Drug Revolution Named STI571

 

No drug has captured the public imagination since the interferon craze in the early 1980s to such an extent as Novartis' STI571. Under the trade name GleevecTM, ​​this drug won US Food and Drug Administration approval on May 10 to treat chronic myeloid leukemia after a very short 2 ½ month assessment.

The TV network carried special coverage and Time magazine's cover story covered the drug. American Society of Clinical Oncology chairman Larry Norton MD, in the New York Times called the STI571 "the beginning of a major change - and I would say conservatively - in the way we practice medicine."

The effectiveness of this drug is simply amazing. In phase I trials, 98% of patients with chronic myeloid leukemia (CML) achieved a complete hematologic response, and phase II results were almost staggering. Across America, only 4500 people experience CML per year. The question that arises is: can more common cancers also respond to drugs like STI571, or is STI571 for CML a one-off success?

The main reason for this doubt is that CML is caused by a single genetic disorder - namely the Philadelphia chromosome translocation that produces the Bcr-Abl fusion protein. Targeting STI571 at Bcr-Abl has been shown to be effective, but other cancers, which are more common, usually involve multiple genetic changes, causing multiple abnormalities that result in uncontrolled cell growth.

Therefore, it may be necessary to have separate drugs intended for each disorder and used in the correct combination. Such complex therapies may take decades to develop. Could there be a drug on the way to work well against breast cancer, prostate cancer, lung cancer and colon cancer?

"I would venture that the answer is yes, with certain qualifications," says Dr. Charles Sawyers of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles. First, says Sawyers, we must identify the signaling pathways that lead to various cancers. "There may be 5 or more different types of prostate cancer," he predicts, "each triggered by different signaling pathways or genetic events."

For example, EGF - epidermal growth factor - is a receptor tyrosine kinase which plays a role in various cancers such as breast and prostate. "A drug that is good for the EGF receptor will probably have a high response rate - if you can identify the right patient," he says. Several EGF receptor inhibitors are currently entering the final phase of phase III clinical trials.

Sawyers argues that researchers should start from molecularly identifying the phenotype of each cancer to predict which patients will respond to a drug. "I think everyone knows this, they just don't want to admit it," he continued. Herceptin for example, is usually only given to breast cancer patients who show (with immunohistochemical staining) overexpression of the Her2/neu receptor.

However, various other kinases are triggered not only by overexpression. The EGF system, for example, also involves heterodimerization, receptor mutations and autocrine/paracrine activation by multiple ligands. Predicting which patients will respond to EGF-targeted drugs, particularly in combination therapy forms, "will require a great deal of clinical experience," says Nick Lydon, PhD, vice chairman of small molecule drug discovery at Amgen Inc. in Thousand Oaks, California.

For that reason, Sawyers invites to do research that is more sophisticated, involving various assays to measure the activation status of receptors. However, the most predictive markers for patient response are unknown. "We just can't use the general results of those trials," Sawyers concedes. We have to take the tissue of patients who are going to have those tests, so we can find out the answers."

Several clinical oncologists have started it. Charles Blanke, MD of Oregon Health Sciences University, Portland, reported dramatic results at the last ASCO annual meeting of a phase II trial in patients with gastrointestinal stromal tumors (GIST), rare but highly aggressive solid tumors, treated with STI571. The overall response is 59% and it takes time.

Blanke typed each patient for a mutation in the c-Kit gene, a tyrosine kinase that triggers GIST. "Mutational activation in exon 11 strongly predicts response (to STI571)," he reported.

However, gathering this kind of information is hard work that often requires multiple tumor biopsies, so it's not always done, says Sawyers. However, he emphasized that it had to be done. "Maybe we should give a speech to oncologists or to pharmaceutical researchers," said Sawyers. "If oncologists say (to drug companies), 'You have to do it this way,' they will."

Source: Novertis