Little Girl with Cancer Holding her IV Pole
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A study by researchers at St. Jude Children’s Research Hospital delving into drug response across a swath of genetic subtypes of acute lymphoblastic leukemia (ALL), could provide a map for clinicians to more precisely match available treatments with a patient’s specific form of cancer. The results, from what the investigators say is the largest pharmacotyping study of ALL to date, were published today in the journal Nature Medicine.

ALL is the most common of all childhood cancers and is also one of the most treatable—roughly 98% of patients going into remission within weeks of starting therapy, and 90% will eventually be cured. Current treatment for ALL is risk-adapted and takes into account a patient’s clinical features, the genetic of their leukemia, and the presence of minimal residual disease (MRD).

The St. Jude researchers, however, wanted to better understand how each patient’s cancer genetics affected drug response. This pharmacogenomic study using data from more than 800 patients and studied children with newly-diagnosed ALL, spanning different St. Jude flagship Total Therapy ALL clinical trials. The trials cover a period of more than 20 years, generating a large and unique cohort of patient data. The scientists determined the sensitivity of leukemia cells to 18 different chemotherapy drugs in patients representing 23 molecular subtypes defined by leukemia genomics.

“Compared to traditional cancer genomics research, our pharmacogenomics work starts with defining the drug response phenotype of each patient, after which we look into genomics to search for the biological basis for the inter-patient variability in leukemia drug sensitivity,” said Jun J. Yang, PhD of St. Jude Department of Pharmacy and Pharmaceutical Sciences and a corresponding author. “This approach sheds light on the therapeutic implications of specific genomic alterations, which may help clinicians alter care through a better understanding of how and why patients respond to treatment.”

Importantly, this research found that ALL subtypes with the best prognosis more closely tied to two chemotherapies: asparaginase and glucocorticoids. One surprise result of the analysis showed that while some subtypes were shown to be genetically similar, they exhibited different patterns of drug sensitivity. Further, even after accounting for known risk factors, the investigators found they could divide the patients into distinct groups based on their drug sensitivity profiles, which was associated with prognosis. This finding, the researchers noted, show the importance of understanding ALL pharmocotypes for survival outcomes.

This study adds functional understanding to previous research that identified high-risk or favorable ALL subtypes. As an example, ETV6-RUNX1 ALL, which has a favorable prognosis while BCR-ABL1-like ALL has a poor prognosis. These pharmacogenomics findings provided insight into why individuals with those subtypes had certain types of prognoses.

The researchers also noted that their findings—which analyzed hundreds of thousands of individual data points—highlight underlying biological pathways that drive ALL. “We hope our data will lead to more discoveries and new targets to drive a new generation of ALL trials in the near future,” said first-author Shawn Lee, MBBS, formerly of St. Jude and now of Khoo Teck Puat-National University Children’s Medical Institute, National University Hospital Singapore.

To build on this research, the investigators at St. Jude hope to expand their findings to encompass greater patient diversity.

“This work is a big step in the right direction to individualize ALL therapy to spare children the side effects of drugs that will not work against their cancer, as well as to steer them to the novel therapies against which their cancer will likely respond,” Yang concluded. “It is functional precision medicine, it’s not just about the genetics and the targets but also about using the right drugs for the right patients.”

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