Researchers Using Genomics, Immunotherapy to Tackle Hard-to-Treat Cancers in Children
Children who develop cancer in the United States have a much better chance of surviving than they did in decades past—about 80% on average now, up from 10% in the 1960s. But even though new drugs have helped achieve that, most patients still receive the same basic treatment: chemotherapy and radiation. Soon, however, children with cancer may receive therapies that manipulate a tumor cell’s function to strangle it or train a patient’s immune system to identify and kill cancer cells, researchers said at AAAS.
One of the key challenges for researchers is that children’s cancers are very different from adult cancers—they are caused by different genetic defects, and use different biological pathways in the body to grow, researchers say. That means drugs used to treat adult cancers often aren’t effective for children. Children are also more susceptible to developing long-term side effects from the highly toxic drugs and radiation used to kill cancers, but as adults, most survivors don’t have their full medical history and their doctors lack the information they need to monitor them for conditions that develop later in life.
Four cancer researchers described projects that are addressing those problems at a 19 October symposium, “Pediatric Cancer in the 21st Century: Harnessing Science to Improve Outcomes,” sponsored by the AAAS journal Science Translational Medicine and the Washington Academy of Sciences.
Will Parsons, director of the Pediatric Center for Personal Cancer Genomics & Therapeutics at Texas Children’s Cancer Center, said that by identifying the specific mutations and biological pathways used by specific tumors, researchers can begin to distinguish more precisely the type of cancer a child has, and then provide therapies targeted at those pathways.
As an example, Parsons showed the survival rates for children with a type of brain cancer called medulloblastoma. Researchers have found that it uses four different biological pathways to develop. One of the medulloblastoma types responds very well to current drugs, so children with that type are almost always cured, Parsons said.
But children with medulloblastomas caused by a different set of genes are “one group where our standard treatment isn’t working at all,” Parsons said. “They’re essentially all dying within 10 years of diagnosis.” Those are the patients who doctors should be trying to identify early on, to prevent them from getting painful, ineffective treatments, and to develop new treatments that target their cancer’s pathway, he explained.
“The key point is we don’t just have one type of cancer [in medulloblastoma], we have four types of cancer. And they’re very different, both in their biology and clinical outcomes,” Parsons said.
New therapies are being enabled by an “avalanche of data” from studies going on now of thousands of cancer genomes that will identify the specific mutations that drive childhood cancers, said Malcolm Smith, associate chief of the Clinical Investigations Branch in the Cancer Therapy Evaluation Program at the National Cancer Institute.
“In the next year or two, we will know the recurrent genomic regions for most childhood cancers,” Smith said. The research is the result of an NCI-sponsored initiative called TARGET (Therapeutically Applicable Research to Generate Effective Treatments) that will help improve diagnosis of a child’s specific sub-type of cancer identified by mutations and help to develop more effective therapies.
However, that won’t solve all the challenges. For instance, not all cancers will be able to be targeted by drugs or other agents, he said, since some cancers are driven by a deletion of a tumor suppressor gene. “It’s hard to target something that’s not there,” Smith said. Likewise, “we’ll have to learn to ‘drug’ the currently ‘undruggable’ genes that drive childhood cancers,” he said, such as genes that can modify proteins in harmful ways, but that scientists don’t yet know how to target.
One promising treatment alternative is immunotherapy, which trains the body to use its own disease-fighting pathways to recognize cancer cells as foreign and kill them. While the idea is a century old, it’s only in the past 20 years that researchers have been able to identify antigens that the immune system can use to identify and attack tumors, said Crystal Mackall, chief of pediatric oncology at the National Cancer Institute’s Center for Cancer Research. Such an approach is important for hard-to-treat cancers, like solid tumors that have metastasized, she said. Those patients’ survival rate is less than 20%, and has not improved over the past 20 years.
Mackall is investigating ways to train a patient’s T cells—a white blood cell that naturally helps the immune system fight illness and infection—to identify cancer cells. One technique, called chimeric antigen receptor (CAR) therapy, draws white blood cells out of a patient’s body, genetically modifies them in the laboratory to recognize and attack tumor cells, then injects them back into the patient. The CAR technique goes a step beyond a therapeutic cancer vaccine, which uses an altered virus to introduce parts of cancer cells or pure antigens into a patient’s body to stimulate an immune response. CAR therapy takes less time than vaccines to stimulate a response, since the body is slower at creating the trained T cells than the laboratory process. CAR therapy could be especially important for attacking solid tumors, which have been harder to treat, Mackall said.
But it’s not enough to create cancer-fighting white blood cells. The researchers also have had to find a way to get a patient to start making any white blood cells again after getting chemotherapy and radiation to give these immunotherapies the best chance of working.
“Chemotherapy is profoundly immunosuppressive,” Mackall said, since the drugs are designed to kill any quickly-replicating cell, a broad target that includes the healthy tissue that creates white blood cells. “Often, the tumor recovers faster than the immune system.” Researchers have successfully boosted T-cell production in pediatric patients participating in a clinical trial, which seems to be helping their response to a cancer vaccine and caused only mild side-effects, Mackall said.
Finally, as more children survive cancer, it is becoming more important to have methods to ensure they will get proper medical care to help diagnose and treat conditions that they are at increased risk of developing due to cancer drugs and other treatments. Not only are they often at risk of developing a second cancer, but some drugs can increase their risk of a variety of medical problems, including heart attacks, cataracts, and infertility.
A lack of consistent long-term follow-up care and the difficulty pediatric patients have getting their medical records when they are adults means many don’t get screened for these conditions, said David Poplack, director of the Texas Children’s Cancer Center. Doctors also often have no way to reach survivors if they identify a new health risk associated with a particular drug or treatment.
“You can imagine that the parents of a 6-year-old child are pleased that the child recovers, but they’re also concerned about whether the child will get appropriate follow-up care after they’re gone,” Poplack said.
The lack of coordination has become “a major public health problem,” Poplack said. To address it, the Texas Children’s Cancer Center has collaborated with the Children’s Oncology Group to develop an Internet-based program that generates care guidelines for cancer survivors based on the medical history they provide. By describing the drugs or radiation they received, their age and type of cancer, the program will tell them what their doctors need to look for. The “Passport for Care” program will eventually be made available for adult cancer survivors as well, he said.
Lois Shaler, a nurse at the Walter Reed Hospital’s Pediatric Hematology-Oncology Clinic who attended the symposium, said she found the potential advances in treatment to be interesting and hopeful, particularly the program to improve follow-up care. “You want each patient to be the underdog that makes it,” she said.
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