Outlook on PI3K/AKT/mTOR inhibition in acute leukemia
Lars Fransecky,Liliana H. Mochmann,Claudia D. Baldus +2 more
- Vol. 3, Iss: 1, pp 2-2
TLDR
In this paper, the authors summarized key findings leading to aberrant activation of PI3K/AKT/mTOR pathways in acute leukemia and reflected on both promises and challenges of targeting PI3k/AKt/mtor in the acute leukemia setting.Abstract:
Technological advances allowing high throughput analyses across numerous cancer tissues have allowed much progress in understanding complex cellular signaling. In the future, the genetic landscape in cancer may have more clinical relevance than diagnosis based on tumor origin. This progress has emphasized PI3K/AKT/mTOR, among others, as a central signaling center of cancer development due to its governing control in cellular growth, survival, and metabolism. The discovery of high frequencies of mutations in the PI3K/AKT/mTOR pathway in different cancer entities has sparked interest to inhibit elements of this pathway. In acute leukemia pharmacological interruption has yet to achieve desirable efficacy as targetable downstream mutations in PI3K/AKT/mTOR are absent. Nevertheless, mutations in membrane-associated genes upstream of PI3K/AKT/mTOR are frequent in acute leukemia and are associated with aberrant activation of PI3K/AKT/mTOR thus providing a good rationale for further exploration. This review attempts to summarize key findings leading to aberrant activation and to reflect on both promises and challenges of targeting PI3K/AKT/mTOR in acute leukemia. Our emphasis lies on the insights gained through high-throughput data acquisition that open up new avenues for identifying specific subgroups of acute leukemia as ideal candidates for PI3K/AKT/mTOR targeted therapy.read more
Citations
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Drug repurposing from the perspective of pharmaceutical companies.
Yoonjeong Cha,T Erez,Ian J. Reynolds,D Kumar,Jermaine Ross,Grigoriy Koytiger,Rebecca Kusko,Benjamin Zeskind,S Risso,E Kagan,S Papapetropoulos,Iris Grossman,Daphna Laifenfeld +12 more
TL;DR: Some of the main approaches to systematic repurposing are described and the various players in this field are discussed and the need for strategic collaborations to increase the likelihood of success in bringing existing molecules to new indications is discussed.
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miR-126 Regulates Distinct Self-Renewal Outcomes in Normal and Malignant Hematopoietic Stem Cells
Eric R. Lechman,Eric R. Lechman,Bernhard Gentner,Stanley W.K. Ng,Erwin M. Schoof,Erwin M. Schoof,Peter van Galen,Peter van Galen,James A. Kennedy,James A. Kennedy,Silvia Nucera,Fabio Ciceri,Kerstin B. Kaufmann,Kerstin B. Kaufmann,Naoya Takayama,Naoya Takayama,Stephanie M. Dobson,Stephanie M. Dobson,Aaron Trotman-Grant,Aaron Trotman-Grant,Gabriela Krivdova,Gabriela Krivdova,Janneke Elzinga,Janneke Elzinga,Amanda Mitchell,Amanda Mitchell,Björn Nilsson,Karin G. Hermans,Karin G. Hermans,Kolja Eppert,Rene Marke,Ruth Isserlin,Veronique Voisin,Gary D. Bader,Peter W. Zandstra,Todd R. Golub,Benjamin L. Ebert,Jun Lu,Mark D. Minden,Mark D. Minden,Jean C.Y. Wang,Jean C.Y. Wang,Luigi Naldini,John E. Dick,John E. Dick +44 more
TL;DR: Combined transcriptome and proteome analysis demonstrates that miR-126 targets the PI3K/AKT/MTOR signaling pathway, preserving LSC quiescence and promoting chemotherapy resistance.
Journal ArticleDOI
Natural products targeting the PI3K-Akt-mTOR signaling pathway in cancer: A novel therapeutic strategy.
TL;DR: Various preclinical and clinical studies on bioactive compounds and constituents, which are derived from natural products, to target the PI3K-Akt-mTOR signaling pathway for cancer prevention and intervention are summarized and critically analyzed.
Journal ArticleDOI
Potent efficacy of combined PI3K/mTOR and JAK or ABL inhibition in murine xenograft models of Ph-like acute lymphoblastic leukemia.
Sarah K. Tasian,Sarah K. Tasian,David T. Teachey,David T. Teachey,Yong Li,Feng Shen,Richard C. Harvey,I-Ming Chen,Theresa Ryan,Tiffaney Vincent,Cheryl L. Willman,Alexander E. Perl,Stephen P. Hunger,Stephen P. Hunger,Mignon L. Loh,Martin Carroll,Stephan A. Grupp,Stephan A. Grupp +17 more
TL;DR: Overall, PI3K/mTOR inhibition potently decreased ALL burden in vivo; antileukemia activity was further enhanced with combination inhibitor therapy.
Journal ArticleDOI
The PI3K-Akt-mTOR Signaling Pathway in Human Acute Myeloid Leukemia (AML) Cells.
Ina Nepstad,Kimberley Joanne Hatfield,Kimberley Joanne Hatfield,Ida Sofie Grønningsæter,Ida Sofie Grønningsæter,Håkon Reikvam,Håkon Reikvam +6 more
TL;DR: Observations suggest that constitutive activation of the PI3K-Akt-mTOR pathway differs between patients, and that increased activity within this pathway is an adverse prognostic parameter in AML.
References
More filters
Journal ArticleDOI
A cell initiating human acute myeloid leukaemia after transplantation into SCID mice
Tsvee Lapidot,Christian Sirard,Josef Vormoor,Barbara Murdoch,Trang Hoang,Julio R. Caceres-Cortes,Mark D. Minden,Bruce Paterson,Michael A. Caligiuri,John E. Dick +9 more
TL;DR: This in vivo model replicates many aspects of human AML and defines a new leukaemia-initiating cell which is less mature than colony-forming cells.
Journal ArticleDOI
Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining.
TL;DR: An unsuspected abnormality in all cells from the nine patients with chronic myelogenous leukaemia has been detected with quinacrine fluorescence and various Giemsa staining techniques, suggesting that there may be a hitherto undetected translocation between the long arm of 22 and thelong arm of 9, producing the 9q+ chromosome.
Journal ArticleDOI
Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia
Timothy J. Ley,Christopher A. Miller,Li Ding,Benjamin J. Raphael,Andrew J. Mungall,Gordon Robertson,Katherine A. Hoadley,Timothy J. Triche,Peter W. Laird,Jack Baty,Lucinda Fulton,Robert S. Fulton,Sharon Heath,Joelle Kalicki-Veizer,Cyriac Kandoth,Jeffery M. Klco,Daniel C. Koboldt,Krishna L. Kanchi,Shashikant Kulkarni,Tamara Lamprecht,David E. Larson,G. Lin,Charles Lu,Michael D. McLellan,Joshua F. McMichael,Jacqueline E. Payton,Heather Schmidt,David H. Spencer,Michael H. Tomasson,John W. Wallis,Lukas D. Wartman,Mark A. Watson,John S. Welch,Michael C. Wendl,Adrian Ally,Miruna Balasundaram,Inanc Birol,Yaron S.N. Butterfield,Readman Chiu,Andy Chu,Eric Chuah,Hye Jung E. Chun,Richard Corbett,Noreen Dhalla,Ranabir Guin,An He,Carrie Hirst,Martin Hirst,Robert A. Holt,Steven J.M. Jones,Aly Karsan,Darlene Lee,Haiyan I. Li,Marco A. Marra,Michael Mayo,Richard A. Moore,Karen Mungall,Jeremy Parker,Erin Pleasance,Patrick Plettner,Jacquie Schein,Dominik Stoll,Lucas Swanson,Angela Tam,Nina Thiessen,Richard Varhol,Natasja Wye,Yongjun Zhao,Stacey Gabriel,Gad Getz,Carrie Sougnez,Lihua Zou,Mark D.M. Leiserson,Fabio Vandin,Hsin-Ta Wu,Frederick Applebaum,Stephen B. Baylin,Rehan Akbani,Bradley M. Broom,Ken Chen,Thomas C. Motter,Khanh Thi-Thuy Nguyen,John N. Weinstein,Nianziang Zhang,Martin L. Ferguson,Christopher Adams,Aaron D. Black,Jay Bowen,Julie M. Gastier-Foster,Thomas Grossman,Tara M. Lichtenberg,Lisa Wise,Tanja Davidsen,John A. Demchok,Kenna R. Mills Shaw,Margi Sheth,Heidi J. Sofia,Liming Yang,James R. Downing,Greg Eley,Shelley Alonso,Brenda Ayala,Julien Baboud,Mark Backus,Sean P. Barletta,Dominique L. Berton,Anna L. Chu,Stanley Girshik,Mark A. Jensen,Ari B. Kahn,Prachi Kothiyal,Matthew C. Nicholls,Todd Pihl,David Pot,Rohini Raman,Rashmi N. Sanbhadti,Eric E. Snyder,Deepak Srinivasan,Jessica Walton,Yunhu Wan,Zhining Wang,Jean Pierre J. Issa,Michelle M. Le Beau,Martin Carroll,Hagop M. Kantarjian,Steven M. Kornblau,Moiz S. Bootwalla,Phillip H. Lai,Hui Shen,David Van Den Berg,Daniel J. Weisenberger,Daniel C. Link,Matthew J. Walter,Bradley A. Ozenberger,Elaine R. Mardis,Peter Westervelt,Timothy A. Graubert,John F. DiPersio,Richard K. Wilson +138 more
TL;DR: It is found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients and the databases from this study are widely available to serve as a foundation for further investigations of AMl pathogenesis, classification, and risk stratification.
Journal ArticleDOI
Mutational landscape and significance across 12 major cancer types
Cyriac Kandoth,Michael D. McLellan,Fabio Vandin,Kai Ye,Beifang Niu,Charles Lu,Mingchao Xie,Qunyuan Zhang,Joshua F. McMichael,Matthew A. Wyczalkowski,Mark D.M. Leiserson,Christopher A. Miller,John S. Welch,Matthew J. Walter,Michael C. Wendl,Timothy J. Ley,Richard K. Wilson,Benjamin J. Raphael,Li Ding +18 more
TL;DR: Data and analytical results for point mutations and small insertions/deletions from 3,281 tumours across 12 tumour types are presented as part of the TCGA Pan-Cancer effort, and clinical association analysis identifies genes having a significant effect on survival.
Journal ArticleDOI
Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.
Gary R. Hudes,Michael A. Carducci,Piotr Tomczak,Janice P. Dutcher,Robert A. Figlin,Anil Kapoor,Elzbieta Staroslawska,Jeffrey A. Sosman,David F. McDermott,Istvan Bodrogi,Zoran Kovacevic,Vladimir Lesovoy,Ingo G.H. Schmidt-Wolf,Olga Barbarash,Erhan Gokmen,Timothy O'Toole,Stephanie Lustgarten,Laurence Moore,Robert J. Motzer +18 more
TL;DR: As compared with interferon alfa, temsirolimus improved overall survival among patients with metastatic renal-cell carcinoma and a poor prognosis.
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