Multinuclear NMR and MRI Reveal an Early Metabolic Response to mTOR Inhibition in Sarcoma

Gialleonardo, Valentina Di; Aldeborgh, Hannah N.; Miloushev, Vesselin Z.; Folkers, Kelly McBride; Granlund, Kristin L.; Tap, William D.; Lewis, Jason S.; Keshari, Kayvan R.

doi:10.1158/0008-5472.can-16-3310

Cited by 19 publications

(22 citation statements)

References 30 publications

(28 reference statements)

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“…7,26 Moreover, mTOR pathway activation has been reported to promote tumour cell capacitation through anaerobic glycolysis, and mTOR pathway inhibitors have been demonstrated to inhibit tumour cell growth when combined with existing chemotherapeutic agents. 27 LKB1 forms a heterotrimeric complex with ste20-related adaptor and CAB39. 10 LKB1 tumour-suppressor activity is caused partly by AMPK-mediated inhibition of inappropriate mTOR activation.…”

Section: Discussionmentioning

confidence: 99%

MiR-107 confers chemoresistance to colorectal cancer by targeting calcium-binding protein 39

Zhu

Hou

et al. 2020

Br J Cancer

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BACKGROUND: Chemoresistance remains a critical event that accounts for colorectal cancer (CRC) lethality. The aim of this study is to explore the ability of dichloroacetate (DCA) to increase chemosensitivity in CRC and the molecular mechanisms involved. METHODS: The effects of combination treatment of DCA and oxaliplatin (L-OHP) were analysed both in vitro and in vivo. The DCAresponsive proteins in AMPK pathway were enriched using proteomic profiling technology. The effect of DCA on CAB39-AMPK signal pathway was analysed. In addition, miRNA expression profiles after DCA treatment were determined. The DCA-responsive miRNAs that target CAB39 were assayed. Alterations of CAB39 and miR-107 expression were performed both in vitro and on xenograft models to identify miR-107 that targets CAB39-AMPK-mTOR signalling pathway. RESULTS: DCA increased L-OHP chemosensitivity both in vivo and in vitro. DCA could upregulate CAB39 expression, which activates the AMPK/mTOR signalling pathway. CAB39 was confirmed to be a direct target of miR-107 regulated by DCA. Alterations of miR-107 expression were correlated with chemoresistance development in CRC both in vitro and in vivo. CONCLUSION: These findings suggest that the miR-107 induces chemoresistance through CAB39-AMPK-mTOR pathway in CRC cells, thus providing a promising target for overcoming chemoresistance in CRC.

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Section: Discussionmentioning

confidence: 99%

MiR-107 confers chemoresistance to colorectal cancer by targeting calcium-binding protein 39

Zhu

Hou

et al. 2020

Br J Cancer

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“…Decreased flow through the glycolytic pathway due to treatment with TMZ in a preclinical GB model had also been detected, but in this instance the reduced Lac/Pyr ratio after injection of hyperpolarized Pyr was caused not by LDHA expression changes but by downregulation of the M2 isoform of the pyruvate kinase enzyme (PKM2). Furthermore, mTOR inhibition alone in a preclinical xenograft model of sarcoma also resulted in a reduced Lac/Pyr ratio after injection of hyperpolarized Pyr, 24 h after the mTOR inhibitor administration (rapamycin) and prior to any anatomic detectable changes …”

Section: Mrs(i)‐detectable Metabolic Hallmarks Of Cancer: Applicationmentioning

confidence: 98%

Cancer metabolism in a snapshot: MRS(I)

2019

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The contribution of MRS(I) to the in vivo evaluation of cancer-metabolism-derived metrics, mostly since 2016, is reviewed here. Increased carbon consumption by tumour cells, which are highly glycolytic, is now being sampled by 13 C magnetic resonance spectroscopic imaging (MRSI) following the injection of hyperpolarized [1-13 C] pyruvate (Pyr). Hot-spots of, mostly, increased lactate dehydrogenase activity or flow between Pyr and lactate (Lac) have been seen with cancer progression in prostate (preclinical and in humans), brain and pancreas (both preclinical) tumours. Therapy response is usually signalled by decreased Lac/Pyr 13 C-labelled ratio with respect to untreated or nonresponding tumour. For therapeutic agents inducing tumour hypoxia, the 13 C-labelled Lac/bicarbonate ratio may be a better metric than the Lac/Pyr ratio. 31 P MRSI may sample intracellular pH changes from brain tumours (acidification upon antiangiogenic treatment, basification at fast proliferation and relapse). The steady state tumour metabolome pattern is still in use for cancer evaluation. Metrics used for this range from quantification of single oncometabolites (such as 2-hydroxyglutarate in mutant IDH1 glial brain tumours) to selected metabolite ratios (such as total choline to N-acetylaspartate (plain ratio or CNI index)) or the whole 1 H MRSI(I) pattern through pattern recognition analysis. These approaches have been applied to address different questions such as tumour subtype definition, following/predicting the response to therapy or defining better resection or radiosurgery limits. KEYWORDSanimal model study, cancer, cellular and molecular cancer imaging, hyperpolarized C-13, MRS and MRSI methods, phosphorus MRS/MRSI | TEMPORAL AND THEMATIC BOUNDARIES OF THE TOPICS COVEREDThe authors of this review declare at the outset that there is no intention of being exhaustive or systematic. The temporal boundaries reviewed will be modest: only relevant literature since 2016, chosen according to our bias. Earlier work or reviews will only be referred to in order to put recent findings in due perspective. Authors hope that this summary will give readers a picture of how far cancer metabolism analysis with MRS(I) has advanced and, perhaps, why it is not advancing further.For quite a long time MRS, rather than MRI, has been the only approach able to evaluate cancer metabolism. Nevertheless, the MRI-derived information related to cancer metabolism should not be forgotten: consider for example the chemical exchange saturation transfer (CEST) effect caused by exchangeable protons in water-derived images of glucose uptake and metabolism in tumours. 1,2 However, apart from these CESTrelated studies, we should acknowledge that most information about cancer metabolism using MR still refers to MRS(I) acquisitions, which are the ones dealt with in our text.Supplementary Figure 1 shows a PUBMED search illustrating the different proportions of articles investigating several cancer types through MRS(I) approaches. The retrieved information can help unders...

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“…Sensitivity enhancement achieved by hyperpolarization of nuclei of a metabolic tracer offers the possibility of using noninvasive magnetic resonance spectroscopy (MRS) and MRI to measure fluxes through individual enzyme-catalyzed reactions. In sarcoma animal models it was observed that quantitative reduction in lactate production after administration of hyperpolarized pyruvate as monitored by hyperpolarized MRI followed the tumor size changes and was useful for monitoring of therapy in this setting [168]. Another study showed the usefulness of this approach in canine patients with sarcomas [169].…”

Section: Molecular Imaging and Theranostic Strategies For Diagnosis Amentioning

confidence: 99%

Molecular Biology of Osteosarcoma

Czarnecka

Synoradzki

Firlej

et al. 2020

Cancers

226

186

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Osteosarcoma (OS) is the most frequent primary bone cancer in children and adolescents and the third most frequent in adults. Many inherited germline mutations are responsible for syndromes that predispose to osteosarcomas including Li Fraumeni syndrome, retinoblastoma syndrome, Werner syndrome, Bloom syndrome or Diamond–Blackfan anemia. TP53 is the most frequently altered gene in osteosarcoma. Among other genes mutated in more than 10% of OS cases, c-Myc plays a role in OS development and promotes cell invasion by activating MEK–ERK pathways. Several genomic studies showed frequent alterations in the RB gene in pediatric OS patients. Osteosarcoma driver mutations have been reported in NOTCH1, FOS, NF2, WIF1, BRCA2, APC, PTCH1 and PRKAR1A genes. Some miRNAs such as miR-21, -34a, -143, -148a, -195a, -199a-3p and -382 regulate the pathogenic activity of MAPK and PI3K/Akt-signaling pathways in osteosarcoma. CD133+ osteosarcoma cells have been shown to exhibit stem-like gene expression and can be tumor-initiating cells and play a role in metastasis and development of drug resistance. Although currently osteosarcoma treatment is based on adriamycin chemoregimens and surgery, there are several potential targeted therapies in development. First of all, activity and safety of cabozantinib in osteosarcoma were studied, as well as sorafenib and pazopanib. Finally, novel bifunctional molecules, of potential imaging and osteosarcoma targeting applications may be used in the future.

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Multinuclear NMR and MRI Reveal an Early Metabolic Response to mTOR Inhibition in Sarcoma

Cited by 19 publications

References 30 publications

MiR-107 confers chemoresistance to colorectal cancer by targeting calcium-binding protein 39

MiR-107 confers chemoresistance to colorectal cancer by targeting calcium-binding protein 39

Cancer metabolism in a snapshot: MRS(I)

Molecular Biology of Osteosarcoma

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