the other 50 percent of patients who don't have Notch mutations," he says.
Whether those discoveries move to the clinic as fast as Notch inhibitors remains to be seen, but Dr. Ferrando thinks faster translations will soon become more common.
"The trials of Notch inhibitors is an example of how information from two very different fields can come together and bring forth new therapies," he says. "It is now the exception, but we feel we're at the beginning of a new era where this will become more the rule."

"Not Just Another Cancer Gene"
PTEN, discovered by P&S researchers in 1997, is one of the most commonly mutated cancer genes. Here, bladder cancer cells that have lost PTEN appear blue.
Reporting on discovery of the PTEN tumor suppressor more than eight years ago, the New York Times quoted noted cancer researcher Bert Vogelstein of Johns Hopkins: "This is not just another cancer gene.
For one thing, news of the new gene made a splash in the mass media. The New York Times, the Wall Street Journal, NPR, CNN, and the network news shows all covered PTEN's discovery made independently by Columbia's Ramon Parsons, M.D., Ph.D., Avon Foundation Associate Professor of Pathology and Medicine (in the Institute for Cancer Genetics), and by Peter Steck of the M.D. Anderson Cancer Center.
But the gene also excited scientists who saw hints in the first reports that PTEN would be a particularly important tumor suppressor involved in many common kinds of cancer, and over time that has been proved. PTEN is one of the most commonly mutated genes in human cancer, almost equaling that of p53. Loss of PTEN itself, or one of its protein partners, is common in breast, brain, advanced prostate, melanoma, and endometrial cancers.

Banking on Big Molecules
While the average savings account offers miniscule interest rates these days, a new bank at CUMC is offering cancer researchers — and ultimately patients — a much bigger payoff. When researchers want to know whatís going on in real human cancers, they turn to specimens collected and frozen by the pathology department. But each investigator would have to check the quality of the specimens, extract DNA and RNA from the tissue, make slides of each specimen, and retrieve the clinical data.
"These are huge hurdles," says Dr. Hanina Hibshoosh, "and they were slowing down progress." If the study was a side project, many investigators simply couldnít afford the time to pursue it.
With financial help from the Avon Foundation, CUMC pathologists have spent the past three years sorting the good samples from the bad and performing all the tedious prep work. Now stored in the new Macromolecule Bank, DNA and RNA from about 500 breast tumors are readily available to any CUMC researcher, along with clinical data and "tissue chips," which have become a powerful new tool for high throughput research.
One tissue chip (or tissue microarray) can hold a hundred different samples on a single slide, so data for an entire study can be analyzed by staining one or two microarrays, instead of hundreds of conventional slides.
Dr. Hibshoosh is now using the tissue chips to develop new diagnostic tests that will be necessary for the upcoming PTEN trials and the future of "personalized" cancer care. "By creating the Macromolecule Bank, we now have a ready-to-go platform and it has really turbo-charged all of our studies and enhanced the translational enterprise."
Dr. Parsons and his colleagues thought therapies based on PTEN had great potential, but cautioned in an interview with CNN soon after the discovery, "This is going to take a long time."
Eight years later, Dr. Parsons says it's taken as long as he expected to finally start moving the laboratory findings into the clinic.
In that time, Dr. Parsons and other researchers uncovered important intermediaries that link PTEN with cancer and could be targeted by drugs. One such intermediary turned out to be a protein called mTOR (for mammalian target of rapamycin), which becomes hyperactive and fuels cancer cell growth when PTEN is lost. Rapamycin, which turns mTOR off, has shown promising results in studies Dr. Parsons has conducted in mice. In those experiments, the drug stopped the growth of PTEN-negative tumors and, in some instances, shrunk them.
"The next question is: Can this work in people?" Dr. Parsons says. "But designing good clinical trials to test rapamycin, like all other targeted drugs, is difficult. We predict that our therapy will only work in tumors with lesions in the PTEN pathway. If you gave these drugs to all comers, you may not see a great effect."
Columbia trials, currently in the design phase, will test rapamycin analogs with current chemotherapy drugs in breast and advanced prostate cancer patients, but only in patients whose tumors have mutations or other changes in the PTEN pathway. Other institutions have already started phase I and II trials with the drugs, but have not stratified patients.
"You could do the trials without knowing what's going on in the tumor and identify good responders after the fact," Dr. Parsons says, "but that's very expensive and you treat many patients inappropriately."
It's a huge team effort that also requires the development of new diagnostic tools from pathologists, including Hanina Hibshoosh, M.D, associate professor of clinical pathology, who are in the process of developing fast and accurate tests to measure changes in the PTEN pathway.
"This is a good time to start these trials," Dr. Hibshoosh says. "We know enough about the pathway to rationally design a trial and at the same time there are enough reagents available to measure the different members of the pathway."
Perfecting the new diagnostics won't be easy, Dr. Hibshoosh adds. Pathologists will have to determine which types of tests are appropriate, which among the many available reagents are best, and what's an appropriate cutoff for positive and negative. "It took decades to perfect the analysis of the estrogen receptor on tissue sections, so our tests will undoubtedly be modified several times."
Once these diagnostic tests are ready, Dr. Parsons will try different drugs to see which ones are capable of hitting the target in people before starting trials. If the drug can't hit the target in people, the drug won't work and it won't be moved into trials.
Trials for advanced prostate cancer will be designed and run by Daniel Petrylak, M.D., associate professor of medicine; trials for breast cancer will be designed and run by George Raptis, M.D., assistant professor of clinical medicine, and Dawn Hershman, M.D., assistant professor of medicine and epidemiology.
"After the success of Gleevac and Avastin, people are excited about the potential of drugs that inhibit these types of pathways," Dr. Parsons says. "But they won't be magic bullets. Tumors are still a black box. We know more than we did before, but often we still don't know why they're misbehaving. We probably won't get clean cures until we learn a lot more."

A Sampling of Other CUMC "Smart" Drugs
>The first pediatric trial of Avastin, a drug designed to cut off a tumorís blood supply, is being conducted by Julia Glade Bender, M.D., assistant professor of clinical pediatrics. The concept of the trial is based on original laboratory research by Darrell Yamashiro, M.D., Ph.D., Irving Assistant Professor of Pediatrics and Pathology, and Jessica Kandel, M.D., associate professor of surgery (in the Institute for Cancer Genetics), which showed that blocking blood vessel development prevents the growth of several types of pediatric tumors.
>Daniel Petrylak, M.D., associate professor of medicine, led a phase III clinical trial that showed for the first time that chemotherapy ó docetaxel combined with estramustine ó extends the life of men with advanced prostate cancer. The combination of docetaxel and estramustine was piloted by Dr. Petrylakís research group in the Irving Center for Clinical Research after researchers found that the two worked synergistically to kill cancer cells in vitro. Results of the phase III trial were published in the Oct. 7, 2004, issue of the New England Journal of Medicine.
>A new vaccine for kidney cancer, TroVax, is being tested by Howard Kaufman, M.D., associate professor of surgery and pathology, in combination with interleukin-2 (IL-2), the cancerís standard treatment. IL-2 stimulates the immune systemís T killer cells, while the vaccine steers the attack toward kidney cancer cells.
> GTX was named after a gasoline additive, but it is also a chemotherapy regimen devised by Robert Fine, M.D., Herbert Irving Associate Professor of Medicine and director of experimental therapeutics. In the laboratory, Dr. Fineís group discovered that GTX, a complex combination of Gemzar, Taxotere, and Xeloda, worked synergistically against metastatic pancreatic cancer cells. In a phase II trial, the trio of drugs succeeded in raising median survival from 4.5 months to 11.2 months, the longest survival ever reported in metastatic pancreatic cancer.

Immobilizing the Molecular Motors
That Drive Brain Cancer

The brain tumor in a Powerpoint presentation Steven Rosenfeld, M.D., Ph.D., professor of neurology and pathology, shows looks like a bomb that's exploded. About one-third of the brain looks scorched, with so many blood vessels packed in that the tumor looks black. From the edges of the dark mass, deep red tendrils radiate out into the rest of the brain's normal pink-colored tissue.
It looks like an explosion and that's probably not far from the truth. "Gliomas, the most common type of malignant brain tumors, are wildly infiltrative and can grow so fast that in six weeks the tumor can grow from nothing to the size of a golf ball," Dr. Rosenfeld says.
The tendency to spread rapidly through the brain is one of several reasons why brain cancer is so deadly. But for researchers like Dr. Rosenfeld, who since May has led the neuro-oncology division in the Department of Neurology, the rapid growth of the cancer actually suggests new ways to fight the cancer.
"This is the major change in brain cancer biology these days," Dr. Rosenfeld says. "We used to take drugs for other cancers and blindly try them in brain cancer. Now we're looking at unique targets in brain cancer, studying them in animals, and then moving drugs into the clinic."
Dr. Rosenfeld has plenty of experience steering lab discoveries into new treatments for patients. Before coming to Columbia, he built the Brain Tumor Treatment and Research Program at the University of Alabama at Birmingham into one of the nation's leading centers of brain cancer research. In his 10 years there, he successfully bid for one of NCI's highly coveted "brain SPOREs" — specialized programs of research excellence — and he increased the number of active clinical trials from two to 22.
Of these, the death stalker scorpion trial has grabbed the most attention. Now undergoing phase II testing in patients with malignant glioma, it all started by chance when a UAB researcher discovered a chloride channel present only in glioma cells. Researchers subsequently discovered the scorpion's venom blocked the channel and stopped glioma cells from shrinking down to a size necessary to squeeze through the tiny intracellular spaces in the brain to migrate. When the toxin had no effect on normal cells, everyone knew it could evolve into one of the first targeted drugs for brain cancer.

LEFT: Cutting the ribbon for the Irving Cancer Research Center in May are, from left, New York State Assemblyman Herman "Denny" Farrell Jr.; Herbert Pardes, president and CEO of New York-Presbyterian Hospital; Lee Bollinger, president of Columbia University; Andrew von Eschenbach, director of the National Cancer Institute; Florence and Herbert Irving; Gerald Fischbach, Columbia University Medical Center executive vice president and dean; and Riccardo Dalla-Favera, director of the Herbert Irving Comprehensive Cancer Center.
RIGHT: Interior views of the Irving Cancer Research Center

Riccardo Dalla-Favera
Riccardo Dalla-Favera
Making Room for Research
As new director of the Herbert Irving Comprehensive Cancer Center, Riccardo Dalla-Favera's vision for the center includes increasing the number of cancer researchers at Columbia who aggressively pursue avenues for new and better treatments.
That job should be easier with the completion of the new Irving Cancer Research Center, officially opened during a ribbon-cutting ceremony in May. The nine-story building — a testament to Herbert and Florence Irving's passion to fight cancer — is almost entirely dedicated to cancer research.
"This building, this spectacular gift from the Irvings, marks the start of what I believe will be a new era in the history of the HICCC," say Dr. Dalla-Favera.
The 120,000-square-foot Irving Cancer Research Center doubles the research capacity of the HICCC, which encompasses all cancer-related research, treatment, prevention, and education efforts at CUMC and New York-Presbyterian. The Avon Foundation Breast Imaging Center for medically underserved women, opened in August 2004, occupies the building's first floor.
Herbert and Florence Irving became self-described cancer fighters in the early 1990s and since then have committed nearly $100 million to the HICCC.
"This is undoubtedly one of the happiest days of my life," Mr. Irving said at the dedication. "Today we are a comprehensive cancer center bursting at the seams, ready to do fantastic things in the future."
Dr. Dalla-Favera's plan for the HICCC in the next five years builds on his previous achievements at Columbia. Fifteen years ago, researchers devoted to the study of cancer were underrepresented at Columbia. As part of a restructuring of the pathology department, Riccardo Dalla-Favera, M.D., was recruited from NYU in 1989 to lead the department's division of experimental oncology. Since then, under Dr. Dalla-Favera's leadership, the number of cancer researchers has steadily increased, a new Institute for Cancer Genetics was established in 1999, and, in 2003, the Leukemia & Lymphoma Society designated Columbia as a specialized center of research.

As with other UAB discoveries, Dr. Rosenfeld helped shepherd this drug — ultimately modified to carry radioactivity for even greater effect — through successful phase I testing. His goal is to repeat those translational successes at Columbia.
"One of the things that attracted me to Columbia was the strong focus on cell migration among the basic scientists," Dr. Rosenfeld says. "My plan is to get the basic investigators here interested in brain tumor research and build a pipeline that will take their lab discoveries into preclinical models and finally phase I, II, and III trials."
He'll also continue translating his own research on the molecular motors that propel glioma cells through the brain into new therapies. While it would seem obvious to treat glioma by targeting these motors, Dr. Rosenfeld says the concept has been largely unexplored. He has found one motor inhibitor that is now in a phase I trial but continues to search for others with high throughput screening.
"We need new imaginative therapies based on the biology of this disease," Dr. Rosenfeld says. "We shouldn't be telling our patients that they should just go home and
wait to die."

Like Going to the Moon
It's been more than 30 years since President Richard Nixon declared a war on cancer, yet it's clear that no single weapon has been identified to defeat it. Researchers must discover the problem with each of the hundreds of subtypes of cancer, determining not just how prostate cancer differs from breast cancer but also discovering how several different types of prostate cancer differ from each other.
"It sounds like going to the moon now," Dr. Dalla- Favera says. "But in 10 years treating cancer will be like treating pneumonia, where you test to see what is causing the infection so you can select the appropriate drug."

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