The most comprehensive study yet has described the variations in drug response across different genetic subtypes of acute lymphoblastic leukaemia (ALL), providing what researchers call a blueprint for precision medicine.
The study, completed by scientists at St. Jude Children’s Research Hospital, Memphis, Tennessee, USA, studied the pharmacogenomics of ALL by examining how the cancer cells respond to different therapeutics in the context of their cancer genomics. This involved testing 18 drugs on samples donated by more than 800 patients over 20 years.
The results revealed wide variability across ALL, as well as distinct patterns of drug sensitivity by subtype. The findings are published in the journal Nature Medicine.
Corresponding author Dr Jun Yang, from the St. Jude Department of Pharmacy and Pharmaceutical Sciences, said compared to traditional cancer genomics research, pharmacogenomics starts by defining the drug response phenotype of each patient – also known as a ‘pharmacotype’.
Afterwards, they studied genomics to search for the biological basis for the inter-patient variability in leukaemia drug sensitivity.
“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,” he added.
The research team found that ALL subtypes with the most favourable prognosis are closely tied to sensitivity to the chemotherapeutic drugs asparaginase and glucocorticoids.
They also found that patients could be divided into distinct groups based on their drug sensitivity profiles, which was associated with prognosis even after accounting for known risk factors.
The researchers studied children with newly-diagnosed ALL, spanning different St. Jude flagship Total Therapy ALL clinical trials over 20 years. They determined the sensitivity of leukaemia cells to 18 different chemotherapy drugs in patients, representing 23 molecular subtypes defined by leukaemia genomics.
“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 joint first author Dr Shawn Lee, formerly of St. Jude and now of Khoo Teck Puat-National University Children’s Medical Institute, National University Hospital Singapore.
“ALL is actually a very heterogeneous disease - there are a lot of differences between genomic subtypes, such as presenting features and prognosis. Now, we have shown how drug sensitivity also varies between subtypes.”
The researchers want to expand the findings with added population diversity.
Dr Yang said: “This work is a big step in the right direction to individualise 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.
“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.”
Lee SHR, Yang W, Gocho Y, John A, Rowland L, Smart B, Williams H, Maxwell D, Hunt J, Yang W, Crews KR, Roberts KG, Jeha S, Cheng C, Karol SE, Relling MV, Rosner GL, Inaba H, Mullighan CG, Pui CH, Evans WE, Yang JJ. (2023) “Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response.” Nature Medicine, doi: 10.1038/s41591-022-02112-7
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