Off Target

April 27, 2014

Once considered the Holy Grail for cancer treatment, targeted therapy is losing its luster.

Once considered the Holy Grail for cancer treatment, targeted therapy is losing its luster.

The U.S. Food and Drug Administration usually takes about six months to approve cancer drugs. In 2001, Novartis’ Gleevec made it through the process in less than three.

Its speedy regulatory success was based on striking results from clinical trials of patients with Philadelphiachromosome positive chronic myelogenous leukemia, or CML, a rare cancer that affects 6,000 people a year. Gleevec, also known by its generic name imatinib, was designed to seek out and kill only cancer cells, leaving healthy cells untouched — and it accomplished the task with remarkable precision. Before Gleevec, CML’s five-year survival rate was only 30 percent. But with the targeted therapy, 90 percent of patients were cured.

For nearly four decades, scientists had searched for a molecular therapy that would target cancer cells exclusively. It was the Holy Grail for researchers, and Gleevec was proof that it was possible. Tommy Thompson, then secretary of the U.S. Department of Health and Human Services, hailed the drug as a major scientific and medical breakthrough and announced a 12 percent increase in cancer funding for the National Institutes of Health. Things were looking up for targeted cancer therapy research.

Researchers analyzed the genome in dozens of adult and childhood malignancies, hoping that all cancers had a silver bullet oncogene like the one Novartis had discovered in CML. Time and again, they were disappointed. It appeared that CML’s dramatic response to targeted therapy was an anomaly.

Deflated, many believers in targeted cancer therapy began to have doubts. How could something that once seemed like such a sure thing turn out to be so wrong?


Targeted therapies aim to inhibit certain molecular functions specific to cancer cells. Some block enzymes that otherwise instruct cells to reproduce with abandon while others attempt to directly program cancer cell death or prevent the growth of blood vessel infrastructure around tumors. The goal is to kill only oncogenic cells, unlike standard chemotherapy, which destroys fast-replicating cells indiscriminately. In theory, the side effects of targeted therapies are less severe than those of traditional cancer treatments.

CML’s “miracle” drug worked by accurately targeting an abnormal enzyme in and around cancer cells that promotes uncontrolled growth of tumors, inhibiting the enzyme’s function and resulting in slowed cell growth and eventual death. But scientists now know that Philadelphia-chromosome positive CML is rare in two key respects. First, its cause (an abnormal chromosome pattern produced by genes leads to overexpression of the targeted enzyme) is the same in both adults and children with the disease. Second, this irregularity is causative instead of a consequence of the disease.

Unlike CML’s simple enzymatic “on” switch, any given disease may have multiple pathways that can cause malignant transformation in a cell. Nearly all types of cancers result from a complex network of genetic, cellular and environmental interactions. Couple that with the ability to adapt and use other pathways to grow and reproduce, and the target does more than just move — it morphs into another target altogether.

“What is alarming is how quickly a cell adapts to using another pathway,” says Peter Houghton, PhD, director of the Center for Childhood Cancer and Blood Diseases in The Research Institute at Nationwide Children’s Hospital. “It’s like a balloon. You squeeze it in one place and it pops out in another. Cells can change malignant pathways, probably in minutes when they’re under stress.”

This explains why many targeted therapies for childhood cancer have resulted in only short-term improvements. Even excellent initial responses may disappear three months later as resistance develops.

“Just because they’re molecularly targeted doesn’t mean you’re not going to get resistance,” explains Dr. Houghton, who also directs the National Cancer Institute’s Pediatric Preclinical Testing Program, which is based at Nationwide Children’s.

The next logical strategy becomes blocking multiple pathways to decrease the chance of resistance, but oncologist Timothy Cripe, MD, PhD, warns of escalating toxicities with combined targeted therapies. Shutting off a cancer’s alternate malignant pathway options may impact healthy cells that need those processes to function normally.“A better approach may be to combine targeted therapies with traditional cancer treatments,” says Dr. Cripe, chief of the Division of Hematology, Oncology and Blood and Marrow Transplant at Nationwide Children’s. “But really outmaneuvering cancer means thinking more long-term than initially anticipated, seeing the bigger picture.”


Some researchers have attempted to transfer findings from adult clinical cancer trials to the treatment of children with the same diagnosis, hoping to spread the wealth from effective therapies in the adult world. But a single cancer can have dozens of subtypes, each with its own malignant actor, and the molecular cause of an adult cancer may differ significantly from the cause of the same disease in kids. This throws a major wrench into the pursuit of curative therapies for childhood cancers, Dr. Cripe says, since advancements in pediatric oncology often depend on progress in the adult world.

“In pediatrics, there don’t appear to be a lot of specific cancer ‘on’ switches like there are in many adult cancers,” Dr. Cripe says. “In many cases, the genome is relatively quiet. When there are no obvious molecular triggers, it’s hard to develop a targeted therapy.”

Scientists will have to figure out which childhood cancers have viable targets for molecular therapies — and whether they match targets in adult cancers — before there can be productive sharing between the world of adults and kids, he says. But even in the case of common triggers, targeted therapies considered effective from the viewpoint of adult oncology may fall short of expectations in pediatrics.

“When you talk of extending a 6-year-old’s life by three months, I think you put it in perspective,” says Dr. Houghton. “A brief extension of life is not the end goal of pediatric cancer research. We have to look at molecularly targeted drugs in the context of curative therapy.”

Ideally, children survive decades after a cancer diagnosis, so long-term effects of targeted therapies also matter. Growth, fertility and quality of life cannot be ignored when developing and testing such treatments.

“Right now, there are few data to show the long-term side effects of many of the targeted agents in children, so we don’t yet know what a lifetime of these drugs might do,” says Lia Gore, MD, founder and leader of the Experimental Therapeutics Program at Children’s Hospital Colorado and co-director of the Pediatric Oncology Experimental Therapeutics Investigators’ Consortium. “Hitting some targets may have deleterious effects on normal mechanisms of childhood growth and development.”

Beyond the biological challenges in developing targeted therapies for pediatric cancers, the financial difficulty of developing drugs specifically for rare diseases and the understandable limitations on pediatric clinical trials can also restrict the field’s progress.

“It can be frustrating,” Dr. Cripe admits. “We’re left with the drippings of the adult world when it comes to new drugs and options for clinical trials.”

A small pool of potential trial participants further complicates the matter. About 13 million adults in the United States currently have cancer, while only 35,000 children do. The fact that these children have many different cancers also means that, for any given molecular target, there may be only a handful of eligible children each year to test a particular experimental targeted therapy.

Even the most common pediatric cancer, acute lymphoblastic leukemia, is more than 20 different diseases on a molecular level. Further reducing the number of potential clinical trial participants is the fact that approximately 90 percent of children diagnosed with cancer each year in the United States respond well to existing initial treatments. Only those who are unresponsive or relapse are typically eligible to try experimental therapeutics.

“It’s a problem of our prior success,” says Michael Link, MD, professor of pediatrics at Stanford University School of Medicine. “It’s very difficult for an institutional review board to consent to a brand new therapy when the standard treatment, even with its side effects, still has an 80 percent chance of a cure.”

Adding a targeted therapy to standard cancer treatments partially ameliorates the challenge of a limited population for clinical trials, Dr. Link says, but it does nothing to address what is, perhaps, the most significant barrier to the future of targeted therapy in pediatric oncology: money.

“More important than the lack of federal funding for pediatric oncology research is the lack of pharmaceutical company interest,” says Dr. Link, past president of the American Society of Clinical Oncology and the first pediatric oncologist to have held that position. “Unlike adult cancers, all childhood cancers are rare; it would be nice if there were a better incentive for developing drugs for what are essentially orphan diseases.”


Dr. Houghton has devoted more than 20 years to the search for a molecular-level solution to treat these rare diseases. He admits he’s disappointed with the current lack of evidence to support targeted therapeutics for most childhood cancers. But he also isn’t ready to give up.

“I do believe that at some point we will be able use effective targeted therapies to tailor treatment to the particular molecular characteristics of patients’ tumors,” he says.

Biology has offered a tough reality check for the field’s proponents but still provided enough success to leave researchers cautiously optimistic.

“Targeted therapy is in its infancy in pediatrics,” Dr. Gore says. “We have a long way to go to understand what targeted agents are most promising, how to use them with or without current standard therapies and what the longterm effects of targeted therapies will be.”

Many molecular targets remain unexplored, and slow but steady progress in the field may yet offer targeted drugs an auspicious — albeit limited — future in childhood cancer treatment.

“We just have to be smart enough to get from where we are now to that future of using highly effective targeted therapies,” says Dr. Link. “I can’t believe that 20 years from now we won’t be targeting cancers in this way.”

However the future of such therapies for pediatric cancers may take shape, the road to their development is likely to be winding. Emerging methods of cancer research, such as immunotherapy and viral therapy, are gradually garnering more scientific attention and federal funding, shrinking the spotlight on targeted therapy.

“I think targeted therapy will be a strategy in the future of pediatric cancer treatment,” says Dr. Cripe, whose viral therapy research aims to specifically infect and kill cancer cells without having to find and turn off their oncogenic drivers. “It won’t be the magic bullet, but it will definitely be a part of the oncologist’s arsenal.”