Molecularly targeted cancer drugs may cause cognitive and behavioral deficits in developing brains; impacts reversible
Environmental stimulation and physical activity post-treatment diminish deficits
Scientists in the Center for Neuroscience Research found that molecularly targeted cancer treatments may cause cognitive and behavioral deficits in other areas of the developing brain beyond their intended targets. These deficits, however, diminish when environmental stimulation and physical exercise are provided after treatment.
The study, which appeared in Cancer Research, is the first to demonstrate the vulnerability of the developing brain when this class of drugs is administered. The findings are based on a pre-clinical study looking specifically at the unique impacts of drugs including gefitinib (Iressa), sunitinib malate (Sutent) and rapamycin (Sirolimus) that target the pathways controlling epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR) or platelet-derived growth factor receptor (PDGFR) while the brain is undergoing rapid growth and development, as in childhood.
“We knew that many of same the pathways these drugs target happen to be particularly active pathways in the young developing brain,” says Joseph Scafidi, D.O., M.S., the study’s lead author and a neonatal neurologist at Children’s National Health System. “We hypothesized that in periods of brain growth where these pathways are more active, we might see that the drugs targeting tumors via these pathways might influence other brain functions at the same time.”
The team found that these agents do alter signaling pathways in the developing brain, including decreasing the number of oligodendrocytes and therefore altering white matter development and function. Additionally, the agents also impact the function of specific cells within the hippocampus related to learning and memory. When younger preclinical subjects were treated, impacts of exposure were more significant. Tests on the youngest pre-clinical subjects showed significantly diminished capacity to complete cognitive and behavioral tasks and somewhat older, e.g. adolescent subjects showed somewhat fewer deficits. Adult subjects saw little or no deficit.
“The impacts on cognitive and behavioral function for the developing brain, though significant, are still less detrimental than the widespread impacts of chemotherapy on that young brain,” Dr. Scafidi notes. “Pediatric oncologists and neuro-oncologists should be aware of the potential impacts of using these molecularly targeted drugs in children, but should still consider them as a treatment option when necessary.”
Researchers also found measurable improvements in cognitive and behavioral function when rehabilitation strategies such as environmental stimulation, cognitive therapy and physical activity were applied after drug exposure.
“The plasticity of the developing brain does make it susceptible to treatments that alter its pathways,” says Dr. Scafidi. “Thankfully, that same plasticity means we have an opportunity to mitigate the damage from necessary and lifesaving treatments by providing the right support after the treatment is over.”
Many major pediatric oncology centers, including the Center for Cancer and Blood Disorders at Children’s National, already incorporate rehabilitation strategies such as cognitive therapy and increased physical activity to help pediatric patients return to normal life following treatment. The results from this study suggest that these activities after treatment for pediatric brain tumors may play a vital role in improving recovery of brain cognitive and behavioral function in the pediatric population.
This research was funded by grants to Dr. Scafidi from the National Brain Tumor Society, Childhood Brain Tumor Foundation, and the National Institutes of Health.