Venetoclax is already Food and Drug Administration–approved for use in other pediatric cancers, making it an attractive candidate. The drug has proven safe in those settings, paving the way for future approval in B-ALL treatment. The largest hurdle was understanding how venetoclax works with asparaginase to stop B-cell leukemia.
B-cell development stage is a challenge and vulnerability in B-ALL
B-ALL is a cancer derived from white blood cells called B cells. Under normal circumstances, B cells develop from immature to fully mature, passing through eight steps. In cancers, cells can get stuck in an intermediate stage of development. In a related disease, T-cell acute lymphoblastic leukemia, Yang and Yu previously found, as reported in Nature Cancer 2021, that the developmental stage where T cells get stuck determines their sensitivity to therapeutics. The researchers wanted to understand what made cells in a specific stage respond to which drug, hoping that such understanding would present new therapeutic opportunities.
"In this case, we found tumor B cells are stuck in two major stages," Yu said. "One is an earlier stage that is more resistant to asparaginase and another later stage that is more sensitive to it."
Yu looked at gene expression data from hundreds of thousands of individual cancerous B cells to understand what was different about them. After identifying the two dominant B-cell development stages of B-ALL, pre-pro-B (early) and pro-B (late), his lab looked for the genes upregulated in the resistant early cells to identify potential vulnerabilities to target therapeutically.
"The protein BCL-2 caught our attention, as it seems to be a driver of asparaginase-resistance in leukemia cells with pre-pro-B features," Yu said.
B cell lymphoma protein 2 (BCL-2) is a protein involved in cell death. Cancer cells use it to evade the systems that normally cause them to self-destruct. The protein is also downstream of mTOR, the protein targeted by asparaginase. Findings showed that BCL-2 was activated in cancer cells resistant to that drug. That resistance relationship motivated the scientists to try venetoclax, which targets the protein BCL-2, in a combination approach.
"When you add asparaginase, you hit mTOR signaling," Yang said. "In turn, that upregulates the BCL-2 activity, making the cells more sensitive to venetoclax."
The work also has implications for other cancers because incorrect development underlies many forms of the disease. Single-cell gene sequencing and analysis may provide similar opportunities to improve therapies in those contexts.
"We showed that developmental arrest of cancer cells can make them sensitive to certain drugs," Yang said. "Once we determine the pathways involved, we can find new drug combinations to improve treatment outcomes."
Authors and funding
The study's co-first authors are Xin Huang and Yizhen Li, of St. Jude, and Jingliao Zhang, formerly of St. Jude and now of the Chinese Academy of Medical Sciences & Peking Union Medical College. The study's other authors are Xiaofan Zhu and Yingchi Zhang, Chinese Academy of Medical Sciences & Peking Union Medical College; Mark Litzow, Mayo Clinic; Wendy Stock, University of Chicago; Nitin Jain, Elias Jabbour and Steven Kornblau, The University of Texas MD Anderson Cancer Center; Marina Konopleva and Elisabeth Paietta, Albert Einstein College of Medicine; Lei Yan, Huanbin Zhao, Liang Ding, Sheetal Bhatara, Xu Yang, Satoshi Yoshimura, Wenjian Yang, Seth Karol, Hiroto Inaba, Charles Mullighan, Ching-Hon Pui and William Evans, St. Jude.
The study was supported by grants from the National Institutes of Health (R01GM134382, U01CA264610, R35GM141947, R01CA264837, U10CA180820, UG1CA189859 and UG1CA232760), Department of Defense (W81XWH-20-1-0567), St. Baldrick's Foundation, the Lynch family and ALSAC, the fundraising and awareness organization of St. Jude.
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