A recent breakthrough by scientists at the St. Jude Children’s Research Hospital has shed light on which tumor cells in B-cell acute lymphoblastic leukemia (B-ALL) resist treatment and how this resistance can be overcome. The researchers, led by senior co-corresponding author Jun J. Yang, PhD, vice chair of the Department of Pharmacy and Pharmaceutical Sciences, describe a new understanding of B-ALL sensitivity to the chemotherapy drug asparaginase. Their findings of this vulnerability in leukemia, published in the journal Cancer Cell, informed the development of a new combination therapy that better controlled high-risk B-ALL in mouse models.
“We found a new explanation of B-ALL sensitivity to asparaginase, which is one of the most commonly used drugs for this disease,” said Yang. “Although asparaginase has been around for almost 50 years, the way we use this drug for ALL remains imprecise. This is partly because we still do not fully understand the mechanism by which it kills leukemia cells.”
While B-ALL, the most prevalent form of childhood cancer has an overall high survival rate of 94 percent, for those that do relapse, treatment is challenging and survival rates among this group of patients drops to between 30 and 50 percent.
The St. Jude researchers employed single-cell systems biology analysis and integrated it with drug sensitivity profiling and bulk RNA-sequencing data for their research.
“Our single-cell network analysis revealed the protein BCL-2 as a hidden vulnerability in the asparaginase-resistant tumor developmental stage,” noted Jiyang Yu, PhD, St. Jude department of computational biology interim chair and co-corresponding author.
Yu analyzed 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)—Yu’s lab looked for the genes upregulated in the resistant early cells to identify potential vulnerability in leukemia 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.
BCL-2 (B cell lymphoma protein 2) is a protein involved in apoptosis. Cancer cells harness this protein to evade the systems that would normally cause these cells to self-destruct. It is also downstream of the protein targeted by asparaginase, MTOR. The researchers found that BCL-2 was activated in cancer cells resistant to the chemotherapy, which led the investigators to the BCL-2 targeting drug venetoclax as part of a combination therapy 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.”
Co-author Ching-Hon Pui, MD, St. Jude Department of Oncology Fahad Nassar Al-Rashid Endowed Chair of Leukemia Research, said this combination therapy could lower the risk of ALL relapses, which is a major cause of treatment failure.
“Ideally, we aim for venetoclax to potentiate the anti-leukemia properties of asparaginase while keeping its toxicity levels in check,” Pui noted. “These concepts warrant further investigation in future clinical trials.”
Venetoclax is an FDA-approved drug that has been cleared for use in other pediatric cancers. Proven safe in these other treatment settings, this could provide a path forward for it to be used in the treatment of B-ALL.
The team noted that this finding could serve as an underpinning for the treatment of other forms of cancers, as incorrect development is an underlying cause of disease development, employing single-cell sequencing could prove a useful tool to suggest improved treatments in these areas.
