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“I think in the next ten years, we are going to have genetic testing [for cancer patients] upfront and decisions based on genetic testing will be available.”

Dr. Navin Pinto, Comer Children’s Hospital at The University of Chicago, March 2012. Chemotherapy–intravenously administering cancer-fighting drugs–works for about 80 percent of cancer patients; Dr. Navin Pinto wants to understand why it fails the remaining 20 percent or, in other words, why certain patients are resistant to chemotherapy. He thinks the answer in a patient’s genes (i.e., DNA), and his research plan to understand and address chemotherapy resistance can be divided into four major phases). As of mid-2012, Dr. Pinto and his colleagues have completed Phases 1 & 2, dedicating over two years in the laboratory and hundreds of thousands of dollars from individuals through private funding organizations. So far, their results indicate that changes in genes are responsible for chemotherapy resistance.

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Researchers have identified genetic changes associated with chemotherapy resistance.

Chemotherapy decreases white blood cell counts. Capitalizing on this phenomenon, Dr. Pinto and his colleagues used white blood cells from 450 healthy volunteers as a means of studying chemotherapy resistance in test tubes: they considered white blood cells that died slowly from chemotherapy drugs to be chemotherapy resistant. Once the researchers identified chemotherapy resistant cells, they extracted the cell DNA and determined the DNA sequence (the order in which the four DNA building blocks are arranged, as if beads on a string). They repeated the process with white blood cells non-resistant to chemotherapy, i.e., cells that died quickly from chemotherapy. By comparing the DNA sequences of chemotherapy resistant and non-resistant white blood cells side-by-side, the researchers identified specific changes in the DNA sequence of chemotherapy resistant cells. These changes support the hypothesis that chemotherapy resistance results from changes at the genetic (DNA) level. Genetic Changes 101, a fact sheet with introductory information about DNA and more details about how researchers identify changes at the genetic level.  

Researchers validated the presence of genetic changes associated with chemotherapy resistance in the DNA of chemotherapy resistant patients but not others.

Dr. Pinto and his colleagues obtained the DNA sequences of 3,500 pediatric cancer patients who had undergone chemotherapy with known outcomes, i.e., some were cured, relapsed, or died following treatment. The researchers analyzed the DNA sequences of the 3,500 post-chemotherapy patients and observed that many of the genetic changes associated with chemotherapy resistance identified during their test tubes studies were present in the DNA of the patients who died following chemotherapy, i.e., patients who were chemotherapy resistant, but not others. This finding further supports the hypothesis that chemotherapy resistance results from specific changes in a patient’s genes. But further studies, such as in Phase 3, are required to determine whether analyzing patients’ DNA for specific genetic changes can reliably predict their resistance to chemotherapy.

Researchers are starting to predict chemotherapy resistance in pediatric cancer patients prior to chemotherapy and will substantiate their predictions by tracking the patients’ chemotherapy outcomes.  

By analyzing the DNA of pediatric cancer patients in a newly underway clinical trial, Dr. Pinto and his colleagues hope to predict which patients are chemotherapy resistant before they receive chemotherapy and confirm their predictions by tracking the patients’ outcomes over the course of the clinical trial. While waiting to determine those outcomes, the researchers will study how genetic changes result in chemotherapy resistance. For example, a certain genetic change might cause a defect in an enzyme that is necessary for chemotherapy to work effectively.

Researchers hope to personalize treatments for pediatric cancer patients within the next decade based on DNA testing.

In Phase 4 of their current research, Dr. Pinto and his colleagues will personalize patients’ medicine with their knowledge about genetic changes leading to chemotherapy resistance and how resistance results. With that understanding, the researchers will be able to test patients’ DNA for genetic changes leading to chemotherapy resistance when patients are first diagnosed with cancer, and individualize treatment decisions based on those DNA testing results. Depending upon the genetic changes found, the recommended treatment might be to forego chemotherapy and instead administer radiation, or augment chemotherapy with medications to compensate for defective enzymes, for example, arising from the observed genetic changes. By personalizing patients’ medicine, caregivers will not only spare them the burden of ineffective, physically taxing treatments, but, more importantly, increase their chances of survival.