Pre-clinical validation of a selective anti-cancer stem cell therapy for Numb-deficient human breast cancers.
Daniela Tosoni,Sarah Pambianco,Blanche Ekalle Soppo,Silvia Zecchini,Giovanni Bertalot,Giancarlo Pruneri,Giuseppe Viale,Pier Paolo Di Fiore,Salvatore Pece +8 more
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TLDR
The data provide a pre‐clinical proof‐of‐concept that targeting Numb/p53 results in a specific anti‐CSC therapy in human BCs and corrected the defective self‐renewal properties of Numb‐deficient CSCs and inhibited CSC expansion, with a marked effect on tumorigenicity and metastasis.Abstract:
The cell fate determinant Numb is frequently downregulated in human breast cancers (BCs), resulting in p53 inactivation and an aggressive disease course. In the mouse mammary gland, Numb/p53 downregulation leads to aberrant tissue morphogenesis, expansion of the stem cell compartment, and emergence of cancer stem cells (CSCs). Strikingly, CSC phenotypes in a Numb-knockout mouse model can be reverted by Numb/p53 restoration. Thus, targeting Numb/p53 dysfunction in Numb-deficient human BCs could represent a novel anti-CSC therapy. Here, using patient-derived xenografts, we show that expansion of the CSC pool, due to altered self-renewing divisions, is also a feature of Numb-deficient human BCs. In these cancers, using the inhibitor Nutlin-3 to restore p53, we corrected the defective self-renewal properties of Numb-deficient CSCs and inhibited CSC expansion, with a marked effect on tumorigenicity and metastasis. Remarkably, a regimen combining Nutlin-3 and chemotherapy induced persistent tumor growth inhibition, or even regression, and prevented CSC-driven tumor relapse after removal of chemotherapy. Our data provide a pre-clinical proof-of-concept that targeting Numb/p53 results in a specific anti-CSC therapy in human BCs.read more
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MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer.
TL;DR: An updated overview about the state of the art of the clinical evaluation of MDM2/X inhibitor compounds with a special attention to hematological malignancies and to the potential for the management of pediatric cancers is given.
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Recent therapeutic trends and promising targets in triple negative breast cancer.
TL;DR: The complicated tumorigenic processes are reviewed and critical findings and therapeutic trends in TNBC are discussed with a focus on promising therapeutic approaches, the clinical trials currently underway, and potent experimental compounds under preclinical and evaluation.
Journal ArticleDOI
Cancer stem cells-emanated therapy resistance: Implications for liposomal drug delivery systems.
Hassan Dianat-Moghadam,Maryam Heidarifard,Rana Jahanban-Esfahlan,Yunes Panahi,Hamed Hamishehkar,Farhad Pouremamali,Reza Rahbarghazi,Mohammad Nouri +7 more
TL;DR: In this article, a small subpopulation of cancer cells known as cancer stem cells (CSCs) are shown to be responsible for deriving clonal heterogeneity/diversity in tumors, which render them resistant to conventional treatment regimes.
Journal ArticleDOI
Moving Breast Cancer Therapy up a Notch
Erik Mollen,Erik Mollen,Jonathan Ient,Vivianne C. G. Tjan-Heijnen,Vivianne C. G. Tjan-Heijnen,Liesbeth J. Boersma,Liesbeth J. Boersma,Lucio Miele,Marjolein L. Smidt,Marjolein L. Smidt,Marc Vooijs,Marc Vooijs +11 more
TL;DR: This review summarizes the current knowledge on targeting the Notch pathway to enhance current treatments for breast cancer and to combat treatment resistance and proposes mechanisms to further exploit Notch-based therapeutics in the treatment of breast cancer.
Journal ArticleDOI
A Numb-Mdm2 fuzzy complex reveals an isoform-specific involvement of Numb in breast cancer.
Ivan Nicola Colaluca,Andrea Basile,Lee Freiburger,Veronica D'Uva,Veronica D'Uva,Davide Disalvatore,Manuela Vecchi,Stefano Confalonieri,Daniela Tosoni,Valentina Cecatiello,Maria Grazia Malabarba,Chun Jiun Yang,Chun Jiun Yang,Masatsune Kainosho,Masatsune Kainosho,Michael Sattler,Marina Mapelli,Salvatore Pece,Salvatore Pece,Pier Paolo Di Fiore,Pier Paolo Di Fiore +20 more
TL;DR: It is shown that the Numb–Mdm2 interaction represents a fuzzy complex mediated by a short Numb sequence encompassing its alternatively spliced exon 3 (Ex3), which is necessary and sufficient to inhibit Mdm2 and prevent p53 degradation.
References
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Glioma stem cells promote radioresistance by preferential activation of the DNA damage response
Shideng Bao,Qiulian Wu,Roger E. McLendon,Yueling Hao,Qing Ming Shi,Anita B. Hjelmeland,Mark W. Dewhirst,Darell D. Bigner,Jeremy N. Rich +8 more
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Lyubomir T. Vassilev,Binh Thanh Vu,Bradford Graves,Daisy Carvajal,Frank John Podlaski,Zoran Filipovic,Norman Kong,Ursula Kammlott,Christine Lukacs,Christian Klein,Nader Fotouhi,Liu Emily Aijun +11 more
TL;DR: In this article, the authors identify potent and selective small-molecule antagonists of MDM2 and confirm their mode of action through the crystal structures of complexes, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor xenografts.