Scientists have identified the specific tumor cells that are resistant to treatment and have figured out why they are able to resist it. They have done this by studying the different stages of development of B-cells. They have used this information to create and test a combination of drugs that can effectively treat B-cell leukemia that is resistant to treatment. Despite the fact that the overall survival rate for B-cell acute lymphoblastic leukemia is 94%, it can still be difficult to treat, especially in cases where the cancer has come back or is resistant to treatment, with survival rates falling between 30-50%. This recent discovery by scientists at St. Jude Children’s Research Hospital has provided valuable insight into why some tumor cells are resistant to treatment, and has led to the development of a new combination therapy.
The study identified new strategies for controlling high-risk subtypes of B-ALL in mouse models, which have been published in Cancer Cell.
According to senior co-corresponding author Jun J. Yang, PhD, vice-chair of the St. Jude Department of Pharmacy and Pharmaceutical Sciences, “We have discovered a new explanation for the sensitivity of B-ALL to asparaginase, which is one of the most commonly used drugs for this disease. Despite the drug’s long history, our understanding of how it works to kill leukemia cells remains incomplete, leading to imprecise usage for ALL.”
Scientists discovered a new explanation for B-ALL sensitivity to asparaginase, a commonly used drug for the disease. Jun J. Yang, PhD, vice-chair of the St. Jude Department of Pharmacy and Pharmaceutical Sciences, highlighted the lack of understanding of the drug’s mechanism for killing leukemia cells despite its long history in treatment.The study found that by combining the traditional chemotherapy drug asparaginase with the newer drug venetoclax, they were able to effectively treat B-ALL in laboratory models. The combination of these drugs reduced the number of leukemia cells more than either drug alone and worked faster. This was consistently effective across three different high-risk subtypes of this cancer.
Co-corresponding author Jiyang Yu, PhD, from the St. Jude Department of Computational Biology, stated that the discovery was made possible through single-cell systems biology analysis of B cell development and integration with B-ALL drug sensitivity profiling and bulk RNA-sequencing data.The chairman of the research team stated that their analysis showed that the protein BCL-2 is a weakness in the development of tumors that are resistant to asparaginase. Co-author Ching-Hon Pui, MD, from St. Jude’s Department of Oncology, also mentioned that combining asparaginase with venetoclax could reduce the risk of relapse in acute lymphoblastic leukemia (ALL), which is a major cause of treatment failure. The goal is for venetoclax to enhance the anti-leukemia effects of asparaginase while also managing its toxicity. These ideas will need further study in future clinical trials.venetoclax is already approved by the Food and Drug Administration for use in other pediatric cancers, which makes it a promising option for B-ALL treatment. The drug has been proven to be safe in those cases, clearing the path for potential approval for B-ALL treatment. The main challenge was understanding how venetoclax and asparaginase work together to halt B-cell leukemia.
B-cell maturation is a critical stage in B-ALL
B-ALL is a type of cancer that originates from B cells, a type of white blood cell. Normally, B cells go through eight steps of development from immaturity to full maturation. In cancer, the cells can become stuck in an intermediate stage.The development of T-cell acute lymphoblastic leukemia is influenced by the stage at which the T cells become trapped, according to a study published in Nature Cancer in 2021. Researchers Yang and Yu aimed to uncover why cells at specific stages respond to certain drugs, in the hopes of identifying new treatment options. Yu explained, “In this case, we found tumor B cells are stuck in two major stages. One is an earlier stage that is more resistant to asparaginase and another later stage that is more sensitive.”
Yu’s research focused on analyzing gene expression data from hundreds of thousands of cancerous B cells to uncover their differences. The study identified two primary stages of B-cell development in B-ALL: pre-pro-B (early) and pro-B (late). Yu’s lab then sought out the genes that were upregulated in the resistant early cells in order to pinpoint potential vulnerabilities for therapeutic targeting.
One significant finding was the protein BCL-2, which appeared to drive asparaginase-resistance in leukemia cells with pre-pro-B characteristics, according to Yu. B cell lymphoma protein 2 (BCL-2) plays a role in cell death and is utilized by cancer cells.The researchers found that cancer cells can develop resistance to the drug asparaginase by activating the protein BCL-2, which is downstream of mTOR, the protein targeted by asparaginase. This led the scientists to explore the use of venetoclax, which targets BCL-2, in combination with other treatments to overcome drug resistance. According to Yang, the addition of asparaginase affects mTOR signaling, leading to increased BCL-2 activity and making the cancer cells more susceptible to venetoclax. The implications of this research extend to other types of cancer, as many of them stem from abnormal cell development.The analysis of the gene sequencing in leukemia cells may offer similar opportunities to enhance treatments in those situations. “We found that stopping the development of cancer cells can make them responsive to certain drugs,” explained Yang. “Once we identify the pathways involved, we can discover new combinations of drugs to improve the outcomes of treatment.”
