August 2012

Right on target

Finding therapies that take down only one biological molecule remains a challenge

Since 1990, Richard W. Hanson at the Case Western Reserve University School of Medicine has been living with cancer. An expert in metabolism and an opera aficionado with a weakness for Mozart, 77-year-old Hanson has chronic lymphocytic leukemia, the most common form of leukemia in adults. Over the past 12 years, Hanson has endured six rounds of chemotherapy, taking purine analogs, antibodies and other drugs to stop his mutant B cells from multiplying indiscriminately. Each round of chemotherapy has come faster and harder on the heels of the last. “If you have a disease like CLL, it becomes more than just an abstraction,” says Hanson. “It becomes a critical part of your life.”

But Hanson is a scientist to the core, so he has turned himself into an experiment. Over the past year and a half, he has participated in a clinical trial for a drug that specifically targets a tyrosine kinase in B cells. With the new drug, Hanson sees the promise of targeted therapies: “I can truthfully say that without this drug, I would be in that big lab in the sky.”

Targeted therapies are drugs designed with the knowledge of the target’s mechanism of action and biochemical role. In contrast, traditional drug discovery is more happenstance. Compounds, such as natural products, are screened against a number of targets or cells; the ones that show an effect are then studied to understand why selectivity exists.

Targeted therapies are considered to be a relatively new paradigm in drug discovery. The sequencing of the human genome and the following genomic revolution have dramatically increased the number of possible biological targets. As Vern Schramm at the Albert Einstein College of Medicine of Yeshiva University points out, drugs used to be found by screening combinatorial chemical or natural product libraries. This now means that medications in the U.S. Food and Drug Administration’s current approved list hit perhaps just 1 percent of the biological molecules that can be targets. “We’ve really only scratched the surface,” says Schramm.

Much of the excitement about targeted therapies is seen in the cancer world. Historically, a number of chemotherapeutic drugs, like the purine analogs that Hanson took, were little more than poisons that attacked rapidly dividing cells, both healthy and cancerous.

Therapies for other diseases, such as autoimmune, psychiatric and cardiovascular conditions, fared better. “You knew there was a molecule that was involved in a particular pathology, and you targeted it,” says John Kyriakis of Mercury Pharma. In-depth molecular knowledge was missing for many kinds of cancers for a long time.

But the notion of targeted therapies for cancer is a longstanding one. As Siddartha Mukherjee explained in his Pulitzer prize-winning book “The Emperor of All Maladies,” Paul Ehrlich, who won the 1908 Nobel Prize in medicine, dreamed of finding a magic bullet that could distinguish between malignant and normal cells. Stanley Farber and dozens of other physicians and scientists followed him, hunting for chemicals that could specifically seek out cancer cells.

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