PI3K-mTOR in Cancer and Cancer Therapy PDF
Preview PI3K-mTOR in Cancer and Cancer Therapy
Cancer Drug Discovery and Development Nandini Dey Pradip De Brian Leyland-Jones E ditors PI3K-mTOR in Cancer and Cancer Therapy Foreword by Matthew J. Ellis Cancer Drug Discovery and Development Series editor Beverly A. Teicher Bethesda, Maryland, USA Cancer Drug Discovery and Development, the Springer series headed by Beverly A.Teicher, isthedefinitivebookseries incancer researchandoncology.Volumes covertheprocessofdrugdiscovery,preclinicalmodelsincancerresearch,specific drugtargetgroups,andexperimentalandapprovedtherapeuticagents.Thevolumes are current and timely, anticipating areas where experimental agents are reaching FDAapproval.Eachvolumeiseditedbyanexpertinthefieldcovered,andchapters are authored by renowned scientists and physicians in their fields of interest. More information about this series at http://www.springer.com/series/7625 Nandini Dey Pradip De (cid:129) Brian Leyland-Jones Editors PI3K-mTOR in Cancer and Cancer Therapy Foreword by Matthew J. Ellis Editors NandiniDey BrianLeyland-Jones Avera Cancer Institute Centerfor Precision Avera Cancer Institute Centerfor Precision Oncology Oncology SiouxFalls,SD SiouxFalls,SD USA USA PradipDe Avera Cancer Institute Centerfor Precision Oncology SiouxFalls,SD USA ISSN 2196-9906 ISSN 2196-9914 (electronic) Cancer DrugDiscovery andDevelopment ISBN978-3-319-34209-2 ISBN978-3-319-34211-5 (eBook) DOI 10.1007/978-3-319-34211-5 LibraryofCongressControlNumber:2016939046 ©SpringerScience+BusinessMediaNewYork2016 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpart of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission orinformationstorageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilar methodologynowknownorhereafterdeveloped. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publicationdoesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfrom therelevantprotectivelawsandregulationsandthereforefreeforgeneraluse. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authorsortheeditorsgiveawarranty,expressorimplied,withrespecttothematerialcontainedhereinor foranyerrorsoromissionsthatmayhavebeenmade. Printedonacid-freepaper ThisHumanaPressimprintispublishedbySpringerNature TheregisteredcompanyisSpringerInternationalPublishingAGSwitzerland To the past, present and future patients of Avera Cancer Institute Foreword Analysisofthegenomiclandscapeofcanceroverthelasthalfdecadethroughnext generation sequencing (NGS) studies has revealed a diverse array of somatic mutations that activate the phosphoinositol-3-kinase (PI3 kinase) pathway. These include loss of negative regulators (PTEN, INPP4B) that critically tip the mem- brane phospholipid balance in favor of active signaling. Additionally, gain of functionmutations indownstream PI3 kinase components,most particularly inthe phosphoinositol-3-kinase alpha subunit (PIK3CA); are among the most common somaticeventsinepithelialmalignancies.Interruptionofsignalingfluxthroughthe phospho-inositol-3-kinase pathway is therefore considered key to successful treat- mentand,ultimately,thecureofaverywiderangeofcancertypes.Therehasbeen astrenuousefforttodeveloppharmacologicalinhibitorsofthePI3kinasepathway, spurred by the initial success for analogs of the natural compound rapamycin, which inhibits the mTOR kinase. Rapamycin analogs are now approved for the treatment of renal cell carcinoma, breast cancer, pancreatic neuroendocrine tumors andtuberoussclerosisrelatedmalignancies.API3kinasedeltainhibitor,idelalisib, has been recently approved in chronic lymphocytic leukemia/lymphoma and fol- licular lymphoma. In these indications, PI3 kinase inhibitors are useful palliative treatments but resistance is essentially inevitable. This suggests that rational com- binations based on an understanding of resistance pathways are a critical next step. Another barrier to drug development is the difficulty in predicting response. NGS analysis of samples from an everolimus study in breast cancer as well as smaller studies of selective inhibitors of PI3 kinase has failed to develop a con- vincing genomic profile associated with the response. Newer approaches based on proteomics or perhaps integrated proteogenomic approaches are therefore under study. This book provides a critical summary of these important areas of vii viii Foreword investigation.Withclinicaltrialsreportingoutnewresultsfrommultipleclassesof inhibitors targeting the PI3 kinase pathway at multiple levels, the summaries pro- vided by the authors provide timely and critical context for the interpretation of these investigations and will help drive the design of the next generation of clinical trials. Matthew J. Ellis MB., BChir., Ph.D., FRCP Director, Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston TX Preface Our effort to edit this book is aimed to present readers who sincerely endeavor to examine the role of the PI3K-AKT-mTOR signaling pathway in the context of the emerging challenges of oncology, including energy metabolism, genomic insta- bility, signaling-driven combination therapies, drug response, and drug resistance. Through our effort, we seek to engage translational researchers, clinicians, and clinical researchers who aspire to develop therapies for the management of cancer patients. The book is a reference textbook intended for readers who are actively perusing basic, translational and clinical studies in the course of their graduate classes and fellowship trainings as well as researchers from academia, hospitals, and pharmaceutical industries. We were fortunate to have Prof. Lewis C. Cantley, who had kindly agreed to author the opening chapter of the book. It is any editor’s dream to have an intro- ductorychapterofabookentitled“PI3K-mTORinCancerandCancerTherapy”to bewrittenbynoneotherthanProf.LewisC.Cantley.Wefeelprivilegedandgrateful to Prof. Lewis C. Cantley. The topic of “PI3K-mTOR in Cancer and Cancer Therapy”istoodiverseandextensivetobecoveredinonebookwithlessthanten chapters.Wedecidedtopresentthebookintwoparts,PartIentitled“PI3K-mTOR Pathway in Cancers” containing four Chapters (2–5) and Part II entitled “PI3K-mTOR Pathway in Cancer Medicine” containing four Chapters (6–9). The first part comprises of four basic and translational topics emerging in the field of PI3K-mTOR signals, including cancer cell metabolism, DNA damage repair, drug response prediction and prognostic signatures and resistance to anti PI3K-mTOR pathway related drugs. Keeping in mind the central role of the PI3K-mTOR pathway in sensing tumor cells’nutrientandenergyneedandrewiringitwiththegrowthsignals,theChap.2 ofthefirstpartofthebookiswrittenbyProf.EstelaJacintoandhiscolleagues.The reviewfocusesontheroleofmTORcomplex1andmTORcomplex2indifferent metabolicandbiosyntheticprocesseswithspecialemphasisontheroleofmTORCs inthereprogramming ofcancer metabolism.The chapteralso discusses theroleof mTORinthemetabolicprocessesoftumorcellsandhowoncogenicmutationscan ix x Preface trigger metabolic reprogramming. The chapter encourages readers to study the clinicalrelevanceoftargetingmTORandmetabolicpathwaysforcancertherapy.In reading this chapter, a reader will get the basic knowledge to understand how mTORCsreprogrammetabolicandbiosyntheticpathwaysunderspecificoncogenic mutations and how mTORCs signal will influence the sensitivity to chemothera- peutic agents especially towards the development of resistance to mTOR/PI3K inhibitionduetoinduction ofalternativepathways.As wiselypointedoutbyProf. Estela Jacinto that “identifying synthetic lethal interactions and drug resistance mechanisms inherent to metabolic or growth signaling pathways upon mTOR inhibition will be important to develop more effective cancer therapy”. ThePI3K-AKT-mTORpathwayinteractswiththeDNAdamagerepairpathway insolidtumors.InChap.3ofthefirstpartofthebook,wehavetriedtoreviewhow the PI3K-AKT-mTOR pathway cooperates with the DNA damage repair pathway toward oncogenesis of Triple Negative Breast Cancers in the light of the transla- tional relevance of a combination of PARP inhibitors with PI3K-AKT-mTOR inhibitors. Delving into this chapter, a reader will learn that alteration(s) of the PI3K-AKT-mTOR pathway in breast cancers and its subtypes are contextual and DNAdamageresponseisoneofsuchimportantcontextsinTripleNegativeBreast Cancers. We intended to focus on the recent development in the field of a com- bination of PARP inhibitor(s) and PI3K-AKT-mTOR pathway inhibitor(s) in the light of drug-sensitivity and development of resistance. Chapter 4 of the first part of the book is written by Prof. Mariaelena Pierobon and his colleagues on “The AKT-mTOR signaling pathway for drug response prediction and prognostic signatures”. This chapter provides “an overview of the role of the PI3K-AKT-mTOR signaling network as a predictive and prognostic biomarker across different tumors along with a panel of high throughput and multiplex technologies used to broadly investigate functional changes”. Chapter5ofthefirstpartofthebookiswrittenbyProf.SaratChandarlapatyand his colleagues on “Resistance to PI3K pathway inhibition”. The chapter describes thebasiccircuitryofthePI3K-AKT-mTORpathwayanditsmechanismofreaction to inhibitors in bringing the “drug-induced relief-of-feedback results in pathway reactivation” and “drug-induced adaptive/compensatory activation of parallel signaling pathways in the network”. Built on this, the chapter then elegantly introduces the concept of development of resistance to the PI3K-AKT-mTOR pathwayinhibitorsanddiscussesthe“coordinatedactivationofRAS/RAFsignaling in resistance,” “feedback regulation of nuclear hormone signaling,” “Wnt-b- catenin cooperation with PI3K signaling,” “Myc amplification,” and “JAK2/ STAT5 inhibition.” We are convinced that in reading this chapter, a reader will comprehend “mechanisms of resistance common to cellular signaling pathways”. In the second part of the book, we have compiled four chapters describing the state-of-art of the PI3K-mTOR pathway based cancer therapies in selected solid and liquid tumors. Keeping in mind that the PI3K-mTOR pathway is one of the most geneticallyalteredpathwaysincancersandavastintellectualwealththatisvestedon exploiting this pathway towards the development of therapies to manage cancers, Chap. 6 is written by Prof. Funda Meric-Bernstam and Prof. Gordon Mills. In this
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