Inhibition of Myc family proteins eradicates KRas-driven lung cancer in mice
Laura Soucek,Laura Soucek,Jonathan Whitfield,Jonathan Whitfield,Nicole M. Sodir,Nicole M. Sodir,Daniel Massó-Vallés,Erika Serrano,Anthony N. Karnezis,Lamorna Brown Swigart,Gerard I. Evan,Gerard I. Evan +11 more
TLDR
It is demonstrated that metronomic Myc inhibition not only contains Ras-driven lung tumors indefinitely, but also leads to their progressive eradication, endorsing Myc as a compelling cancer drug target.Abstract:
The principal reason for failure of targeted cancer therapies is the emergence of resistant clones that regenerate the tumor. Therapeutic efficacy therefore depends on not only how effectively a drug inhibits its target, but also the innate or adaptive functional redundancy of that target and its attendant pathway. In this regard, the Myc transcription factors are intriguing therapeutic targets because they serve the unique and irreplaceable role of coordinating expression of the many diverse genes that, together, are required for somatic cell proliferation. Furthermore, Myc expression is deregulated in most—perhaps all—cancers, underscoring its irreplaceable role in proliferation. We previously showed in a preclinical mouse model of non-small-cell lung cancer that systemic Myc inhibition using the dominant-negative Myc mutant Omomyc exerts a dramatic therapeutic impact, triggering rapid regression of tumors with only mild and fully reversible side effects. Using protracted episodic expression of Omomyc, we now demonstrate that metronomic Myc inhibition not only contains Ras-driven lung tumors indefinitely, but also leads to their progressive eradication. Hence, Myc does indeed serve a unique and nondegenerate role in lung tumor maintenance that cannot be complemented by any adaptive mechanism, even in the most aggressive p53-deficient tumors. These data endorse Myc as a compelling cancer drug target.read more
Citations
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Book ChapterDOI
Methods for Determining Myc-Induced Apoptosis
Dan Lu,Trevor D. Littlewood +1 more
TL;DR: Techniques to detect Myc-induced apoptosis in vitro using flow cytometry and microscopy and in vivo using immunohistochemical staining are described.
Book ChapterDOI
The Myc world within reach.
Nicole M. Sodir,Laura Soucek +1 more
TL;DR: This issue of "The Myc gene: Methods and Protocols" provides a rich collection of techniques developed or routinely used by Myc investigators and serves as an invaluable resource for exploring the pleiotropic and still puzzling Myc biological functions.
Targeting the Oncogenic MYC Pathway by Miniproteins: Understanding Mechanism of Action
TL;DR: This work designed an alternative mini-protein derived from the MXD1 protein, a cellular antagonist to MYC, referred to as Mad1, which is ten-fold more potent than Omomyc in cells and is cell penetrant, with Mad1 localizing to the nucleus upon treatment of cells.
Journal ArticleDOI
Pharmacokinetic Analysis of Omomyc Shows Lasting Structural Integrity and Long Terminal Half-Life in Tumor Tissue
Marie-Eve Beaulieu,Sandra Martínez-Martín,J. Kaur,Virginia Castillo Cano,Daniel Massó-Vallés,Laia Foradada Felip,Sergio López-Estévez,Erika Serrano del Pozo,H. Thabussot,Laura Soucek +9 more
TL;DR: In this paper , the authors used a mass spectrometry approach to evaluate the stability of Omomyc in tumor biopsies from murine xenografts following its intravenous administration.
Book ChapterDOI
Unraveling and targeting RAS-driven metabolic signaling for therapeutic gain.
TL;DR: In this paper , the authors outline the unique metabolic requirements induced by aberrant RAS signaling and how these altered dependencies present opportunities for therapeutic intervention, and demonstrate how these dependencies can be therapeutically exploited in vitro and in vivo with many metabolic inhibitors currently in clinical trials.
References
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Journal ArticleDOI
BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc
Jake Delmore,Ghayas C Issa,Madeleine E. Lemieux,Peter B. Rahl,Junwei Shi,Hannah M. Jacobs,Efstathios Kastritis,Timothy Gilpatrick,Ronald M. Paranal,Jun Qi,Marta Chesi,Anna C. Schinzel,Michael R. McKeown,Timothy P. Heffernan,Christopher R. Vakoc,P. Leif Bergsagel,Irene M. Ghobrial,Paul G. Richardson,Richard A. Young,William C. Hahn,William C. Hahn,Kenneth C. Anderson,Andrew L. Kung,James E. Bradner,Constantine S. Mitsiades +24 more
TL;DR: In this paper, a small-molecule bromodomain inhibitor, JQ1, was used to identify BET proteins as regulatory factors for c-Myc oncoprotein.
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Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras
Erica L. Jackson,Nicholas A. Willis,Kim L. Mercer,Roderick T. Bronson,Denise Crowley,Raymond Montoya,Tyler Jacks,David A. Tuveson +7 more
TL;DR: It is shown that the use of a recombinant adenovirus expressing Cre recombinase (AdenoCre) to induce K-ras G12D expression in the lungs of mice allows control of the timing and multiplicity of tumor initiation.
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RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia
Johannes Zuber,Junwei Shi,Junwei Shi,Eric Wang,Amy R. Rappaport,Amy R. Rappaport,Harald Herrmann,Edward Allan R. Sison,Daniel Magoon,Jun Qi,Katharina Blatt,Mark Wunderlich,Meredith J. Taylor,Christopher Johns,Agustin Chicas,James C. Mulloy,Scott C. Kogan,Patrick Brown,Peter Valent,James E. Bradner,Scott W. Lowe,Scott W. Lowe,Scott W. Lowe,Christopher R. Vakoc +23 more
TL;DR: The results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention.
Journal ArticleDOI
Endogenous oncogenic K-rasG12D stimulates proliferation and widespread neoplastic and developmental defects
David A. Tuveson,Alice T. Shaw,Alice T. Shaw,Alice T. Shaw,Nicholas A. Willis,Daniel P. Silver,Erica L. Jackson,Sandy Chang,Kim L. Mercer,Rebecca Grochow,Hanno Hock,Denise Crowley,Sunil R. Hingorani,Tal Z. Zaks,Catrina King,Michael A. Jacobetz,Lifu Wang,Roderick T. Bronson,Stuart H. Orkin,Stuart H. Orkin,Ronald A. DePinho,Tyler Jacks +21 more
TL;DR: It is demonstrated that the conditional expression of an endogenous K-ras(G12D) allele in murine embryonic fibroblasts causes enhanced proliferation and partial transformation in the absence of further genetic abnormalities.
Journal ArticleDOI
Modelling Myc inhibition as a cancer therapy
Laura Soucek,Jonathan Whitfield,Carla P. Martins,Andrew J. Finch,Daniel J. Murphy,Nicole M. Sodir,Anthony N. Karnezis,Lamorna Brown Swigart,Sergio Nasi,Gerard I. Evan +9 more
TL;DR: It is shown that Myc inhibition triggers rapid regression of incipient and established lung tumours, defining an unexpected role for endogenous Myc function in the maintenance of Ras-dependent tumours in vivo.
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BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc
Jake Delmore,Ghayas C Issa,Madeleine E. Lemieux,Peter B. Rahl,Junwei Shi,Hannah M. Jacobs,Efstathios Kastritis,Timothy Gilpatrick,Ronald M. Paranal,Jun Qi,Marta Chesi,Anna C. Schinzel,Michael R. McKeown,Timothy P. Heffernan,Christopher R. Vakoc,P. Leif Bergsagel,Irene M. Ghobrial,Paul G. Richardson,Richard A. Young,William C. Hahn,William C. Hahn,Kenneth C. Anderson,Andrew L. Kung,James E. Bradner,Constantine S. Mitsiades +24 more