Celebrating Gleevec – and Basic Research

VN:F [1.9.22_1171]
Rating: +5 (from 7 votes)
CML

Chronic myeloid leukemia cells (NCI).

When 23-year-old Glamour magazine editor Erin Zammett Ruddy went for a routine physical in November 2001, she expected reassurance that her healthy lifestyle had been keeping her well. After all, she felt great.

What Erin received, a few days later, was a shock. Instead of having 4,000 to 10,000 white blood cells per milliliter of blood, she had more than 10 times that number – many of the cells cancerous. Erin had chronic myeloid leukemia (CML). Two years before her diagnosis, CML was a death sentence. But the drug Gleevec saved her and many others. It offers perhaps the best example of translational medicine.

A LIFE TURNED UPSIDE DOWN BY CANCER
“I had just returned from a nice, long lunch to find a message from my doctor. Could I call back? Something had come up in my blood work,” Erin told me in 2007, when I met her at her office in midtown Manhattan.

I’d read Erin’s blog and invited her to tell her story in my human genetics textbook, which she did, with a photo of her grimacing during one of her many bone marrow samplings. And what a success story it’s been!

Ph1 bookNext week Erin celebrates the start of her 11th year with the cancer essentially gone, thanks to Gleevec. Also next week the story of the drug, The Philadelphia Chromosome by fellow PLOS blogger Jessica Wapner, will be published. At the same time panoramic yet detailed, the new book chronicles the researchers and molecules behind Gleevec, beautifully complementing Erin’s 2005 book “My So-Called (Normal) Life.”

When Erin was diagnosed, Glamour had just published a story about the new drug, which the FDA had approved in May 2001. Erin contacted the physician heading the 3-center clinical trial, Brian Druker, MD, director of the Knight Cancer Institute at the Oregon Health & Science University and Howard Hughes Medical Institute Investigator. She flew to Portland for tests, and soon began taking one pill of Gleevec every day. After a short bout of stomach cramps and a little eye puffiness, she, like nearly everyone to receive the drug, responded. 

Over a few weeks, Erin’s cancer ebbed away — and stayed away, even with brief hiatuses for two pregnancies. She announced her third last week.

Before Erin’s story, my textbook had covered the discoveries that led up to Gleevec, because they are a classic in genetics. I’d thought the story would make a terrific book, but couldn’t see how I could tell such a complicated and technical tale. Now Jessica Wapner has done exactly that, in her masterpiece “The Philadelphia Chromosome.”

BRAIDING THE RESEARCH THREADS

Peter Nowell and David Hungerford discovered the Philadelphia chromosome (Penn Medicine)

Peter Nowell and David Hungerford discovered the Philadelphia chromosome (Penn Medicine)

Gleevec arose from an unexpected assembly of pieces that no one initially realized went to the same puzzle. First came the discovery of an unusual “minute” (small) chromosome in 1960, in two men with CML whose cells wound up in the lab of pathologist Peter Nowell at the University of Pennsylvania, where PhD student in cytogenetics David Hungerford, from the nearby Fox Chase Cancer Center, worked. Nowell and Hungerford’s telltale “Philadelphia chromosome” – Ph1 — showed up in other CML patients too. Dr. Nowell tells the story in the Journal of Clinical Investigation.

It wasn’t until 1972 that Janet Rowley at the University of Chicago, using new, higher resolution chromosome stains and famously spreading out her images on her kitchen table, discovered that the Philadelphia chromosome is a translocation – one chromosome 9 and one chromosome 22 swap parts (chromosomes are numbered by size, 1 the largest).

By 1984, with generic chromosome staining having evolved into the DNA-sequence-specific “FISH,” (fluorescence in situ hybridization) researchers zeroed in on the two genes juxtaposed in the translocation: the Abelson oncogene (abl) from #9, and the breakpoint cluster region (bcr) from #22.

nci-vol-7153-72The two genes, cut and rejoined, generate two unusual chromosomes. The larger, #9 with a bit of #22, has no known effect; the other, tiny #22 with a smidgeon of #9, called the bcr-abl fusion gene, drives certain white blood cells to divide like crazy, becoming leukemia.

The cancer isn’t inherited; it just happens, for cancer is a genetic alteration of somatic cells. “The only difference between normal cells and CML cells was that in the former, bcr and abl were separate and that in the latter, bcr and abl were fused. And that fusion turned the once harmless abl into an oncogene,” Wapner writes.

The BCR-ABL oncoprotein that the bcr-abl fusion gene encodes was already very familiar to drug developers – it’s a tyrosine kinase, a member of a family of enzymes that oversee signal transduction pathways. But pharma had been focusing on cancers more common than CML.

If the pharmaceutical industry learned anything from this saga, it was that curing the rare can lead to curing the common. And the BCR-ABL oncoprotein was the key to halting Erin’s cancer, CML. The drug-to-be was first called CGP-57148B while at Ciba-Geigy and largely ignored, then STI-571 when Ciba-Geigy and Sandoz merged to beget Novartis. After clinical trials and lightning-speed FDA approval – 10 weeks — STI-571 became Gleevec in the US, soon Glivec elsewhere.

Gleevec

Gleevec

HOW GLEEVEC WORKS
The drug fits into a pocket of the BCR-ABL oncoprotein, displacing the energy molecule ATP. This prevents the jettisoning of a lone phosphate that starts the bucket-brigade-like passing that sends signals inside the cell. A tyrosine kinase is an enzyme that adds a phosphate to a tyrosine amino acid on a particular protein. When ATP binds the abnormal oncoprotein, continuous cell division results. Slapping on Gleevec is a little like shutting up a blabbermouth.

Gleevec's mechanism (NCI)

(NCI)

Preclinical experiments took years – in rodents, beagles, rabbits, monkeys, and most tellingly, the bone marrow cells of CML patients, where the drug worked. In people the intravenous infusion that the company pushed was ineffective, but the pills that some of the researchers and Dr. Druker favored did work – as a far less invasive daily orange pill. And that wasn’t the only unusual thing – compared to standard chemo, Gleevec has no side effects, other than transient eye puffiness, cramps, and bone pain as the cancer cells die off.

Gleevec is the first drug to combat cancer at its source, rather than targeting cancer cells by their excess antigens, the way that the breast cancer drug Herceptin works. And the clinical trial results for Gleevec were astonishing. I remember reading the abstract in the April 5, 2001 New England Journal of Medicine many times, in utter disbelief. Of 54 patients, 53  responded to the drug.

As Gleevec did its job, three measures of success were clear. Numbers plummeted: leukemic cells, Philadelphia chromosomes, and copies of the messenger RNA representing the fusion gene. The speed of FDA’s evaluation and approval of the submitted data set a record that still holds. “The Philadelphia chromosome” opens with one patient’s experience as this happened, and the book includes the names and contributions of the many individuals who made Gleevec a reality.

Wapner flawlessly weaves the three threads of Gleevec’s beginnings into a tightly knit fabric: how viruses subvert normal cell division genes into killer oncogenes, the development of kinase inhibitors, and the Philadelphia chromosome tale. The success was most stunning in the sickest patients. She writes:

“The responses began within a week after starting STI-571. Among several dying patients, white blood cell counts dropped, making room for restorative red blood cells to proliferate and heal the body. The color returned to their faces. They gained strength. They got up and out of their wheelchairs and walked out of the hospital.”

Wapner also captures Dr. Druker’s realization that what he’d predicted had actually happened, as the first patients brought back from the brink of death tearfully thanked him. “I realized they were so far ahead of me. They already accepted that this drug had worked and had changed their lives,” Dr. Druker said.

NOBELS NEXT?
Gleevec was 41 years in the making, from 1960, when two young medical researchers in Philadelphia noted an unusual tiny chromosome that their leukemia patients shared, to FDA approval in 2001. Writes Wapner, with hindsight, “The story of how the Philadelphia chromosome led to CML was like a hundred painters applying brushes to a canvas at some time or another over twenty-five years, driven only by curiosity and, sometimes, a vague hope that their work might eventually be relevant to human cancer. There’d been no final picture in mind and no awareness that they were even painting something together. And yet there it was. A scientific masterpiece.”

2013_recipients_slideOn May 17, Peter Nowell, Janet Rowley, and Brian Druker will share the
Albany Medical Center Prize in Medicine and Biomedical Research for their work on Gleevec. “Their collective achievements opened new fields of cancer research and have improved the lives of many,” said Joseph R. Testa, Ph.D., co-director of the Cancer Biology Program at the Fox Chase Cancer Center. Dr. Hungerford died in 1993, at age 66, of lung cancer.

The Gleevec story didn’t end with Erin’s rare cancer, CML. Gleevec is currently approved in the U.S. to treat 10 cancers, and has been tweaked so that patients whose cells become resistant can continue to benefit. And Druker has developed other drugs for when resistance persists, always staying one step ahead of the cancer.

More than fifteen kinase inhibitors have been FDA-approved, treating different cancers, with 500 more in clinical trials at half that many companies. Gleevec led the way.

“This type of targeted therapy is the future of cancer drug therapy and the future is here,” said Druker on learning of the Albany prize. “With the technology we have available today, what took 40 years — the discovery of the Philadelphia chromosome to the approval of Gleevec — can happen in a matter of months. It’s an exciting time to work in this field.”

THE PHILADELPHIA CANCER STORY: THE SEQUEL
A small molecule like Gleevec is only one new way to combat cancer. A completely different type of cancer treatment based on an engineered immune system molecule is unfolding, again in Philadelphia, right now. Novartis, sponsor of Gleevec, has given $20 million to build a facility for “chimeric antigen receptor,” or CAR, technology, on the Penn campus. CAR technology is in clinical trials to treat several cancers and HIV infection.

CAR_cartoonA chimeric antigen receptor is part T cell receptor, part antibody segment, its mosaic gene delivered aboard lentivirus (disabled HIV) to T cells. The CAR leads the T cells to the cancer cells distinguished by their many copies of the corresponding antigen. Zelig Eshhar, at the Weizmann Institute of Science, originated the general idea of retooling T cell receptors in the 1980s .

CAR technology was pioneered on patients with acute lymphoblastic leukemia (ALL), which affects 70,000 people in the U.S.. The New York Times chronicled the recovery of 6-year-old Emma Whitehead. Bruce Levine, one of the inventors of CAR technology with Carl June and others, told me all about Emma and the other patients now in complete remission, at a recent gene therapy conference – which I’ll cover in a future blog.

Let’s celebrate the translation of knowledge of the basic life sciences — cell biology, biochemistry, genetics, and immunology — into saving lives.

VN:F [1.9.22_1171]
Rating: +5 (from 7 votes)

Creative Commons License
The Celebrating Gleevec – and Basic Research by DNA Science Blog, unless otherwise expressly stated, is licensed under a Creative Commons Attribution 3.0 Unported License.

This entry was posted in Uncategorized. Bookmark the permalink.

One Response to Celebrating Gleevec – and Basic Research

  1. Pingback: Celebrating Gleevec – and Basic Research | DNA Science Blog | linkstream2 microblog