Scientists at St. Jude Children’s Research Hospital are using an innovative approach that combines pharmacology and systems biology tools to identify the next generation of acute lymphoblastic leukemia (ALL) treatments. They found that dasatinib, already approved to treat B Cell ALL (B-ALL), may also be effective in T Cell ALL (T-ALL). Their approach highlighted the importance of looking beyond genetics to suggest new therapies. The work was published online today in Nature Cancer.
The cure rate for pediatric ALL is 95%. Advances in cancer genetics have revealed vulnerabilities in cancer cells that have been exploited by treatment. However, new strategies for identifying therapeutic targets are needed for the cases that do not have known genetic drivers. Researchers are looking beyond genetics to better understand the biology of these cancers and identify new treatment strategies.
“Ultimately, we want to revolutionize ALL therapy by developing a new batch of drugs that are targeted to the biology of each patient’s disease,” said co-senior author Jun J. Yang, Ph.D., of the St. Jude departments of Pharmaceutical Sciences and Oncology. “Genetics are just the tip of the iceberg. We want to look beyond mutations to really understand what is going on in ALL in the context of treatment.”
A new purpose for an existing drug
Dasatinib is a targeted therapy used to treat B-ALL with BCR-ABL fusions (nicknamed the Philadelphia chromosome). Dasatinib is not currently used to treat T-ALL because this subtype does not regularly harbor the BCR-ABL alterations. However, the researchers found that as much as 41% of T-ALL in children may respond to dasatinib, using a new technique called pharmacotyping. This platform enables scientists to directly test leukemia cells in the laboratory for their sensitivity to a diverse set of chemotherapies.
To understand why this drug may be successful in T-ALL, the researchers turned to NetBID, a network-based systems biology algorithm developed at St. Jude. NetBID enables researchers to expose hidden drivers that may not be genetically altered or exhibit differential expression. The program lets users analyze RNA-Seq data beyond differences in gene expression, to infer protein activity by using an intracellular signaling network built from an independent cohort of T-ALL RNA-seq profiles.
“We created NetBID to help overcome the limitations of existing technology and provide a new way to integrate multi-omics data to identify unrecognized drivers that may be missed by conventional mutation or differential expression analyses,” said co-senior author Jiyang Yu, Ph.D., of St. Jude Computational Biology. “With NetBID, we can transform expression profiles into activity profiles to tell us much more about what is going on in the leukemia cells. It helped us explain the unexpected sensitivity of dasatinib in T-ALL and identify novel therapeutic targets.”
Network connections reveal a new weakness
Findings from their NetBID analysis of T-ALL treated with dasatinib led the researchers to LCK, a protein associated with the maturation of blood cells (differentiation). They showed that leukemic cells get stuck at a stage of their development where LCK would normally be active for T cell development. Because these cancer cells get stuck, their remarkable LCK activation presents a therapeutic opportunity. The work highlights the need for researchers interested in new treatments for ALL to look at biologic processes beyond genetics, such as differentiation.
This research provides support for developing clinical trials to test dasatinib for treating T-ALL. The work also provides a blueprint for how researchers can shift their thinking about ALL treatment and move beyond genetics to exploit every vulnerability.
“Very few new drugs have been developed for T-ALL in the past three decades. Using this novel research method, we are excited to see that dasatinib, a drug used to treat several high-risk subtypes of B-ALL, is also quite effective for a large proportion of patients with T-ALL,” said author Ching-Hon Pui, M.D., St. Jude Oncology Department chair. “Not only is this a new drug that may improve clinical outcomes for children with T-ALL, but we’ve also discovered a new methodology to identify more effective drugs in the future.”
The study’s co-first authors are Yoshihiro Gocho, Jingjing Liu and Jianzhong Hu, all of St. Jude. Other St. Jude authors include Wentao Yang, Jingliao Zhang, Hao Shi, Guoqing Du, August John, Ting-Nien Lin, Jeremy Hunt, Xin Huang, Bensheng Ju, Lauren Rowland, Lei Shi, Dylan Maxwell, Brandon Smart, Kristine Crews, Wenjian Yang, Kohei Hagiwara, Kathryn Roberts, Hong Wang, Scott Newman, John Easton, Jinghui Zhang, Junmin Peng, Hongbo Chi, Stanley Pounds, Mary Relling, Hiroto Inaba, Charles Mullighan and William Evans. Additional authors of the paper are Neekesh Dharia and Kimberly Stegmaier of Dana-Farber Cancer Institute and Broad Institute of Harvard and MIT; Yingchi Zhang and Xiaofan Zhu of the Chinese Academy of Medical Science and Peking Union Medical College; Elias Jabbour, Steven Kornblau and Marina Konopleva of University of Texas MD Anderson Cancer Center; Wendy Stock and Bartholomew Eisfelder of University of Chicago Medical Center; Elisabeth Paietta of Montefiore Medical Center; Giovanni Roti of Dana-Farber Cancer Institute and University of Parma; Mark Litzow of Mayo Clinic; and David Teachey of University of Pennsylvania.
The research was funded in part by grants from the National Institutes of Health (R35CA210030, R37CA36401, P50GM115279, R01GM118578, R01GM134382 and P30CA21765), the St. Baldrick’s Foundation, the Pan-Mass Challenge Team Crank, Tokyo Children’s Cancer Study group overseas scholarship, Nippon Medical School and ALSAC, the fundraising and awareness organization of St. Jude.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer and other life-threatening diseases. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20 percent to 80 percent since the hospital opened more than 50 years ago. St. Jude freely shares the breakthroughs it makes, and every child saved at St. Jude means doctors and scientists worldwide can use that knowledge to save thousands more children. Families never receive a bill from St. Jude for treatment, travel, housing and food — because all a family should worry about is helping their child live. To learn more, visit stjude.org or follow St. Jude on social media at @stjuderesearch.