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Augmenting chemotherapy with low-dose decitabine through an immune-independent mechanism
Wade R. Gutierrez, … , Varun Monga, Rebecca D. Dodd
Wade R. Gutierrez, … , Varun Monga, Rebecca D. Dodd
Published October 13, 2022
Citation Information: JCI Insight. 2022;7(22):e159419. https://doi.org/10.1172/jci.insight.159419.
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Research Article Oncology

Augmenting chemotherapy with low-dose decitabine through an immune-independent mechanism

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Abstract

The DNA methyltransferase inhibitor decitabine has classically been used to reactivate silenced genes and as a pretreatment for anticancer therapies. In a variation of this idea, this study explores the concept of adding low-dose decitabine (DAC) following administration of chemotherapy to bolster therapeutic efficacy. We find that addition of DAC following treatment with the chemotherapy agent gemcitabine improves survival and slows tumor growth in a mouse model of high-grade sarcoma. Unlike prior studies in epithelial tumor models, DAC did not induce a robust antitumor T cell response in sarcoma. Furthermore, DAC synergizes with gemcitabine independently of the immune system. Mechanistic analyses demonstrate that the combination therapy induces biphasic cell cycle arrest and apoptosis. Therapeutic efficacy was sequence dependent, with gemcitabine priming cells for treatment with DAC through inhibition of ribonucleotide reductase. This study identifies an apparently unique application of DAC to augment the cytotoxic effects of conventional chemotherapy in an immune-independent manner. The concepts explored in this study represent a promising paradigm for cancer treatment by augmenting chemotherapy through addition of DAC to increase tolerability and improve patient response. These findings have widespread implications for the treatment of sarcomas and other aggressive malignancies.

Authors

Wade R. Gutierrez, Amanda Scherer, Jeffrey D. Rytlewski, Emily A. Laverty, Alexa P. Sheehan, Gavin R. McGivney, Qierra R. Brockman, Vickie Knepper-Adrian, Grace A. Roughton, Dawn E. Quelle, David J. Gordon, Varun Monga, Rebecca D. Dodd

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Figure 1

Gem + DAC slows tumor growth and extends survival in a primary mouse model of high-grade sarcoma.

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Gem + DAC slows tumor growth and extends survival in a primary mouse mod...
(A) KP tumors were induced in KP mice using i.m. injection of Cre recombinase adenovirus (Ad-Cre) to locally activate oncogenic Kras and delete p53. After tumor initiation, mice were randomized to 1 of 4 treatment groups: PBS, Gem, DAC, or Gem + DAC. Tumor dimensions were measured by caliper 3 times weekly, and terminal tumor tissue was collected for molecular analyses. (B) At the time of tumor detection, mice were placed in 1 of 4 experimental arms: 6 doses of PBS, 1 dose of Gem (150 mg/kg), 5 doses of DAC (0.2 mg/kg), or 1 dose of Gem followed by 5 doses of decitabine. (C) Treatment with Gem + DAC significantly slowed tumor growth compared with PBS or single-agent controls. Growth rates are reported as the time required for tumors to triple in volume (n = 20–25/group). Boxes represent 25th and 75th percentiles. Whiskers represent minimum and maximum values. Horizontal line represents median; + represents mean. (D) Treatment with Gem + DAC extended survival longer than single-agent treatments. Welch’s ANOVA and Dunnett’s T3 multiple comparison test were used to analyze the data in C. Log-rank (Mantel-Cox) tests with Bonferroni correction were used to analyze the data in D. Adjusted α = 0.00833. *P < 0.05 in C. *P < 0.00833 in D.

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ISSN 2379-3708

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