A team of researchers from Roswell Park Comprehensive Cancer Center and the Markey Cancer Center in Lexington, Kentucky, report that the efficacy of doxorubicin, a widely used chemotherapy drug, was enhanced in preclinical lymphoma models when it was combined with propranolol, a beta-2 adrenergic receptor (beta-AR) blocker commonly used to treat high blood pressure, and which also blocks the effects of stress in the body. The approach illustrates the team’s findings that the metabolic fitness of myeloid-derived suppressor cells (MDSCs) — white blood cells that can suppress the immune system and support tumor growth and metastasis — limits response to therapy.
Led by Roswell Park postdoctoral fellow Saeed Daneshmandi, PhD, and senior author Hemn Mohammadpour, DVM, PhD, Assistant Professor of Oncology in the Department of Cell Stress Biology at Roswell Park, the study, “Myeloid-derived suppressor cell mitochondrial fitness governs chemotherapeutic efficacy in hematologic malignancies,” is newly published in Nature Communications.
Hematologic malignancies, such as lymphoma, leukemia and myeloma, are commonly treated with chemotherapeutic agents such as doxorubicin, which works by killing cancer cells directly. And while higher numbers of MDSCs are associated with poor prognosis in patients with hematologic malignancies, chemotherapy also increases the number of MDSCs, and the cells’ metabolic fitness helps them thrive in the tumor microenvironment.
Dr. Mohammadpour and his colleagues found that their metabolic fitness grew stronger with the activation of beta2-AR, which triggered signal transducer and activator of transcription 3 (STAT3) signaling, which promotes metastasis and angiogenesis, the growth of blood vessels that support the tumor.
The study is especially notable because the research team revealed the previously unknown roles of two elements regulated by STAT3 signaling, both of which influence the efficacy of chemotherapy: mitochondrial adenosine triphosphate (ATP), which provides energy for MDSC metabolic fitness and is associated with aggressive cancers, and itaconate, which regulates the immune metabolism of MDSCs.
Using T lymphoblastic lymphoma and acute myeloid leukemia (AML) preclinical models, the investigators combined doxorubicin with the beta blocker to reduce beta-AR signaling, which disrupted the STAT3 pathway and decreased the metabolic fitness of MDSCs. The strategy resulted in reduced tumor growth and extended survival.
“Together, these studies reveal the STAT3, and ATP and Itaconate metabolism as key regulators of MDSC metabolic fitness which determines the response to doxorubicin therapy in the EL4 lymphoma model,” the authors note. “The STAT3 pathway ATP and Itaconate metabolism are targets for clinical trial development to improve current chemotherapy regimens in hematologic malignancies.”
“This work provides us with a deeper understanding of how stress signaling affects cancer treatment outcomes,” says Dr. Daneshmandi, study first author.
The authors gratefully acknowledge support from donors to the Roswell Park Alliance Foundation, including Brendan and Elise McCarthy, as well as grant support from the National Cancer Institute and other National Institutes of Health agencies (grant numbers P30CA177558, K99HL155792, R00HL155792, R01 CA205246, F30CA265127 and P30CA016056).
Roswell Park has opened a first-in-human clinical trial for B-cell lymphoma using “armored” Car T-Cells, that are manufactured on-site.
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