Glioblastoma

Description

Glioblastoma is the most aggressive form of astrocytoma and one of the most metabolically inflexible cancers known. GBM cells are entirely locked into the Warburg effect and rely almost exclusively on glucose and glycolysis for survival. Unlike a few tumors such as BRAF-mutated melanoma or rare leukemias, GBM shows virtually zero ability to oxidize fatty acids or use ketones. They lack ketolytic enzymes, have no transport capacity for ketones, show no mitochondrial upregulation in ketosis, and gain absolutely no survival benefit from fat or ketone availability. GBM cells massively overexpress IGF-1 receptors and depend heavily on insulin/IGF-1 → PI3K–Akt–mTOR growth signalling, which drives rapid proliferation, blocks apoptosis, and shuts down autophagy. Because they cannot use ketones or fat for biomass or energy, GBM cells collapse when glucose, insulin, and IGF-1 fall. Deep ketosis or fasting creates an extremely hostile environment for glioblastoma by lowering glucose, suppressing mTOR, activating autophagy, and removing the growth-factor signalling the tumor requires. GBM is one of the cancers most vulnerable to glucose restriction and metabolic therapy.

Root Causes

Carbohydrate consumption

[ 1 ] Saeid Doaei et al. (2019) DOI PMID [ 2 ] Anna E Arthur et al. (2018) DOI PMID [ 3 ] Christian A Maino Vieytes et al. (2019) DOI PMID [ 4 ] Jian Huang et al. (2017) DOI PMID [ 5 ] Maria V Liberti et al. (2017) DOI PMID [ 6 ] Takahiko Nakagawa et al. (2020) DOI PMID [ 7 ] Siyuan Xia et al. (2017) DOI PMCID PMID

Insulin Resistance

[ 8 ] F S Facchini et al. (2001) DOI PMID

IGF-1 (Insulin-like Growth Factor 1)

[ 9 ] Pollak M et al. (2004) DOI PMID [ 10 ] Baserga R et al. (2003) DOI PMID [ 11 ] O Larsson et al. (2005) DOI PMID

Systemic Inflammation

[ 12 ] Balkwill F et al. (2001) DOI PMID

mTOR (Mechanistic Target of Rapamycin)

[ 13 ] Robert A. Saxton et al. (2017) DOI PMID [ 14 ] Alejo Efeyan et al. (2010) DOI PMID [ 15 ] David A Fruman et al. (2017) DOI PMID [ 16 ] Panomwat Amornphimoltham et al. (2008) DOI PMID [ 17 ] Ma'anit Shapira et al. (2006) DOI PMID [ 18 ] David T Teachey et al. (2006) DOI PMID

Treatment Options

Fasting

[ 19 ] Lee C et al. (2012) DOI PMID [ 20 ] Sagun Tiwari et al. (2022) DOI PMID [ 21 ] Sebastian Brandhorst et al. (2021) DOI PMID [ 22 ] Maira Di Tano et al. (2020) DOI PMID [ 23 ] Alessio Nencioni et al. (2019) DOI PMID [ 24 ] Yichun Xie et al. (2024) DOI PMID [ 25 ] Albin Sjölin et al. (2022) Link [ 26 ] Stefanie de Groot et al. (2019) DOI PMID [ 27 ] M Mansilla-Polo et al. (2024) DOI PMID [ 28 ] Ciara H O'Flanagan et al. (2017) DOI PMCID PMID

Ketogenic Diet

[ 29 ] Irene Caffa et al. (2020) DOI PMID [ 30 ] Salvatore Cortellino et al. (2023) DOI PMID [ 25 ] Albin Sjölin et al. (2022) Link [ 21 ] Sebastian Brandhorst et al. (2021) DOI PMID [ 31 ] Giulia Salvadori et al. (2021) DOI PMID [ 27 ] M Mansilla-Polo et al. (2024) DOI PMID

Susceptibilities

Autophagy

Sources

[1] Dietary Carbohydrate Promotes Cell Survival in Cancer Via the Up-Regulation of Fat Mass and Obesity-Associated Gene Expression Level

[ 1 ] Saeid Doaei et al. (2019) DOI PMID

[2] Higher carbohydrate intake is associated with increased risk of all-cause and disease-specific mortality in head and neck cancer patients: results from a prospective cohort study

[ 2 ] Anna E Arthur et al. (2018) DOI PMID

[3] Carbohydrate Nutrition and the Risk of Cancer

[ 3 ] Christian A Maino Vieytes et al. (2019) DOI PMID

[4] A meta-analysis between dietary carbohydrate intake and colorectal cancer risk: evidence from 17 observational studies

[ 4 ] Jian Huang et al. (2017) DOI PMID

[5] The Warburg Effect: How Does it Benefit Cancer Cells?

[ 5 ] Maria V Liberti et al. (2017) DOI PMID

[6] Fructose contributes to the Warburg effect for cancer growth

[ 6 ] Takahiko Nakagawa et al. (2020) DOI PMID

[7] Prevention of Dietary-Fat-Fueled Ketogenesis Attenuates BRAF V600E Tumor Growth

[ 7 ] Siyuan Xia et al. (2017) DOI PMCID PMID

[8] Insulin resistance as a predictor of age-related diseases

[ 8 ] F S Facchini et al. (2001) DOI PMID

[9] Insulin-like growth factor-I and risk of breast cancer by age and hormone receptor status

[ 9 ] Pollak M et al. (2004) DOI PMID

[10] The role of the IGF-I receptor in cancer

[ 10 ] Baserga R et al. (2003) DOI PMID

[11] Role of insulin-like growth factor 1 receptor signalling in cancer

[ 11 ] O Larsson et al. (2005) DOI PMID

[12] Inflammation and cancer: back to Virchow?

[ 12 ] Balkwill F et al. (2001) DOI PMID

[13] mTOR signaling in growth control and disease

[ 13 ] Robert A. Saxton et al. (2017) DOI PMID

[14] mTOR and cancer: many loops in one pathway

[ 14 ] Alejo Efeyan et al. (2010) DOI PMID

[15] The PI3K-AKT-mTOR pathway in human cancer: genetic alterations and therapeutic implications

[ 15 ] David A Fruman et al. (2017) DOI PMID

[16] Inhibition of mTOR by Rapamycin Causes the Regression of Carcinogen-Induced Skin Tumor Lesions

[ 16 ] Panomwat Amornphimoltham et al. (2008) DOI PMID

[17] The mTOR inhibitor rapamycin down-regulates the expression of the ubiquitin ligase subunit Skp2 in breast cancer cells

[ 17 ] Ma'anit Shapira et al. (2006) DOI PMID

[18] The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL

[ 18 ] David T Teachey et al. (2006) DOI PMID

[19] Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy

[ 19 ] Lee C et al. (2012) DOI PMID

[20] Effect of fasting on cancer: A narrative review of scientific evidence

[ 20 ] Sagun Tiwari et al. (2022) DOI PMID

[21] Fasting and fasting-mimicking diets for chemotherapy augmentation

[ 21 ] Sebastian Brandhorst et al. (2021) DOI PMID

[22] Synergistic effect of fasting-mimicking diet and vitamin C against KRAS mutated cancers

[ 22 ] Maira Di Tano et al. (2020) DOI PMID

[23] Fasting and cancer: molecular mechanisms and clinical application

[ 23 ] Alessio Nencioni et al. (2019) DOI PMID

[24] Fasting as an Adjuvant Therapy for Cancer: Mechanism of Action and Clinical Practice

[ 24 ] Yichun Xie et al. (2024) DOI PMID

[25] Cancer whitepaper

[ 25 ] Albin Sjölin et al. (2022) Link

[26] Effects of short-term fasting on cancer treatment

[ 26 ] Stefanie de Groot et al. (2019) DOI PMID

[27] Popular Diets and Skin Effects: A Narrative Review

[ 27 ] M Mansilla-Polo et al. (2024) DOI PMID

[28] When less may be more: calorie restriction and response to cancer therapy

[ 28 ] Ciara H O'Flanagan et al. (2017) DOI PMCID PMID

[29] Fasting-mimicking diet and hormone therapy induce breast cancer regression

[ 29 ] Irene Caffa et al. (2020) DOI PMID

[30] Fasting mimicking diet in mice delays cancer growth and reduces immunotherapy-associated cardiovascular and systemic side effects

[ 30 ] Salvatore Cortellino et al. (2023) DOI PMID

[31] Intermittent and Periodic Fasting, Hormones, and Cancer Prevention

[ 31 ] Giulia Salvadori et al. (2021) DOI PMID