Acute myeloid leukemia (AML) cells have high oxidative phosphorylation and mitochondrial mass and low respiratory chain spare reserve capacity. We reasoned that targeting the mitochondrial RNA polymerase (POLRMT), which indirectly controls oxidative phosphorylation, represents a therapeutic strategy for AML. POLRMT-knockdown OCI-AML2 cells exhibited decreased mitochondrial gene expression, decreased levels of assembled complex I, decreased levels of mitochondrially-encoded Cox-II and decreased oxidative phosphorylation. POLRMT-knockdown cells exhibited an increase in complex II of the electron transport chain, a complex comprised entirely of subunits encoded by nuclear genes, and POLRMT-knockdown cells were resistant to a complex II inhibitor theonyltrifluoroacetone. POLRMT-knockdown cells showed a prominent increase in cell death. Treatment of OCI-AML2 cells with 10-50 μM 2-C-methyladenosine (2-CM), a chain terminator of mitochondrial transcription, reduced mitochondrial gene expression and oxidative phosphorylation, and increased cell death in a concentration-dependent manner. Treatment of normal human hematopoietic cells with 2-CM at concentrations of up to 100 μMdid not alter clonogenic growth, suggesting a therapeutic window. In an OCI-AML2 xenograft model, treatment with 2-CM (70 mg/kg, i.p., daily) decreased the volume and mass of tumours to half that of vehicle controls. 2-CM did not cause toxicity to major organs. Overall, our results in a preclinical model contribute to the functional validation of the utility of targeting the mitochondrial RNA polymerase as a therapeutic strategy for AML.
MicroRNAs (miRNAs) are small non-coding RNA molecules that have key regulatory roles in cancer, acting as both oncogenes and tumor suppressors. Due to the potential roles of miRNAs in improving cancer prognostic, predictive, diagnostic and therapeutic approaches, they have become an area of intense research focus in recent years. MiRNAs harbor attractive features allowing for translation to the clinical world, such as relatively simple extraction methods, resistance to molecular degradation, and ability to be quantified. Numerous prognostic, predictive and diagnostic miRNA signatures have been developed. To date however, miRNA analysis has not been adopted for routine clinical use. The objectives of this article are to provide an overview of miRNA research and review a selection of miRNA studies in breast cancer, cervical cancer, sarcoma, and nasopharyngeal carcinoma to highlight advances and challenges in miRNA cancer research.
PURPOSE: Li-Fraumeni Syndrome (LFS) is a genetic disorder associated with a significant risk of early-onset cancer. This condition is largely driven by germline mutations in the TP53 tumor suppressor, which has a broad spectrum of functions including the transcriptional regulation of radiation response. Termed the guardian of the genome, TP53 serves as a critical checkpoint which coordinates DNA repair, cell cycle progression and apoptosis following DNA damage, ultimately controlling the fate of the cell. Aberrant or deficient TP53 function, such as occurs in LFS, contributes to radiation vulnerability. As a result, there is particular caution in the use of radiotherapy to treat primary LFS tumors, in order to prevent the formation of secondary, radiation-induced malignancies. To this end, therapeutic options for LFS are often limited to surgery and chemotherapy, posing substantial constraints for the treatment of patients who may otherwise benefit from primary tumor radiation. Metformin, a commonly prescribed anti-diabetic drug, is associated with lower cancer incidence in populations worldwide. Recent studies have shed light on the potential utility of metformin as a pharmacopreventive agent for primary tumors in LFS; hence, we hypothesize that the utility of metformin can be extended to the prevention of secondary malignancies following radiotherapy in LFS. METHODS/RESULTS: To explore the chemopreventive potential of metformin in LFS, we completed tumor challenges using a p53R172H/+ LFS mouse model. Mice treated prophylactically with metformin showed slower xenograft tumor growth compared to vehicle-treated mice. Ongoing work in our lab aims to characterize the effects of metformin on tumor growth following the administration of localized ionizing radiation (IR) to LFS mice. Briefly, these mice are treated with either vehicle or metformin, and IR is administered to the left hindlimbs to induce tumor formation. The timing and rates of tumor growth are monitored using magnetic resonance imaging. At endpoint, excised tumors are subjected to global profiling via RNA sequencing, proteomic analysis, and single-cell sequencing of discrete cell populations to characterize the effects of metformin on the development of radiation-induced malignancies. Results of these studies will be presented. SIGNIFICANCE: Overall, this work will advance our understanding of the chemopreventive effects of metformin, with the potential to broaden the treatment options available to LFS patients. Citation Format: Pamela Psarianos, Nicholas Fischer, Camilla Giovino, Noel Ong, David Malkin. Characterization and prevention of radiation-induced malignancies in Li-Fraumeni Syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 849.
Background: Soft tissue radiation fibrosis (RF) affects up to 70% of cancer survivors post-radiotherapy. RF is an irreversible and progressive side effect of radiotherapy characterized by poor tissue elasticity and increased ECM deposition, clinically translating to increased morbidity due to hardening, distortion, and pain. Recent evidence has highlighted the potential role of metabolic alterations in the onset and progression of fibrosis. Adipose derived stromal cells (ADSCs) have been used effectively for enhancing complex wound repair in a number of clinical trials. The therapeutic effect of ADSCs has been attributed to its secretion of paracrine factors, which can regulate the metabolism of target cells. Even so, the metabolic effects of ADSCs on target cells is not well described. Methods and Results: Transcriptomic profiling and targeted metabolomics of human radiated tissue and a murine model of RF revealed that suppression of fatty acid oxidation (FAO) is hallmark of RF. TGF-B, a master regulator of fibrosis, has a large effect in suppressing FAO in primary human fibroblasts in vitro through downregulating genes in the PPAR pathway, a major regulatory pathway for FAO, and through inhibiting oxidation of the long chain fatty acid, palmitic acid (p<0.05, t-test). Treatment of TGF-B stimulated fibroblasts with ADSC conditioned media resulted in an improvement in FAO and a reduction in fibronectin, collagen-1, and PAI-1 protein levels, three of major contributors to fibrosis. Transplantation of ADSCs into murine RF resulted in a metabolic shift back to FAO and a significant reduction in RF both functionally (percentage leg contracture 36% vs 26%, 2-way ANOVA < 0.05) and histologically through image analysis of trichrome staining (p<0.01, t-test). Pathway analysis of significant genes altered by ADSCs revealed an upregulation of the PPAR pathway was the most significant effect of ADSC transplantation. Untargeted metabolomics confirmed that FAO metabolites were significantly upregulated with ADSC transplantation. To confirm the importance of metabolic regulation by ADSCs, we utilized a pharmacogenomics strategy to uncover a compound that mimicked the effect of ADSCs. Drug A ranked highest and replicated the anti-fibrotic and pro-FAO effects of ADSCs both on TGF-B stimulated primary fibroblasts and in murine RF. Etomoxir, a FAO inhibitor, inhibited the effect of ADSCs and Drug A in regulating protein levels of fibronectin and collagen, revealing that ADSCs and Drug A require an intact FAO pathway to exert their anti-fibrotic effects. Conclusions: Inhibition of FAO is a novel hallmark of RF. ADSC-mediated metabolic reprogramming resulted in an enhancement of FAO and a reduction in RF through upregulating the PPAR pathway. ADSC-directed pharmacogenomics uncovered Drug A, which mimicked the pro-FAO and anti-fibrotic effects of ADSCs. Our research has highlighted the importance of reversing metabolic aberrations to reduce RF. Citation Format: Xiao Zhao, Laleh Soltan Ghoraie, Pamela Psarianos, Kenneth Yip, Laurie Ailles, Benjamin Haibe-Kains, Fei-Fei Liu. Metabolic reprogramming of radiation fibrosis using adipose derived stromal cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5212. doi:10.1158/1538-7445.AM2017-5212
3.7 (P Z 0.013). Eleven physicians (84.6%) demonstrated improvement of their CR score. The mean and maximum physician score improvements were 4.3% and 9.7%. Scores showed no statistically significant differences amongst physicians, facilities, treatment intent, or RT technique. Mean head and neck scores were statistically significantly lower than that of the overall case pool (3.5 vs. 3.7, P Z 0.02). Conclusion: Prospective peer review CR before treatment planning is feasible and impacts up to 25% of new patient starts. Several variables, including appropriateness of contours, accuracy of the WD, and use of departmental CPs, can be combined to transparently quantify clinical performance in a single metric for every case prior to RT. Sequencing CR prior to treatment planning avoids the risks and inefficiencies associated with replanning as compared to traditional chart rounds occurring after treatment planning and initiation of therapy. Head and neck cases required more modifications, which is likely attributable to the anatomic and disease complexity. CR has created a shared culture where peer review is appreciated and accepted. Based on our findings, prospective CR should be universally explored to enhance the efficiency of treatment planning, quality management and to decrease error risks associated with replanned cases.
Introduction: Radiation fibrosis affects up to half of all patients undergoing radiotherapy for head and neck cancer treatment. It is characterized by excess extracellular matrix deposition, leading to tissue dysfunction, distortion, hardening, and pain. There are currently no effective treatments for radiation fibrosis. A fundamental challenge has been to understand and modulate the function of fibroblasts, a key mediator in extracellular matrix production and degradation. Recent evidence has demonstrated that metabolic regulation plays an important role in altering cell behavior in cancer biology and immunology. However, little is known about how metabolic changes affect fibroblast phenotype. Hypothesis: We propose that metabolic reprogramming may be an effective strategy to modulate fibroblast function and reduce radiation fibrosis. Results: An interplay between fatty acid oxidation and glycolysis was found to be a convergence point directly governing fibroblast behavior. It was demonstrated that manipulating the balance between FAO and glycolysis in fibroblasts induced either an extracellular matrix anabolic or catabolic phenotype. Specifically, anabolic fibroblasts relied on a fatty acid oxidation to glycolysis shift to produce extracellular matrix components. Reversal of this metabolic shift generated a catabolic fibroblast, which downregulated extracellular matrix synthesis and upregulated extracellular matrix lysosomal degradation. We further uncovered that CD36, a multifunctional fatty acid transporter, was a crucial link connecting fibroblast metabolism with extracellular matrix regulation, as its depletion completely inhibited collagen-1 internalization and degradation. Finally, through metabolic reprogramming using fibroblasts expressing high levels of CD36, but not CD36 knockout fibroblasts, metabolic balance could be restored, and in turn extracellular matrix accumulation was reduced in murine radiation fibrosis. Conclusions: We have uncovered that a fibroblast’s phenotype can be differentiated and regulated based on its metabolic signature. These findings have significant implications for drug development and for future cellular therapies to reduce radiation fibrosis. Citation Format: Xiao Zhao, Pamela Psarianos, David Goldstein, Ralph Gilbert, Ian Witterick, Laurie Ailles, Benjamin Haibe-Kains, Fei-Fei Liu. Utilizing metabolic reprogramming to regulate fibroblast phenotype and reduce radiation fibrosis [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr B13.
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