Hyperpolarized MRI Visualizes Warburg Effects and Predicts Treatment Response to mTOR Inhibitors in Patient-Derived ccRCC Xenograft Models

Dong, Yiyu; Eskandari, Roozbeh; Ray, Chelsea; Granlund, Kristin L.; Santos-Cunha, Lidia Dos; Miloushev, Vesselin Z.; Tee, Sui Seng; Jeong, Sangmoo; Aras, Ömer; Chen, Ying-Bei; Cheng, Emily H.; Hsieh, James J.; Keshari, Kayvan R.

doi:10.1158/0008-5472.can-18-2231

Cited by 27 publications

(43 citation statements)

References 30 publications

(37 reference statements)

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“…The proapoptotic effect of everolimus combined with paclitaxel has been successfully shown for HeLa and SiHa cell lines. In addition, it has been demonstrated that both compounds inhibit the PI3K/AKT/mTOR pathway (210).…”

Section: Mtorc1 As a Therapeutic Targetmentioning

confidence: 99%

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

et al. 2019

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Continuous proliferation of tumor cells requires constant adaptations of energy metabolism to rapidly fuel cell growth and division. This energetic adaptation often comprises deregulated glucose uptake and lactate production in the presence of oxygen, a process known as the "Warburg effect." For many years it was thought that the Warburg effect was a result of mitochondrial damage, however, unlike this proposal tumor cell mitochondria maintain their functionality, and is essential for integrating a variety of signals and adapting the metabolic activity of the tumor cell. The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of numerous cellular processes implicated in proliferation, metabolism, and cell growth. mTORC1 controls cellular metabolism mainly by regulating the translation and transcription of metabolic genes, such as peroxisome proliferator activated receptor γ coactivator-1 α (PGC-1α), sterol regulatory element-binding protein 1/2 (SREBP1/2), and hypoxia inducible factor-1 α (HIF-1α). Interestingly it has been shown that mTORC1 regulates mitochondrial metabolism, thus representing an important regulator in mitochondrial function. Here we present an overview on the role of mTORC1 in the regulation of mitochondrial functions in cancer, considering new evidences showing that mTORC1 regulates the translation of nucleus-encoded mitochondrial mRNAs that result in an increased ATP mitochondrial production. Moreover, we discuss the relationship between mTORC1 and glutaminolysis, as well as mitochondrial metabolites. In addition, mitochondrial fission processes regulated by mTORC1 and its impact on cancer are discussed. Finally, we also review the therapeutic efficacy of mTORC1 inhibitors in cancer treatments, considering its use in combination with other drugs, with particular focus on cellular metabolism inhibitors, that could help improve their anti neoplastic effect and eliminate cancer cells in patients. de la Cruz López et al. mTORC1 and Mitochondrial Functions Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The handling editor declared a shared affiliation, though no other collaboration, with with several of the authors AG and KC.

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Section: Mtorc1 As a Therapeutic Targetmentioning

confidence: 99%

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

et al. 2019

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“…A similar decrease in lactate-to-pyruvate ratios was observed in GS-2 glioblastoma rat models following treatment with Everolimus after seven days [35]. HP-MR also predicts treatment response to mTOR inhibitor (rapamycin) in patient-derived ccRCC xenograft models [36].…”

Section: Assessment Of Different Therapeutic Interventionsmentioning

confidence: 77%

Assessing Therapeutic Efficacy in Real-time by Hyperpolarized Magnetic Resonance Metabolic Imaging

Dutta

Salzillo

Pudakalakatti

et al. 2019

Cells

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Precisely measuring tumor-associated alterations in metabolism clinically will enable the efficient assessment of therapeutic responses. Advances in imaging technologies can exploit the differences in cancer-associated cell metabolism as compared to normal tissue metabolism, linking changes in target metabolism to therapeutic efficacy. Metabolic imaging by Positron Emission Tomography (PET) employing 2-fluoro-deoxy-glucose ([18F]FDG) has been used as a routine diagnostic tool in the clinic. Recently developed hyperpolarized Magnetic Resonance (HP-MR), which radically increases the sensitivity of conventional MRI, has created a renewed interest in functional and metabolic imaging. The successful translation of this technique to the clinic was achieved recently with measurements of 13C-pyruvate metabolism. Here, we review the potential clinical roles for metabolic imaging with hyperpolarized MRI as applied in assessing therapeutic intervention in different cancer systems.

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“…In the renal cortex, gluconeogenic enzymes (phosphoenolpyruvate carboxykinase (PEPCK), fructose-1,6-bisphosphatase glucose-6-phosphatase) synthesise glucose-6-phosphate from precursors such as lactate, glutamine, glycerol and alanine (37,44). (mechanistic target of rapamycin) inhibition, a therapeutic target in RCC, can be observed as early as 24 hours after the initiation of treatment in a murine model (52). Initial patient data confirm that hyperpolarised imaging is feasible in patients with RCC and highlight the need for further clinical research to define the future role of this modality in uro-oncological imaging (54).…”

Section: Imaging Glycolysis With [1-13 C]pyruvatementioning

confidence: 90%

Hyperpolarised 13C-MRI metabolic and functional imaging: an emerging renal MR diagnostic modality

Pedersen

Ursprung

Jensen

et al. 2019

Magn Reson Mater Phy

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Magnetic Resonance Imaging (MRI) is a well-established modality for assessing renal morphology and function, as well as changes that occur during disease. However, the significant metabolic changes associated with renal disease are more challenging to assess with MRI. Hyperpolarized carbon-13 MRI is an emerging technique which provides an opportunity to probe metabolic alterations at high sensitivity by providing an increase in the signal-to-noise ratio of 20,000-fold or more. This review will highlight the current status of hyperpolarised 13 C-MRI and its translation into the clinic and how it compares to metabolic measurements provided by competing technologies such as Positron Emission Tomography (PET).

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Hyperpolarized MRI Visualizes Warburg Effects and Predicts Treatment Response to mTOR Inhibitors in Patient-Derived ccRCC Xenograft Models

Cited by 27 publications

References 30 publications

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

Assessing Therapeutic Efficacy in Real-time by Hyperpolarized Magnetic Resonance Metabolic Imaging

Hyperpolarised 13C-MRI metabolic and functional imaging: an emerging renal MR diagnostic modality

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