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Else Driehuis - One of the best experts on this subject based on the ideXlab platform.
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abstract ct075 Fasting mimicking diet and hormone therapy modulates metabolic factors to promote breast cancer regression and reduce side effects
Cancer Research, 2020Co-Authors: Irene Caffa, Vanessa Spagnolo, Claudio Vernieri, Francesca Valdemarin, Pamela Becherini, Sebastian Brandhorst, Chiara Zucal, Else Driehuis, Min Wei, Lorenzo FerrandoAbstract:Breast cancer (BC) is the most common malignancy with 1.7 million new diagnoses/year and is responsible for more than 450,000 yearly deaths worldwide. Two thirds of BC express the estrogen receptor (ER) and/or progesterone receptor and are referred to as hormone receptor-positive (HR+) BC. Endocrine therapy (ET) is usually active in these tumors, although drug resistance and side effects limit its benefit. Growth factor signaling through the PI3K/AKT/mammalian target of rapamycin (mTOR) and MAP kinase axes enhances ER activity and is a key mechanism underlying endocrine resistance. Water-only Fasting (Fasting) or plant-based, low-calorie, carbohydrate- and protein-restricted Fasting-mimicking diets (FMDs) reduce circulating growth factors, such as insulin and IGF1 Therefore, we hypothesized that these dietary interventions could be used to enhance the activity of ET and delay the occurrence of resistance. For our in vitro experiments we used the HR+ BC cell lines, MCF7, T47D, and ZR-75-1, as well as metastases-derived organoids from patients with HR+ BC. Our in vivo experiments in mouse xenografts of human BC cell lines, were conducted in six-to-eight-week old female NOD SCID or athymic Nude-FoxN1 mice treated with ET w/ or w/o 48-72 hours of Fasting/FMD. We monitored tumor growth and mouse survival and collected tumor masses and blood to detect circulating levels of several growth factors, adipokines and cytokines. In vivo add back experiments with Fasting-reduced factors were done with IGF1, insulin and leptin. Circulating growth factors and adipo-cytokines were also detected in blood samples from 36 patients with HR+ BC, who were enrolled in either one of two clinical trials (NCT03595540 and NCT03340935) assessing safety and feasibility of periodic FMD in cancer patients. Patient nutritional status and response to treatment were also monitored in our clinical trials.We found that in HR+ BC models, periodic Fasting or FMD enhanced tamoxifen and fulvestrant activity by lowering circulating IGF1, insulin, and leptin levels and by blocking AKT-mTOR signaling via EGR1 and PTEN upregulation. When fulvestrant was combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic FMD cycles promoted long-lasting tumour regressions and reverted acquired resistance to this regime. Moreover, both Fasting and FMD prevented tamoxifen-induced endometrial hyperplasia. In HR+ BC patients receiving ET, FMD cycles caused metabolic changes analogous to those observed in mice, including reduced leptin and IGF1 levels, which were found to remain low for extended periods. In mice, these long-lasting effects were associated with carryover anticancer activity. Overall, our results provide the rationale for conducting further clinical studies of Fasting-based dietary strategies as an adjuvant to ET w/ or w/o CDK4/6 inhibitors in patients with HR+ BC. Citation Format: Irene Caffa, Vanessa Spagnolo, Pamela Becherini, Francesca Valdemarin, Claudio Vernieri, Min Wei, Sebastian Brandhorst, Chiara Zucal, Else Driehuis, Lorenzo Ferrando, Luca Mastracci, Michele Cilli, Francesco Piacente, Anna Laura Cremonini, Mario Passalacqua, Valerio Vellone, Gabriele Zoppoli, Michele Cea, Giulia Salvadori, Salvatore Cortellino, Hans Clevers, Filippo De Braud, Alessandro Provenzani, Valter D. Longo, Alessio Nencioni. Fasting-mimicking diet and hormone therapy modulates metabolic factors to promote breast cancer regression and reduce side effects [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT075.
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Fasting-mimicking diet and hormone therapy induce breast cancer regression
Nature, 2020Co-Authors: Irene Caffa, Vanessa Spagnolo, Claudio Vernieri, Francesca Valdemarin, Pamela Becherini, Sebastian Brandhorst, Chiara Zucal, Else Driehuis, Lorenzo Ferrando, Francesco PiacenteAbstract:In mice, periodic Fasting or a Fasting-mimicking diet enhances the efficacy of endocrine therapy for breast cancer and delays acquired resistance to it; in patients with breast cancer, a Fasting-mimicking diet recreates the metabolic changes observed in mice. Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit^ 1 , 2 . Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic Fasting or a Fasting-mimicking diet^ 3 – 5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT–mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a Fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both Fasting and a Fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a Fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a Fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.
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Fasting mimicking diet and hormone therapy induce breast cancer regression
Nature, 2020Co-Authors: Irene Caffa, Vanessa Spagnolo, Claudio Vernieri, Francesca Valdemarin, Pamela Becherini, Sebastian Brandhorst, Chiara Zucal, Else Driehuis, Min WeiAbstract:Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit1,2. Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic Fasting or a Fasting-mimicking diet3-5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a Fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both Fasting and a Fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a Fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a Fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.
Irene Caffa - One of the best experts on this subject based on the ideXlab platform.
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abstract ct075 Fasting mimicking diet and hormone therapy modulates metabolic factors to promote breast cancer regression and reduce side effects
Cancer Research, 2020Co-Authors: Irene Caffa, Vanessa Spagnolo, Claudio Vernieri, Francesca Valdemarin, Pamela Becherini, Sebastian Brandhorst, Chiara Zucal, Else Driehuis, Min Wei, Lorenzo FerrandoAbstract:Breast cancer (BC) is the most common malignancy with 1.7 million new diagnoses/year and is responsible for more than 450,000 yearly deaths worldwide. Two thirds of BC express the estrogen receptor (ER) and/or progesterone receptor and are referred to as hormone receptor-positive (HR+) BC. Endocrine therapy (ET) is usually active in these tumors, although drug resistance and side effects limit its benefit. Growth factor signaling through the PI3K/AKT/mammalian target of rapamycin (mTOR) and MAP kinase axes enhances ER activity and is a key mechanism underlying endocrine resistance. Water-only Fasting (Fasting) or plant-based, low-calorie, carbohydrate- and protein-restricted Fasting-mimicking diets (FMDs) reduce circulating growth factors, such as insulin and IGF1 Therefore, we hypothesized that these dietary interventions could be used to enhance the activity of ET and delay the occurrence of resistance. For our in vitro experiments we used the HR+ BC cell lines, MCF7, T47D, and ZR-75-1, as well as metastases-derived organoids from patients with HR+ BC. Our in vivo experiments in mouse xenografts of human BC cell lines, were conducted in six-to-eight-week old female NOD SCID or athymic Nude-FoxN1 mice treated with ET w/ or w/o 48-72 hours of Fasting/FMD. We monitored tumor growth and mouse survival and collected tumor masses and blood to detect circulating levels of several growth factors, adipokines and cytokines. In vivo add back experiments with Fasting-reduced factors were done with IGF1, insulin and leptin. Circulating growth factors and adipo-cytokines were also detected in blood samples from 36 patients with HR+ BC, who were enrolled in either one of two clinical trials (NCT03595540 and NCT03340935) assessing safety and feasibility of periodic FMD in cancer patients. Patient nutritional status and response to treatment were also monitored in our clinical trials.We found that in HR+ BC models, periodic Fasting or FMD enhanced tamoxifen and fulvestrant activity by lowering circulating IGF1, insulin, and leptin levels and by blocking AKT-mTOR signaling via EGR1 and PTEN upregulation. When fulvestrant was combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic FMD cycles promoted long-lasting tumour regressions and reverted acquired resistance to this regime. Moreover, both Fasting and FMD prevented tamoxifen-induced endometrial hyperplasia. In HR+ BC patients receiving ET, FMD cycles caused metabolic changes analogous to those observed in mice, including reduced leptin and IGF1 levels, which were found to remain low for extended periods. In mice, these long-lasting effects were associated with carryover anticancer activity. Overall, our results provide the rationale for conducting further clinical studies of Fasting-based dietary strategies as an adjuvant to ET w/ or w/o CDK4/6 inhibitors in patients with HR+ BC. Citation Format: Irene Caffa, Vanessa Spagnolo, Pamela Becherini, Francesca Valdemarin, Claudio Vernieri, Min Wei, Sebastian Brandhorst, Chiara Zucal, Else Driehuis, Lorenzo Ferrando, Luca Mastracci, Michele Cilli, Francesco Piacente, Anna Laura Cremonini, Mario Passalacqua, Valerio Vellone, Gabriele Zoppoli, Michele Cea, Giulia Salvadori, Salvatore Cortellino, Hans Clevers, Filippo De Braud, Alessandro Provenzani, Valter D. Longo, Alessio Nencioni. Fasting-mimicking diet and hormone therapy modulates metabolic factors to promote breast cancer regression and reduce side effects [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT075.
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Fasting-mimicking diet and hormone therapy induce breast cancer regression
Nature, 2020Co-Authors: Irene Caffa, Vanessa Spagnolo, Claudio Vernieri, Francesca Valdemarin, Pamela Becherini, Sebastian Brandhorst, Chiara Zucal, Else Driehuis, Lorenzo Ferrando, Francesco PiacenteAbstract:In mice, periodic Fasting or a Fasting-mimicking diet enhances the efficacy of endocrine therapy for breast cancer and delays acquired resistance to it; in patients with breast cancer, a Fasting-mimicking diet recreates the metabolic changes observed in mice. Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit^ 1 , 2 . Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic Fasting or a Fasting-mimicking diet^ 3 – 5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT–mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a Fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both Fasting and a Fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a Fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a Fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.
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Fasting mimicking diet and hormone therapy induce breast cancer regression
Nature, 2020Co-Authors: Irene Caffa, Vanessa Spagnolo, Claudio Vernieri, Francesca Valdemarin, Pamela Becherini, Sebastian Brandhorst, Chiara Zucal, Else Driehuis, Min WeiAbstract:Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit1,2. Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic Fasting or a Fasting-mimicking diet3-5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a Fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both Fasting and a Fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a Fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a Fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.
Alfred L Goldberg - One of the best experts on this subject based on the ideXlab platform.
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muscle wasting in disease molecular mechanisms and promising therapies
Nature Reviews Drug Discovery, 2015Co-Authors: Shenhav Cohen, James A Nathan, Alfred L GoldbergAbstract:Atrophy occurs in specific muscles with inactivity (for example, during plaster cast immobilization) or denervation (for example, in patients with spinal cord injuries). Muscle wasting occurs systemically in older people (a condition known as sarcopenia); as a physiological response to Fasting or malnutrition; and in many diseases, including chronic obstructive pulmonary disorder, cancer-associated cachexia, diabetes, renal failure, cardiac failure, Cushing syndrome, sepsis, burns and trauma. The rapid loss of muscle mass and strength primarily results from excessive protein breakdown, which is often accompanied by reduced protein synthesis. This loss of muscle function can lead to reduced quality of life, increased morbidity and mortality. Exercise is the only accepted approach to prevent or slow atrophy. However, several promising therapeutic agents are in development, and major advances in our understanding of the cellular mechanisms that regulate the protein balance in muscle include the identification of several cytokines, particularly myostatin, and a common transcriptional programme that promotes muscle wasting. Here, we discuss these new insights and the rationally designed therapies that are emerging to combat muscle wasting.
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sirt1 protein by blocking the activities of transcription factors foxo1 and foxo3 inhibits muscle atrophy and promotes muscle growth
Journal of Biological Chemistry, 2013Co-Authors: Alfred L GoldbergAbstract:In several cell types, the protein deacetylase SIRT1 regulates the activities of FoxO transcription factors whose activation is critical in muscle atrophy. However, the possible effects of SIRT1 on the activity of FoxOs in skeletal muscle and on the regulation of muscle size have not been investigated. Here, we show that after food deprivation, SIRT1 levels fall dramatically in type II skeletal muscles (tibialis anterior), which show marked atrophy, unlike in the liver (where SIRT1 rises) or heart or the soleus, a type I muscle (where SIRT1 is unchanged). Maintenance of high SIRT1 levels by electroporation in mouse muscle inhibits markedly the muscle wasting induced by Fasting as well as by denervation, and these protective effects require its deacetylase activity. SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3. It thus prevents the induction of key atrogenes, including the muscle-specific ubiquitin ligases, atrogin1 and MuRF1, and multiple autophagy (Atg) genes and the increase in overall proteolysis. In normal muscle, SIRT1 overexpression by electroporation causes rapid fiber hypertrophy without, surprisingly, activation of the PI3K-AKT signaling pathway. Thus, SIRT1 activation favors postnatal muscle growth, and its fall appears to be critical for atrophy during Fasting. Consequently, SIRT1 activation represents an attractive possible pharmacological approach to prevent muscle wasting and cachexia.
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atrogin 1 a muscle specific f box protein highly expressed during muscle atrophy
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Marcelo Gomes, Stewart H Lecker, Thomas R Jagoe, Ami Navon, Alfred L GoldbergAbstract:Muscle wasting is a debilitating consequence of Fasting, inactivity, cancer, and other systemic diseases that results primarily from accelerated protein degradation by the ubiquitin-proteasome pathway. To identify key factors in this process, we have used cDNA microarrays to compare normal and atrophying muscles and found a unique gene fragment that is induced more than ninefold in muscles of fasted mice. We cloned this gene, which is expressed specifically in striated muscles. Because this mRNA also markedly increases in muscles atrophying because of diabetes, cancer, and renal failure, we named it atrogin-1. It contains a functional F-box domain that binds to Skp1 and thereby to Roc1 and Cul1, the other components of SCF-type Ub-protein ligases (E3s), as well as a nuclear localization sequence and PDZ-binding domain. On Fasting, atrogin-1 mRNA levels increase specifically in skeletal muscle and before atrophy occurs. Atrogin-1 is one of the few examples of an F-box protein or Ub-protein ligase (E3) expressed in a tissue-specific manner and appears to be a critical component in the enhanced proteolysis leading to muscle atrophy in diverse diseases.
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what do we really know about the ubiquitin proteasome pathway in muscle atrophy
Current Opinion in Clinical Nutrition and Metabolic Care, 2001Co-Authors: R Jagoe, Alfred L GoldbergAbstract:Studies of many different rodent models of muscle wasting have indicated that accelerated proteolysis via the ubiquitin-proteasome pathway is the principal cause of muscle atrophy induced by Fasting, cancer cachexia, metabolic acidosis, denervation, disuse, diabetes, sepsis, burns, hyperthyroidism a
Claudio Vernieri - One of the best experts on this subject based on the ideXlab platform.
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abstract ct075 Fasting mimicking diet and hormone therapy modulates metabolic factors to promote breast cancer regression and reduce side effects
Cancer Research, 2020Co-Authors: Irene Caffa, Vanessa Spagnolo, Claudio Vernieri, Francesca Valdemarin, Pamela Becherini, Sebastian Brandhorst, Chiara Zucal, Else Driehuis, Min Wei, Lorenzo FerrandoAbstract:Breast cancer (BC) is the most common malignancy with 1.7 million new diagnoses/year and is responsible for more than 450,000 yearly deaths worldwide. Two thirds of BC express the estrogen receptor (ER) and/or progesterone receptor and are referred to as hormone receptor-positive (HR+) BC. Endocrine therapy (ET) is usually active in these tumors, although drug resistance and side effects limit its benefit. Growth factor signaling through the PI3K/AKT/mammalian target of rapamycin (mTOR) and MAP kinase axes enhances ER activity and is a key mechanism underlying endocrine resistance. Water-only Fasting (Fasting) or plant-based, low-calorie, carbohydrate- and protein-restricted Fasting-mimicking diets (FMDs) reduce circulating growth factors, such as insulin and IGF1 Therefore, we hypothesized that these dietary interventions could be used to enhance the activity of ET and delay the occurrence of resistance. For our in vitro experiments we used the HR+ BC cell lines, MCF7, T47D, and ZR-75-1, as well as metastases-derived organoids from patients with HR+ BC. Our in vivo experiments in mouse xenografts of human BC cell lines, were conducted in six-to-eight-week old female NOD SCID or athymic Nude-FoxN1 mice treated with ET w/ or w/o 48-72 hours of Fasting/FMD. We monitored tumor growth and mouse survival and collected tumor masses and blood to detect circulating levels of several growth factors, adipokines and cytokines. In vivo add back experiments with Fasting-reduced factors were done with IGF1, insulin and leptin. Circulating growth factors and adipo-cytokines were also detected in blood samples from 36 patients with HR+ BC, who were enrolled in either one of two clinical trials (NCT03595540 and NCT03340935) assessing safety and feasibility of periodic FMD in cancer patients. Patient nutritional status and response to treatment were also monitored in our clinical trials.We found that in HR+ BC models, periodic Fasting or FMD enhanced tamoxifen and fulvestrant activity by lowering circulating IGF1, insulin, and leptin levels and by blocking AKT-mTOR signaling via EGR1 and PTEN upregulation. When fulvestrant was combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic FMD cycles promoted long-lasting tumour regressions and reverted acquired resistance to this regime. Moreover, both Fasting and FMD prevented tamoxifen-induced endometrial hyperplasia. In HR+ BC patients receiving ET, FMD cycles caused metabolic changes analogous to those observed in mice, including reduced leptin and IGF1 levels, which were found to remain low for extended periods. In mice, these long-lasting effects were associated with carryover anticancer activity. Overall, our results provide the rationale for conducting further clinical studies of Fasting-based dietary strategies as an adjuvant to ET w/ or w/o CDK4/6 inhibitors in patients with HR+ BC. Citation Format: Irene Caffa, Vanessa Spagnolo, Pamela Becherini, Francesca Valdemarin, Claudio Vernieri, Min Wei, Sebastian Brandhorst, Chiara Zucal, Else Driehuis, Lorenzo Ferrando, Luca Mastracci, Michele Cilli, Francesco Piacente, Anna Laura Cremonini, Mario Passalacqua, Valerio Vellone, Gabriele Zoppoli, Michele Cea, Giulia Salvadori, Salvatore Cortellino, Hans Clevers, Filippo De Braud, Alessandro Provenzani, Valter D. Longo, Alessio Nencioni. Fasting-mimicking diet and hormone therapy modulates metabolic factors to promote breast cancer regression and reduce side effects [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT075.
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Fasting-mimicking diet and hormone therapy induce breast cancer regression
Nature, 2020Co-Authors: Irene Caffa, Vanessa Spagnolo, Claudio Vernieri, Francesca Valdemarin, Pamela Becherini, Sebastian Brandhorst, Chiara Zucal, Else Driehuis, Lorenzo Ferrando, Francesco PiacenteAbstract:In mice, periodic Fasting or a Fasting-mimicking diet enhances the efficacy of endocrine therapy for breast cancer and delays acquired resistance to it; in patients with breast cancer, a Fasting-mimicking diet recreates the metabolic changes observed in mice. Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit^ 1 , 2 . Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic Fasting or a Fasting-mimicking diet^ 3 – 5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT–mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a Fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both Fasting and a Fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a Fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a Fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.
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Fasting mimicking diet and hormone therapy induce breast cancer regression
Nature, 2020Co-Authors: Irene Caffa, Vanessa Spagnolo, Claudio Vernieri, Francesca Valdemarin, Pamela Becherini, Sebastian Brandhorst, Chiara Zucal, Else Driehuis, Min WeiAbstract:Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit1,2. Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic Fasting or a Fasting-mimicking diet3-5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a Fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both Fasting and a Fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a Fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a Fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.
Vanessa Spagnolo - One of the best experts on this subject based on the ideXlab platform.
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abstract ct075 Fasting mimicking diet and hormone therapy modulates metabolic factors to promote breast cancer regression and reduce side effects
Cancer Research, 2020Co-Authors: Irene Caffa, Vanessa Spagnolo, Claudio Vernieri, Francesca Valdemarin, Pamela Becherini, Sebastian Brandhorst, Chiara Zucal, Else Driehuis, Min Wei, Lorenzo FerrandoAbstract:Breast cancer (BC) is the most common malignancy with 1.7 million new diagnoses/year and is responsible for more than 450,000 yearly deaths worldwide. Two thirds of BC express the estrogen receptor (ER) and/or progesterone receptor and are referred to as hormone receptor-positive (HR+) BC. Endocrine therapy (ET) is usually active in these tumors, although drug resistance and side effects limit its benefit. Growth factor signaling through the PI3K/AKT/mammalian target of rapamycin (mTOR) and MAP kinase axes enhances ER activity and is a key mechanism underlying endocrine resistance. Water-only Fasting (Fasting) or plant-based, low-calorie, carbohydrate- and protein-restricted Fasting-mimicking diets (FMDs) reduce circulating growth factors, such as insulin and IGF1 Therefore, we hypothesized that these dietary interventions could be used to enhance the activity of ET and delay the occurrence of resistance. For our in vitro experiments we used the HR+ BC cell lines, MCF7, T47D, and ZR-75-1, as well as metastases-derived organoids from patients with HR+ BC. Our in vivo experiments in mouse xenografts of human BC cell lines, were conducted in six-to-eight-week old female NOD SCID or athymic Nude-FoxN1 mice treated with ET w/ or w/o 48-72 hours of Fasting/FMD. We monitored tumor growth and mouse survival and collected tumor masses and blood to detect circulating levels of several growth factors, adipokines and cytokines. In vivo add back experiments with Fasting-reduced factors were done with IGF1, insulin and leptin. Circulating growth factors and adipo-cytokines were also detected in blood samples from 36 patients with HR+ BC, who were enrolled in either one of two clinical trials (NCT03595540 and NCT03340935) assessing safety and feasibility of periodic FMD in cancer patients. Patient nutritional status and response to treatment were also monitored in our clinical trials.We found that in HR+ BC models, periodic Fasting or FMD enhanced tamoxifen and fulvestrant activity by lowering circulating IGF1, insulin, and leptin levels and by blocking AKT-mTOR signaling via EGR1 and PTEN upregulation. When fulvestrant was combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic FMD cycles promoted long-lasting tumour regressions and reverted acquired resistance to this regime. Moreover, both Fasting and FMD prevented tamoxifen-induced endometrial hyperplasia. In HR+ BC patients receiving ET, FMD cycles caused metabolic changes analogous to those observed in mice, including reduced leptin and IGF1 levels, which were found to remain low for extended periods. In mice, these long-lasting effects were associated with carryover anticancer activity. Overall, our results provide the rationale for conducting further clinical studies of Fasting-based dietary strategies as an adjuvant to ET w/ or w/o CDK4/6 inhibitors in patients with HR+ BC. Citation Format: Irene Caffa, Vanessa Spagnolo, Pamela Becherini, Francesca Valdemarin, Claudio Vernieri, Min Wei, Sebastian Brandhorst, Chiara Zucal, Else Driehuis, Lorenzo Ferrando, Luca Mastracci, Michele Cilli, Francesco Piacente, Anna Laura Cremonini, Mario Passalacqua, Valerio Vellone, Gabriele Zoppoli, Michele Cea, Giulia Salvadori, Salvatore Cortellino, Hans Clevers, Filippo De Braud, Alessandro Provenzani, Valter D. Longo, Alessio Nencioni. Fasting-mimicking diet and hormone therapy modulates metabolic factors to promote breast cancer regression and reduce side effects [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT075.
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Fasting-mimicking diet and hormone therapy induce breast cancer regression
Nature, 2020Co-Authors: Irene Caffa, Vanessa Spagnolo, Claudio Vernieri, Francesca Valdemarin, Pamela Becherini, Sebastian Brandhorst, Chiara Zucal, Else Driehuis, Lorenzo Ferrando, Francesco PiacenteAbstract:In mice, periodic Fasting or a Fasting-mimicking diet enhances the efficacy of endocrine therapy for breast cancer and delays acquired resistance to it; in patients with breast cancer, a Fasting-mimicking diet recreates the metabolic changes observed in mice. Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit^ 1 , 2 . Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic Fasting or a Fasting-mimicking diet^ 3 – 5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT–mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a Fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both Fasting and a Fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a Fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a Fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.
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Fasting mimicking diet and hormone therapy induce breast cancer regression
Nature, 2020Co-Authors: Irene Caffa, Vanessa Spagnolo, Claudio Vernieri, Francesca Valdemarin, Pamela Becherini, Sebastian Brandhorst, Chiara Zucal, Else Driehuis, Min WeiAbstract:Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit1,2. Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic Fasting or a Fasting-mimicking diet3-5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a Fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both Fasting and a Fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a Fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a Fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.
