AACR Honoree Warns of Crisis in Cancer Research

Janis C. Kelly

February 21, 2011

February 21, 2011 — Susan Band Horwitz, PhD, will receive the Eighth American Association for Cancer Research (AACR) Award for Lifetime Achievement in Cancer Research on April 3.

The award comes 30 years after Dr. Horwitz and Peter B. Schiff, PhD, MD, who was then a PhD candidate in her lab, discovered that paclitaxel (Taxol) poisons cancer cells by causing them to fill up with microtubules and bringing cell division to a halt.

Dr. Susan Horwitz

This was an entirely new mechanism and distinguished paclitaxel from other anticancer agents being studied at the time, most of which disrupted cellular DNA. The discovery laid the groundwork for the development of paclitaxel as a therapy for many common solid tumors, including ovarian, breast, and lung carcinomas.

The AACR Award for Lifetime Achievement in Cancer Research was established in 2004 to honor individuals who have made significant fundamental contributions to cancer research, either through a single scientific discovery or a body of work. These contributions, whether they have been in research, leadership, or mentorship, must have had a lasting impact on the cancer field and must have demonstrated a lifetime commitment to progress against cancer.

"Dr. Horwitz has had a direct impact on millions of cancer patients around the world through her work in understanding the mechanisms of action of paclitaxel and other cytotoxic drugs," said AACR CEO Margaret Foti, PhD, MD, in announcing the award. "Her remarkable career and pivotal scientific contributions have influenced our understanding of how cancer drugs work and how to translate that knowledge into improved strategic treatments."

Crisis in Funding

Dr. Horwitz, who is well regarded as a mentor for new researchers, told Medscape Medical News in an interview that she is concerned that the next generation of researchers will have a harder time preparing for discoveries such as paclitaxel.

"Currently, we are really in a crisis because of funding and related issues," Dr. Horwitz said. "When we have a situation in which only 7% to 10% of grant applications are funded, it is particularly discouraging for young researchers trying to set up labs. This crisis has arrived just as we need more researchers in totally new areas, such as proteomics, deep sequencing, and the many areas that will be needed for personalized medicine, some of which will require finding the best ways to combine targeted therapy with drugs like [paclitaxel] to treat specific cancers."

Dr. Horwitz is currently the Rose C. Falkenstein Professor of Cancer Research and cochair of the Department of Molecular Pharmacology at Albert Einstein College of Medicine of Yeshiva University in New York City. She is also associate director for therapeutics at the Albert Einstein Cancer Center.

Paclitaxel Studies

The studies that led to the discovery of paclitaxel were requested by the National Cancer Institute because of Dr. Horwitz's long-established interest in therapeutic uses for compounds derived from natural products.

In speaking with Medscape Medical News, she pointed out that organisms such as trees and sponges had to develop defensive chemicals because of their lack of mobility.

This is a molecule that only a tree would make.

"Many natural products have very complex chemical structures. As an example take [paclitaxel] — this is a molecule that only a tree would make," Dr. Horwitz said, noting that "small molecules can do great things."

In addition to paclitaxel (from the Pacific yew tree Taxus brevifolia), she has also studied camptothecin (isolated from the bark and stem of the tree Camptotheca acuminata), bleomycin (from the bacterium Streptomyces verticillus), etoposide (VP16, the podophyllotoxin of the American Mayapple plant), the epothilones (from the myxobacterium Sorangium cellulosum), and discodermolide (from the deep-sea sponge Discoderma dissoluta).

Dr. Horwitz began investigating paclitaxel in 1977 after its isolation by the chemists Monroe Wall, PhD, and Mansukh Wani, PhD. "We knew within 1 month that it was special. After incubating cultured HeLa cells with the drug, we found that the cells were totally filled with stable microtubules," she said.

The AACR announcement notes that "Dr. Horwitz has launched countless careers from her own laboratory and inspired innumerable others to embrace questions that change the way we think about fundamental aspects of cell biology."

One person on the receiving end of that mentoring skill is Dr. Schiff, who was first author on the key paclitaxel study and who was put to work on paclitaxel after casting about for a thesis project in Dr. Horwitz's lab.

Casting About for Thesis Project

Dr. Schiff told Medscape Medical News that he had been working on a "sort of boring" drug until a fateful lab meeting.

"Dr. Horwitz had wonderful Monday morning lab meetings, where we would review interesting results from the previous week, discuss major new journal articles, or learn new methods. At the end of one meeting, she had a letter from the National Cancer Institute with a list of 20 or so compounds they wanted investigated. Paclitaxel caught our attention because the information included its chemical structure, which was unusual. As a PhD candidate, I was desperate to find a new, more interesting drug to study, and Dr. Horwitz suggested that I run it through a couple of systems."

A short time later, Dr. Horwitz received a vial containing a couple of tiny grains of paclitaxel, and not-yet-Dr. Schiff put it into one of the lab's HeLa cell cultures.

"Hour by hour we drew out samples for testing. We thought it might be a spindle poison," Dr. Schiff recalled. "I had microtubule assays set up from the previous drug (which required isolating tubulin from calf brains, which we got in big loads from slaughterhouses), and I put paclitaxel in. To my surprise, the in vitro microtubule assay, which relied on light scattering as polymerization advanced, showed that paclitaxel did not block but actually accelerated the microtubule assembly."

The resulting microtubules were shorter, more stable, and more numerous than in normal cells.

You have to come over here and see this.

"The first immunofluorescence studies, which had to be done in a different building because the Horwitz lab did not yet have its own immunofluorescence equipment, were very dramatic. I called Dr. Horwitz and said: 'You have to come over here and see this'."

Paclitaxel had totally altered the cytoskeleton of the HeLa cell.

"Then I knew I had a thesis," said Dr. Schiff, who is now a radiation oncologist at New York University's Langone Medical Center in New York City.

"I admire Dr. Horwitz for tolerating me as I tried to go in a new direction. She attracts a very talented group of graduate students and creates a very exciting environment for research," Dr. Schiff added.

Mentoring Young Investigators

Medscape Medical News asked Dr. Horwitz for advice about mentoring young investigators.

"There is a fine line between encouraging independence, keeping young researchers free-thinking, and not letting them go so far off the main track they will not be able to finish their degrees in a reasonable length of time," Dr. Horwitz said.

"You have to instill confidence in young scientists. Make them speak about their work at lab meetings, even when they don't want to, and at departmental meetings. To succeed, researchers need to do excellent science, but they also need to be able to speak and write well. Of course, scientists must learn to plan good experiments, set them up, and analyze the data. Today, especially, you have to give young researchers time — science is so much more complicated than ever before."

Part of the excitement Dr. Schiff described comes from Dr. Horwitz's endless curiosity about cancer and potential cancer drugs.

"You can't be stagnant in this business, especially if you want to be a good mentor. You must always be learning, being a student yourself," Dr. Horwitz said.

Currently, the Horwitz lab is focused on resistance to taxanes (including P-glycoprotein, mutations in tubulin, and modulation of the expression of tubulin isotypes), new natural products with a mechanism similar to paclitaxel but also with distinct differences that can enhance their therapeutic value, overcoming accelerated senescence, and combining paclitaxel with specific inhibitors of signaling pathways to circumvent resistance.

Many Other Honors

Dr. Horwitz has authored more than 250 publications, advancing our knowledge of antitumor drugs and mechanisms of drug resistance. She has received numerous awards, including the Cain Memorial Award from the AACR, the ASPET Award for Experimental Therapeutics, the Chester Stock Award from Memorial Sloan-Kettering Cancer Center, the American Cancer Society's Medal of Honor, the Bristol-Myers Squibb Cancer Distinguished Achievement Award, the Barnard Medal of Distinction, and the Warren Alpert Foundation Award from Harvard Medical School. She received a Doctor Honoris Causa from the Université de la Méditerranée in Marseilles, France.

Dr. Horwitz served as president of the AACR in 2002/03. She is a member of the American Academy of Arts and Sciences, the National Academy of Sciences, and the Institute of Medicine. She is also a fellow of the National Foundation for Cancer Research and the American Society of Pharmacognosy.

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