Smart Cancer Drug Passes Test Against Multiple Myeloma

A large study published last month showed that bortezomib (Velcade), the first drug of its kind, is twice as good at treating an incurable blood cancer as a conventional medication. To other cancer researchers, the findings represent the first wave of tangible benefits resulting from a molecular understanding of how drugs work against disease.

Photo by Steve Gilbert

Understanding how a drug works at the molecular level helped researchers design clinical trials that led to speedy federal approval of a new kind of drug to treat myeloma. The myeloma translational research team includes (clockwise from bottom right) Kenneth Anderson, Jay Bradner, Constantine Mitsiades, Teru Hideshima, and Paul Richardson.

“It serves as a paradigm for developing agents against other tumor types,” said Wyndham Wilson, chief of the lymphoma section at the National Cancer Institute. “The paradigm is understanding the disease biology, looking for targets that overcome the biology, identifying the targeting agents, demonstrating they work clinically, and confirming to the extent possible they are working in the targeted area.”

In the phase III trial of 669 patients with relapsed multiple myeloma, 38 percent showed a partial or complete response to the new agent, compared to 18 percent who responded to a common salvage drug. One third of patients discontinued one or the other study drug because of side effects. The report, by Dana–Farber Cancer Institute researchers and their colleagues, appears in the June 16 New England Journal of Medicine.

In absolute terms, bortezomib, a proteasome inhibitor, bought a median of three more months of disease control at an estimated price of $45,760 for nine months of treatment. This compares to $170 for the less effective old drug, writes Angela Dispenzieri, associate professor of medicine at the Mayo Clinic in Rochester, Minnesota, in an accompanying editorial.

Still, the disease responses and survival advantage were so striking that the trial was ended early. People in the control arm were switched to bortezomib. And the Food and Drug Administration extended its approval from use as a last-resort drug to include myeloma patients who have received at least one prior therapy.

“These results provide confirmation that bortezomib should be used at first relapse, and they provide a strong rationale for its use as an upfront therapy,” said first author Paul Richardson, clinical director of the Jerome Lipper Multiple Myeloma Center at DFCI and an HMS assistant professor of medicine.

Depending on when you start the clock, bortezomib is one of the fastest drugs ever developed. It took 4.5 years from the first human dose in a phase I general cancer trial to FDA approval on phase II data. The timeline shrinks to three years if you start counting with the first multiple myeloma patient treated in the phase I trial.

Birth of a Drug
Many of the multiple mechanisms of action of bortezomib against myeloma were worked out in the DFCI laboratory of Kenneth Anderson, senior author of the NEJM paper and director of the multiple myeloma center at DFCI, which specializes in translational research on myeloma. The center’s showcase molecular and clinical pipeline has tested three major new myeloma drugs. Numerous other novel therapies are lined up in vitro and in vivo.

Bortezomib was born in a company started by Alfred Goldberg, HMS professor of cell biology, and three Harvard colleagues to develop inhibitors of the proteasome, the cell’s protein garbage disposal that Goldberg codiscovered about 30 years ago. At the company, Julian Adams, now chief scientific officer at Infinity in Cambridge, first modified a popular proteasome inhibitor used in research labs to make it more potent, selective, and clinically usable.

Adams championed the compound, then known as PS-341, for a decade while the disease target for the drug changed as many times as the company switched hands.

The early preclinical tests for the originally intended application, muscle-wasting diseases, were disappointing. Then Goldberg and his Harvard collaborators reported that the proteasome activity was crucial to activate the NF-kappa B transcription factor, and Adams switched the focus to inflammatory diseases. The side effects soon made it clear that the drug would only be acceptable for cancer, where it seemed to slow or block cell division. Follow-up tests in National Cancer Institute cancer cell lines showed enough promise to launch a phase I clinical trial in people with advanced cancers who had exhausted all other conventional treatment options.

This is where the clock starts on the myeloma story.

The power to block NF-kappa B attracted the interest of Teru Hideshima, HMS principal associate in medicine and senior scientist in the Anderson lab. In myeloma cell lines and test tube models of the cancerous plasma cells, soaring NF-kappa B levels confer drug resistance. The transcription factor also augments the cancer cell growth and survival by stronger binding to stroma cells in the bone marrow.

Hideshima’s preclinical studies to dissect the multiple molecular cancer-fighting mechanisms of bortezomid took on greater urgency when a myeloma patient in the phase I trial showed a dramatic response.

“We enrolled a few more myeloma patients, saw a few more dramatic responses, and felt this deserves a phase II investigation,” Adams said.

High-speed Trials
Anderson presented the laboratory and clinical data at a roundtable meeting of the Multiple Myeloma Foundation. “Everybody was very excited,” said Anderson, the Kraft family professor of medicine at HMS. “We hijacked the people there and went into the evening to design the phase II trial.” The initial FDA approval came from an intermediate outcome—time to disease progression—from this study, conducted at 13 centers and led by Richardson. In an unprecedented result, six percent of people with advanced, drug-resistant myeloma reported a complete response, extending their lives by a year or more.

Bortezomib can cripple myeloma that has become resistant to conventional treatment, and it also seems to boost the power of conventional therapies when given in combination. But, in a recurring scenario with the first generation of new targeted therapies, myeloma cells become resistant to bortezomib.

“It is a good drug,” Dispenzieri said. “It is not the cure, but perhaps it will be part of the cure someday.”

Cells have a back-up protein degradation system known as the aggresome, which may compensate when bortezomib hinders the proteasome. Hideshima teamed up with James Bradner, an HMS clinical fellow in medicine at DFCI, to test a specific aggresome inhibitor discovered in the lab of Stuart Schreiber at the Broad Institute of Harvard and MIT.

In test tube models of cancer, the inhibitor, called tubacin, works synergistically with bortezomib to kill myeloma cells. The results provide the preclinical rationale to test the combination in clinical protocols to improve patient outcomes, the researchers conclude in the June 14 Proceedings of the National Academy of Sciences.

Richardson and Anderson have launched clinical trials on another complementary targeted agent after promising preclinical test results pairing a protective molecule called heat shock protein 90 with bortezomib by Constantine Mitsiades, HMS instructor in medicine and senior scientist in the Anderson lab.

“This further supports the view that targeting pathways can have therapeutic efficacy,” Anderson said. “Science is great, but it’s only great if we can help patients.”

—Carol Cruzan Morton

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