A Phase I clinical trial of dose-escalated metabolic therapy combined with concomitant radiation therapy in high-grade glioma

Porper, Keren; Shpatz, Yael; Плоткин, Л. Л.; Pechthold, Ronit Goldman; Talianski, Alisa; Champ, Colin E.; Furman, Orit; Shimoni-Sebag, Ariel; Symon, Zvi; Amit, Uri; Hemi, Rina; Kanety, Hannah; Mardor, Yael; Cohen, Zvi; Jan, Elisheva; Genssin, Hili; Anikster, Yair; Zach, Leor; Lawrence, Yaacov Richard

doi:10.1007/s11060-021-03786-8

Cited by 29 publications

(41 citation statements)

References 49 publications

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“…The rate of hepatic ketogenesis is known to be regulated by the supply of free fatty acid (FFA) [24] and by the hormones insulin and glucagon [25]. Insulin inhibits FFA release from adipose tissue and, hence, ketogenesis [26]; likewise, in our adult cohort, we noted a negative correlation between insulin levels and ketone levels (p = 0.02) [10]. The higher postprandial insulin response seen in older people [17] would hence help explain their difficulty in achieving systemic ketosis.…”

Section: Discussionmentioning

confidence: 48%

“…Exclusion criteria included children with refractory epilepsy who had received treatment with KD for less than three months; patients for whom there was a lack of relevant information from the medical records; and children with known metabolic disease associated with lipid metabolism. (2) A prospective single-institution clinical trial (NCT02149459) [10] amongst adults with newly diagnosed or recurrent high-grade glioma, in which patients received the KD (for a total of eight weeks) prior to, during, and following two or six weeks of radiation therapy. Patients in cohort one received dietary treatment alone, whereas those in cohorts two and three received metformin in addition.…”

Section: Methodsmentioning

confidence: 99%

“…We recently performed a prospective clinical trial in which a very low carbohydrate high-fat diet was administered to adults with brain tumors [10]. Despite the input of an experienced ketogenic-nutrition team, maintenance of nutritional ketosis proved surprisingly difficult in this population.…”

Section: Introductionmentioning

confidence: 99%

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Dietary-Induced Ketogenesis: Adults Are Not Children

et al. 2021

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There is increasing interest in the use of a ketogenic diet for various adult disorders; however, the ability of adults to generate ketones is unknown. Our goal was to challenge the hypothesis that there would be no difference between adults and children regarding their ability to enter ketosis. Methods: Two populations were studied, both treated with identical very low-carbohydrate high-fat diets: a retrospective series of children with epilepsy or/and metabolic disorders (2009–2016) and a prospective clinical trial of adults with glioblastoma. Dietary intake was assessed based upon written food diaries and 24-h dietary recall. Ketogenic ratio was calculated according to [grams of fat consumed]/[grams of carbohydrate and protein consumed]. Ketone levels (β-hydroxybutyrate) were measured in blood and/or urine. Results: A total of 168 encounters amongst 28 individuals were analyzed. Amongst both children and adults, ketone levels correlated with nutritional ketogenic ratio; however, the absolute ketone levels in adults were approximately one quarter of those seen in children. This difference was highly significant in a multivariate linear regression model, p < 0.0001. Conclusions: For diets with comparable ketogenic ratios, adults have lower blood ketone levels than children; consequently, high levels of nutritional ketosis are unobtainable in adults.

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Section: Discussionmentioning

confidence: 48%

Section: Methodsmentioning

confidence: 99%

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Dietary-Induced Ketogenesis: Adults Are Not Children

et al. 2021

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“…First, many ongoing clinical trials are being conducted to investigate the efficacy of metformin as a therapeutic agent for glioblastoma [17,21,22]. The findings of the present study provide some useful clinical information.…”

Section: Discussionmentioning

confidence: 82%

“…According to in vitro and in vivo studies, metformin may inhibit the growth of human glioblastoma cells and enhance therapeutic responses to chemotherapy (e.g., temozolomide) and radiotherapy [18][19][20]. Several clinical trials are being conducted to investigate its potential usefulness in the treatment of MBT but the outcomes remain unknown [17,21,22].…”

Section: Introductionmentioning

confidence: 99%

Metformin and Risk of Malignant Brain Tumors in Patients with Type 2 Diabetes Mellitus

Tseng

2021

Biomolecules

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The risk of malignant brain tumors associated with metformin use has rarely been investigated in humans. This retrospective cohort study investigated such an association. Patients with new-onset type 2 diabetes mellitus diagnosed from 1999 to 2005 in the nationwide database of Taiwan’s national health insurance were used to enroll study subjects. We first identified an unmatched cohort of 153,429 ever users and 16,222 never users of metformin. A cohort of 16,222 ever users and 16,222 never users matched on propensity score was then created from this unmatched cohort. All patients were followed up from 1 January 2006 until 31 December 2011. The incidence density was calculated and hazard ratios were derived from Cox regression incorporated with the inverse probability of treatment weighting using a propensity score. The results showed that 27 never users and 155 ever users developed malignant brain tumors in the unmatched cohort. The incidence rate was 37.11 per 100,000 person-years in never users and 21.39 per 100,000 person-years in ever users. The overall hazard ratio comparing ever users versus never users was 0.574 (95% confidence interval: 0.381–0.863). The respective hazard ratios comparing the first (<27.13 months), second (27.13–58.33 months), and third (>58.33 months) tertiles of cumulative duration of metformin therapy versus never users were 0.897 (0.567–1.421), 0.623 (0.395–0.984), and 0.316 (0.192–0.518). In the matched cohort, the overall hazard ratio was 0.317 (0.149–0.673) and the respective hazard ratios were 0.427 (0.129–1.412), 0.509 (0.196–1.322), and 0.087 (0.012–0.639) for the first, second, and third tertile of cumulative duration of metformin therapy. In conclusion, this study shows a risk reduction of malignant brain tumors associated with metformin use in a dose–response pattern. The risk reduction is more remarkable when metformin has been used for approximately 2–5 years.

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Metabolic profiling of colorectal cancer organoids: A comparison between high‐resolution magic angle spinning magnetic resonance spectroscopy and solution nuclear magnetic resonance spectroscopy of polar extracts

et al. 2022

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Patient‐derived cancer cells cultured in vitro are a cornerstone of cancer metabolism research. More recently, the introduction of organoids has provided the research community with a more versatile model system. Physiological structure and organization of the cell source tissue are maintained in organoids, representing a closer link to in vivo tumor models. High‐resolution magic angle spinning magnetic resonance spectroscopy (HR MAS MRS) is a commonly applied analytical approach for metabolic profiling of intact tissue, but its use has not been reported for organoids. The aim of the current work was to compare the performance of HR MAS MRS and extraction‐based nuclear magnetic resonance (NMR) in metabolic profiling of wild‐type and tumor progression organoids (TPOs) from human colon cancer, and further to investigate how the sequentially increased genetic alterations of the TPOs affect the metabolic profile. Sixteen metabolites were reliably identified and quantified both in spectra based on NMR of extracts and HR MAS MRS of intact organoids. The metabolite concentrations from the two approaches were highly correlated (r = 0.94), and both approaches were able to capture the systematic changes in metabolic features introduced by the genetic alterations characteristic of colorectal cancer progression (e.g., increased levels of lactate and decreased levels of myo‐inositol and phosphocholine with an increasing number of mutations). The current work highlights that HR MAS MRS is a well‐suited method for metabolic profiling of intact organoids, with the additional benefit that the nondestructive nature of HR MAS enables subsequent recovery of the organoids for further analyses based on nucleic acids or proteins.

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A Phase I clinical trial of dose-escalated metabolic therapy combined with concomitant radiation therapy in high-grade glioma

Cited by 29 publications

References 49 publications

Dietary-Induced Ketogenesis: Adults Are Not Children

Dietary-Induced Ketogenesis: Adults Are Not Children

Metformin and Risk of Malignant Brain Tumors in Patients with Type 2 Diabetes Mellitus

Metabolic profiling of colorectal cancer organoids: A comparison between high‐resolution magic angle spinning magnetic resonance spectroscopy and solution nuclear magnetic resonance spectroscopy of polar extracts

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