12:00 AM
Feb 27, 2006
 |  BioCentury  |  Product Development

Targeted =/ narrow

A great deal of nonsense has been written about molecular medicine. This ranges on the one hand from puff pieces claiming that targeted therapeutics will provide the perfect drugs to cure every patient without side effects, all the way to warnings of doom for the industry as markets get sliced into smaller and smaller pieces. Like most such notions based on group-think rather than the hard analytical work, both ideas are simply wrong.

Some of the first targeted cancer therapies, such as Herceptin and Gleevec, have shown complete cures with a single drug will be the exception, even in cancers driven by a specific target, and initial impressive responses may not be durable.

In contrast to Herceptin, which is given only to patients who overexpress HER2, Avastin and Tarceva have no restrictions related to patients' expression of their targets, demonstrating that a targeted drug does not automatically equate to a narrow label.

In fact, deconstructing the short history of targeted therapies shows that a more complex picture is emerging.

For starters, in cancer and other diseases, the targeted therapies themselves have created new markets in patients whose diseases have become resistant to these drugs.

At the same time, researchers are pursuing targeting strategies to restore normal biological processes that clearly will have utility in very broad populations.

The most important lesson is that targeting strategies present clinical researchers with key choices. One is whether to develop molecules that are exquisitely specific or relatively promiscuous. Another is whether - and when - to enrich clinical trials. The choices will be influenced by the knowledge of the biology, the ability to assay for the target, and the regulatory strategy.

The upshot is that targeted therapies will be neither magic bullets, nor the end of blockbuster drugs. Instead, they will help define large, new, biology-driven markets at the same time that they create new niches.

Silver bullets

When the idea of targeted therapeutics gained widespread currency in the mid-1990s, it was viewed in many ways like gene therapy: researchers would find and understand a genetic defect, there would be one target, and the resulting therapy would cure the disease.

The reality has been quite different. With the possible exception so far of Gleevec imatinib from Novartis AG (NVS; SWX:NOVN, Basel, Switzerland), the silver bullets look like they will be rare. Moreover, at least in cancer, even those bullets will provide only a temporary reprieve.

In retrospect, this shouldn't be surprising. Biological systems, including disease systems, generally have multiple workarounds to ensure achievement of critical path goals. In practice, this reality has played out in several ways.

The early lessons came from Herceptin trastuzumab, an anti-HER2 monoclonal antibody from Genentech Inc. (DNA, South San Francisco, Calif.). It was approved in 1998 to treat patients with metastatic breast cancer whose tumors overexpress HER2. Initial approval was as a first-line therapy in combination with paclitaxel, and as a single agent in second- and third-line therapy.

The target population had the characteristics of one that would respond to a silver bullet, as the 20-25% of women with metastatic disease who overexpress HER2 have poor prognoses. Yet despite the fact that only patients who overexpress the target are treated, not all of them respond.

"Sometimes targeted therapies will be a magic bullet, but in general cancers are complicated and have sophisticated systems for mutating, " said Hal Barron, SVP of development and CMO at DNA. "And our ability to differentiate tumors into different pathways that are causing the problem hasn't been perfected yet. Even in HER2 overexpressing patients, other pathways can overcome it."

Over the years, DNA has learned more about the molecular mechanisms that are important in driving tumor growth in patients who progress despite Herceptin therapy.

Several hypotheses have been proposed, according to Kenneth Hillan, vice president of development sciences at DNA. These include activation of the PI3 (phosphoinositide 3) kinase pathway (e.g., via inactivation of PTEN, an intracellular signaling molecule that is a tumor suppressor gene), and up-regulation of other receptor tyrosine kinases such as EGFR and insulin-like growth factor-1 (IGF-1) receptor) (see "Pathway Complexity").

"These hypotheses need to be examined in independent tumor sample sets with robust patient outcome data," Hillan said. "If confirmed, these findings would provide a scientific rationale for the design of combination therapy regimens that could augment tumor cell response to Herceptin."

The next lesson came from Gleevec, which is approved to treat chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST). Gleevec's target populations also had characteristics amenable to a silver bullet, or rather, multiple silver bullets, as the drug targets the tyrosine kinases Bcr-Abl, c-kit and platelet-derived growth factor (PDGF) receptor, as well as the Src family tyrosine kinase Lck.

All CML patients express the mutant kinase fusion protein Bcr-Abl, and in clinical trials, Gleevec produced dramatically high response rates in a variety of CML patients, particularly in early stage patients whose disease is driven by this mutation.

But it doesn't cure. By the time CML has progressed to acute leukemia (blast crisis), it is more genetically complex.

"These patients respond to Gleevec, but the response is not durable, as the tumor is dependent on more than Bcr-Abl," noted George Daley, of the Division of Pediatric Hematology/Oncology at The Children's Hospital Boston and Dana-Farber Cancer Institute. Daley, who also is in the Department of Biological Chemistry and Molecular Pharmacology at Harvard Medical School, proved that Bcr-Abl causes CML.

The inability of most targeted cancer therapies to be curative will generally be driven by two factors: mutation and heterogeneity. In the case of Gleevec and CML, the target enzyme mutates and becomes resistant.

"You can probably deal with this by giving a combination of two or three different inhibitors that are mutually exclusive to inhibition," noted George Scangos, president and CEO of Exelixis Inc. (EXEL, South San Francisco, Calif.). "The other issue, especially with solid tumors, is that they are heterogeneous, so even if you kill 80% of cells expressing, say, EGFR, the remaining 20% of the cells will be driven by other factors."

Thus it is now clear that complete cures with a single drug will be the exception rather than the rule. Instead, cocktails will be the norm, much like in HIV treatment, where multiple drugs help prevent the disease from winning the evolutionary arms race.

"The key is the combination of drugs that prevents the emergence of resistance," said Michael Morrissey, SVP of discovery research at EXEL. "That's the bane of HIV, and it's more complex in cancer because of pathway redundancy - you turn one thing off, and something else turns on."

Thus, said Scangos, "I could see delaying the appearance of resistant mutants, and I see long-term survival, rather than cures, as the future of cancer therapy."

Indeed, as in HIV, the targeted therapies themselves are creating new niche markets for cancers that have become resistant to these drugs.

"Perhaps the best understanding of this problem at a molecular level comes from studies of Gleevec resistance in CML patients," wrote Charles Sawyers in the Nov. 18, 2004, issue of Nature. "Recent preclinical studies have identified second-generation dual Src/Abl kinase inhibitors that retain activity against nearly all the Gleevec-resistant mutants. These compounds are now in early clinical testing, but the expectation is that future therapy will rely on cocktails of inhibitors to prevent the emergence of resistant subclones"(see "Gleevec Progressors").

Sawyers is director of the Prostate Cancer Program at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles.

In CML, there is widespread expectation that Gleevec-resistant patients will be treated with dasatinib (

Read the full 6388 word article

User Sign in

Trial Subscription

Get a 4-week free trial subscription to BioCentury

Article Purchase

$150 USD
More Info >