Fasting-mimicking diet and hormone therapy induce breast cancer regression

Nature. 2020 Jul;583(7817):620-624. doi: 10.1038/s41586-020-2502-7.

Irene Caffa ^# ¹, Vanessa Spagnolo ^# ² ³, Claudio Vernieri ³ ⁴, Francesca Valdemarin ¹ ⁵, Pamela Becherini ¹ ⁵, Min Wei ⁶, Sebastian Brandhorst ⁶, Chiara Zucal ⁷, Else Driehuis ⁸ ⁹, Lorenzo Ferrando ⁵, Francesco Piacente ¹ ⁵, Alberto Tagliafico ¹⁰, Michele Cilli ¹, Luca Mastracci ¹ ¹¹, Valerio G Vellone ¹ ¹¹, Silvano Piazza ⁷, Anna Laura Cremonini ¹ ⁵, Raffaella Gradaschi ¹, Carolina Mantero ¹, Mario Passalacqua ¹², Alberto Ballestrero ¹ ⁵, Gabriele Zoppoli ¹ ⁵, Michele Cea ¹ ⁵, Annalisa Arrighi ⁵, Patrizio Odetti ¹ ⁵, Fiammetta Monacelli ¹ ⁵, Giulia Salvadori ² ³, Salvatore Cortellino ³, Hans Clevers ⁸ ⁹ ¹³, Filippo De Braud ² ⁴, Samir G Sukkar ¹, Alessandro Provenzani ⁷, Valter D Longo ^# ¹⁴ ¹⁵, Alessio Nencioni ^# ¹⁶ ¹⁷

Affiliations

1 IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
2 Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
3 IFOM, FIRC Institute of Molecular Oncology, Milan, Italy.
4 Medical Oncology and Hematology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
5 Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy.
6 Longevity Institute, Leonard Davis School of Gerontology and Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA.
7 Department of Cellular, Computational, and Integrative Biology (CIBIO), University of Trento, Trento, Italy.
8 Oncode Institute and Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, The Netherlands.
9 University Medical Center Utrecht, Utrecht, The Netherlands.
10 Department of Health Sciences, University of Genoa, Genoa, Italy.
11 Department of Integrated Surgical and Diagnostic Sciences, University of Genoa, Genoa, Italy.
12 Department of Experimental Medicine, University of Genoa, Genoa, Italy.
13 Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.
14 IFOM, FIRC Institute of Molecular Oncology, Milan, Italy. [email protected].
15 Longevity Institute, Leonard Davis School of Gerontology and Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA. [email protected].
16 IRCCS Ospedale Policlinico San Martino, Genoa, Italy. [email protected].
17 Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy. [email protected].
# Contributed equally.

PMID: 32669709 DOI: 10.1038/s41586-020-2502-7

Abstract

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-50767

Palbociclib

99.96%, CDK4/6 Inhibitor

CDK

Cancer

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