Designing a broad-spectrum integrative approach for cancer prevention and treatment

ContentslistsavailableatScienceDirect

Seminars

in

Cancer

Biology

j ou rn a l h om ep a ge :w w w . e l s e v i e r . c o m / l o c a t e / s e m c a n c e r

Review

Designing

a

broad-spectrum

integrative

approach

for

cancer

prevention

and

treatment

Keith

I.

Block

a,∗

_,

_Charlotte

_Gyllenhaal

a

_,

_Leroy

_Lowe

b,er,∗∗

_,

_Amedeo

_Amedei

c

_,

A.R.M.

Ruhul

Amin

d

_,

_Amr

_Amin

e

_,

_Katia

_Aquilano

f

_,

_Jack

_Arbiser

d,ep,eq

_,

Alexandra

Arreola

g

_,

_Alla

_Arzumanyan

h

_,

_S.

_Salman

_Ashraf

i

_,

_Asfar

_S.

_Azmi

j

_,

Fabian

Benencia

k

_,

_Dipita

_Bhakta

l

_,

_Alan

_Bilsland

m

_,

_Anupam

_Bishayee

n

_,

_Stacy

_W.

_Blain

o

_,

Penny

B.

Block

a

_,

_Chandra

_S.

_Boosani

p

_,

_Thomas

_E.

_Carey

q

_,

_Amancio

_Carnero

r

_,

Marianeve

Carotenuto

s,t

_,

_Stephanie

_C.

_Casey

u

_,

_Mrinmay

_Chakrabarti

v

_,

Rupesh

Chaturvedi

w

_,

_Georgia

_Zhuo

_Chen

d

_,

_Helen

_Chen

x

_,

_Sophie

_Chen

y

_,

_Yi

_Charlie

_Chen

z

_,

Beom

K.

Choi

aa

_,

_Maria

_Rosa

_Ciriolo

f

_,

_Helen

_M.

_Coley

ab

_,

_Andrew

_R.

_Collins

ac

_,

Marisa

Connell

x

_,

_Sarah

_Crawford

ad

_,

_Colleen

_S.

_Curran

ae

_,

_Charlotta

_Dabrosin

af

_,

Giovanna

Damia

ag

_,

_Santanu

_Dasgupta

ah

_,

_Ralph

_J.

_DeBerardinis

aj

_,

_William

_K.

_Decker

ak

_,

Punita

Dhawan

al

_,

_Anna

_Mae

_E.

_Diehl

am

_,

_Jin-Tang

_Dong

d

_,

_Q.

_Ping

_Dou

j

_,

_Janice

_E.

_Drew

an

_,

Eyad

Elkord

ao

_,

_Bassel

_El-Rayes

ap

_,

_Mark

_A.

_Feitelson

h

_,

_Dean

_W.

_Felsher

u

_,

Lynnette

R.

Ferguson

aq

_,

_Carmela

_Fimognari

ar

_,

_Gary

_L.

_Firestone

as

_,

_Christian

_Frezza

at

_,

Hiromasa

Fujii

au

_,

_Mark

_M.

_Fuster

av

_,

_Daniele

_Generali

aw,ax

_,

_Alexandros

_G.

_Georgakilas

ay

_,

Frank

Gieseler

az

_,

_Michael

_Gilbertson

ba

_,

_Michelle

_F.

_Green

bb

_,

_Brendan

_Grue

bc

_,

Gunjan

Guha

l

_,

_Dorota

_Halicka

bd

_,

_William

_G.

_Helferich

be

_,

_Petr

_Heneberg

bf

_,

Patricia

Hentosh

bg

_,

_Matthew

_D.

_Hirschey

am,bb

_,

_Lorne

_J.

_Hofseth

bh

_,

_Randall

_F.

_Holcombe

bi

_,

Kanya

Honoki

au

_,

_Hsue-Yin

_Hsu

bj

_,

_Gloria

_S.

_Huang

bk

_,

_Lasse

_D.

_Jensen

bl,bm

_,

_Wen

_G.

_Jiang

bn

_,

Lee

W.

Jones

bo

_,

_Phillip

_A.

_Karpowicz

bp

_,

_W.

_Nicol

_Keith

m

_,

_Sid

_P.

_Kerkar

bq

_,

_Gazala

_N.

_Khan

br

_,

Mahin

Khatami

bs

_,

_Young

_H.

_Ko

bt

_,

_Omer

_Kucuk

d

_,

_Rob

_J.

_Kulathinal

h

_,

_Nagi

_B.

_Kumar

bu

_,

Byoung

S.

Kwon

aa,bw

_,

_Anne

_Le

bx

_,

_Michael

_A.

_Lea

by

_,

_Ho-Young

_Lee

bz

_,

_Terry

_Lichtor

ca

_,

Liang-Tzung

Lin

cb

_,

_Jason

_W.

_Locasale

cc

_,

_Bal

_L.

_Lokeshwar

cd

_,

_Valter

_D.

_Longo

ce

_,

Costas

A.

Lyssiotis

cf

_,

_Karen

_L.

_MacKenzie

cg

_,

_Meenakshi

_Malhotra

ch

_,

_Maria

_Marino

ci

_,

Maria

L.

Martinez-Chantar

cj

_,

_Ander

_Matheu

ck

_,

_Christopher

_Maxwell

x

_,

_Eoin

_McDonnell

bb

_,

Alan

K.

Meeker

cl

_,

_Mahya

_Mehrmohamadi

cm

_,

_Kapil

_Mehta

cn

_,

_Gregory

_A.

_Michelotti

am

_,

Ramzi

M.

Mohammad

j

_,

_Sulma

_I.

_Mohammed

co

_,

_D.

_James

_Morre

cp

_,

Irfana

Muqbil

j

_,

_Vinayak

_Muralidhar

cq,cr

_,

_Michael

_P.

_Murphy

cs

_,

Ganji

Purnachandra

Nagaraju

ap

_,

_Rita

_Nahta

d

_,

_Elena

_Niccolai

ct

_,

_Somaira

_Nowsheen

cu

_,

Carolina

Panis

cv

_,

_Francesco

_Pantano

cw

_,

_Virginia

_R.

_Parslow

aq

_,

_Graham

_Pawelec

cx

_,

Peter

L.

Pedersen

cy

_,

_Brad

_Poore

bx

_,

_Deepak

_Poudyal

bh

_,

_Satya

_Prakash

ch

_,

_Mark

_Prince

cz

_,

Lizzia

Raffaghello

da

_,

_Jeffrey

_C.

_Rathmell

bb

_,

_W.

_Kimryn

_Rathmell

g

_,

_Swapan

_K.

_Ray

v

_,

Jörg

Reichrath

db

_,

_Sarallah

_Rezazadeh

dc

_,

_Domenico

_Ribatti

dd

_,

_Luigi

_{Ricciardiello}

de

_,

R.

Brooks

Robey

df,dg

_,

_Francis

_Rodier

dh,di

_,

_H.P.

_Vasantha

_Rupasinghe

dj

_,

_Gian

_Luigi

_Russo

dk

_,

∗ Correspondingauthorat:BlockCenterforIntegrativeCancerTreatment,5230OldOrchardRoad,Skokie,IL60077,UnitedStates. ∗∗ Correspondingauthorat:GettingtoKnowCancer,Room229A,36ArthurStreet,Truro,NovaScotia,Canada.

E-mailaddresses:drblock@blockmedical.com(K.I.Block),Leroy.lowe@gettingtoknowcancer.org(L.Lowe).

http://dx.doi.org/10.1016/j.semcancer.2015.09.007

Elizabeth

P.

Ryan

dl

_,

_Abbas

_K.

_Samadi

dm

_,

_Isidro

_{Sanchez-Garcia}

dn

_,

_Andrew

_J.

_Sanders

bn

_,

Daniele

Santini

cw

_,

_Malancha

_Sarkar

do

_,

_Tetsuro

_Sasada

dp

_,

_Neeraj

_K.

_Saxena

dq

_,

Rodney

E.

Shackelford

dr

_,

_H.M.C.

_Shantha

_Kumara

bv

_,

_Dipali

_Sharma

ds

_,

_Dong

_M.

_Shin

d

_,

David

Sidransky

dt

_,

_Markus

_David

_Siegelin

du

_,

_Emanuela

_Signori

dv

_,

_Neetu

_Singh

dw

_,

Sharanya

Sivanand

dx

_,

_Daniel

_Sliva

dy

_,

_Carl

_Smythe

dz

_,

_Carmela

_Spagnuolo

dk

_,

Diana

M.

Stafforini

ea

_,

_John

_Stagg

eb

_,

_Pochi

_R.

_Subbarayan

ec

_,

_Tabetha

_Sundin

ed

_,

Wamidh

H.

Talib

ee

_,

_Sarah

_K.

_Thompson

ef

_,

_Phuoc

_T.

_Tran

eg

_,

_Hendrik

_Ungefroren

az

_,

Matthew

G.

Vander

Heiden

cr

_,

_Vasundara

_{Venkateswaran}

eh

_,

_Dass

_S.

_Vinay

ai

_,

Panagiotis

J.

Vlachostergios

ei

_,

_Zongwei

_Wang

ej

_,

_Kathryn

_E.

_Wellen

dx

_,

Richard

L.

Whelan

bv

_,

_Eddy

_S.

_Yang

ek

_,

_Huanjie

_Yang

el

_,

_Xujuan

_Yang

be

_,

_Paul

_Yaswen

em

_,

Clement

Yedjou

en

_,

_Xin

_Yin

av

_,

_Jiyue

_Zhu

eo

_,

_Massimo

_Zollo

s,t

a_{BlockCenterforIntegrativeCancerTreatment,Skokie,IL,UnitedStates} b_{GettingtoKnowCancer,Truro,NovaScotia,Canada}

c_{DepartmentofExperimentalandClinicalMedicine,UniversityofFlorence,Florence,Italy} d_{WinshipCancerInstituteofEmoryUniversity,Atlanta,GA,UnitedStates}

e_{DepartmentofBiology,CollegeofScience,UnitedArabEmiratesUniversity,AlAin,UnitedArabEmirates} f_{DepartmentofBiology,UniversityofRome“TorVergata”,Rome,Italy}

g_{LinebergerComprehensiveCancerCenter,UniversityofNorthCarolina,ChapelHill,NC,UnitedStates} h_{DepartmentofBiology,TempleUniversity,Philadelphia,PA,UnitedStates}

i_{DepartmentofChemistry,CollegeofScience,UnitedArabEmiratesUniversity,AlAin,UnitedArabEmirates} j_{DepartmentofOncology,KarmanosCancerInstitute,WayneStateUniversity,Detroit,MI,UnitedStates} k_{DepartmentofBiomedicalSciences,OhioUniversity,Athens,OH,UnitedStates}

l_{SchoolofChemicalandBioTechnology,SASTRAUniversity,Thanjavur,TamilNadu,India} m_{UniversityofGlasgow,Glasgow,UnitedKingdom}

n_{DepartmentofPharmaceuticalSciences,CollegeofPharmacy,LarkinHealthSciencesInstitute,Miami,FL,UnitedStates} o_{DepartmentofPediatrics,StateUniversityofNewYork,DownstateMedicalCenter,Brooklyn,NY,UnitedStates} p_{DepartmentofBioMedicalSciences,SchoolofMedicine,CreightonUniversity,Omaha,NE,UnitedStates} q_{HeadandNeckCancerBiologyLaboratory,UniversityofMichigan,AnnArbor,MI,UnitedStates} r_{InstitutodeBiomedicinadeSevilla,ConsejoSuperiordeInvestigacionesCientificas,Seville,Spain} s_{CentrodiIngegneriaGeneticaeBiotecnologiaAvanzate,Naples,Italy}

t_{DepartmentofMolecularMedicineandMedicalBiotechnology,FedericoII,ViaPansini5,80131Naples,Italy} u_{StanfordUniversity,DivisionofOncology,DepartmentofMedicineandPathology,Stanford,CA,UnitedStates}

v_{DepartmentofPathology,Microbiology,andImmunology,UniversityofSouthCarolina,SchoolofMedicine,Columbia,SC,UnitedStates} w_{SchoolofBiotechnology,JawaharlalNehruUniversity,NewDelhi,India}

x_{DepartmentofPediatrics,UniversityofBritishColumbia,MichaelCuccioneChildhoodCancerResearchProgram,ChildandFamilyResearchInstitute,Vancouver,BritishColumbia,}

Canada

y_{OvarianandProstateCancerResearchLaboratory,Guildford,Surrey,UnitedKingdom} z_{DepartmentofBiology,AldersonBroaddusUniversity,Philippi,WV,UnitedStates}

aa_{CancerImmunologyBranch,DivisionofCancerBiology,NationalCancerCenter,Goyang,Gyeonggi,RepublicofKorea} ab_{FacultyofHealthandMedicalSciences,UniversityofSurrey,Guildford,Surrey,UnitedKingdom}

ac_{DepartmentofNutrition,FacultyofMedicine,UniversityofOslo,Oslo,Norway}

ad_{CancerBiologyResearchLaboratory,SouthernConnecticutStateUniversity,NewHaven,CT,UnitedStates} ae_{SchoolofMedicineandPublicHealth,UniversityofWisconsin-Madison,Madison,WI,UnitedStates}

af_{DepartmentofOncologyandDepartmentofClinicalandExperimentalMedicine,LinköpingUniversity,Linköping,Sweden}

ag_{DepartmentofOncology,IstitutoDiRicoveroeCuraaCarattereScientifico–IstitutodiRicercheFarmacologicheMarioNegri,Milan,Italy} ah_{DepartmentofCellularandMolecularBiology,theUniversityofTexasHealthScienceCenteratTyler,Tyler,TX,UnitedStates}

ai_{SectionofClinicalImmunology,Allergy,andRheumatology,DepartmentofMedicine,TulaneUniversityHealthSciencesCenter,NewOrleans,LA,}

UnitedStates

aj_{Children’sMedicalCenterResearchInstitute,UniversityofTexas–SouthwesternMedicalCenter,Dallas,TX,UnitedStates} ak_{DepartmentofPathology&Immunology,BaylorCollegeofMedicine,Houston,TX,UnitedStates}

al_{DepartmentofSurgeryandCancerBiology,DivisionofSurgicalOncology,VanderbiltUniversitySchoolofMedicine,Nashville,TN,UnitedStates} am_{DepartmentofMedicine,DukeUniversityMedicalCenter,Durham,NC,UnitedStates}

an_{RowettInstituteofNutritionandHealth,UniversityofAberdeen,Aberdeen,Scotland,UnitedKingdom} ao_{CollegeofMedicine&HealthSciences,UnitedArabEmiratesUniversity,AlAin,UnitedArabEmirates} ap_{DepartmentofHematologyandMedicalOncology,EmoryUniversity,Atlanta,GA,UnitedStates}

aq_{DisciplineofNutritionandAucklandCancerSocietyResearchCentre,UniversityofAuckland,Auckland,NewZealand} ar_{DipartimentodiScienzeperlaQualitàdellaVitaAlmaMaterStudiorum-UniversitàdiBologna,Rimini,Italy} as_{DepartmentofMolecular&CellBiology,UniversityofCaliforniaBerkeley,Berkeley,CA,UnitedStates}

at_{MedicalResearchCouncilCancerUnit,UniversityofCambridge,Hutchison/MRCResearchCentre,Cambridge,UnitedKingdom} au_{DepartmentofOrthopedicSurgery,NaraMedicalUniversity,Kashihara,Nara,Japan}

av_{MedicineandResearchServices,VeteransAffairsSanDiegoHealthcareSystem&UniversityofCalifornia,SanDiego,CA,UnitedStates} aw_{DepartmentofMedical,SurgeryandHealthSciences,UniversityofTrieste,Trieste,Italy}

ax_{MolecularTherapyandPharmacogenomicsUnit,AziendaOspedalieraIstitutiOspitalieridiCremona,Cremona,Italy}

ay_{PhysicsDepartment,SchoolofAppliedMathematicsandPhysicalSciences,NationalTechnicalUniversityofAthens,Athens,Greece} az_{FirstDepartmentofMedicine,UniversityHospitalSchleswig-Holstein,CampusLübeck,Lübeck,Germany}

ba_{GettingtoKnowCancer,Guelph,Canada}

bb_{DukeMolecularPhysiologyInstitute,DukeUniversityMedicalCenter,Durham,NC,UnitedStates}

bc_{DepartmentsofEnvironmentalScience,MicrobiologyandImmunology,DalhousieUniversity,Halifax,NovaScotia,Canada} bd_{DepartmentofPathology,NewYorkMedicalCollege,Valhalla,NY,UnitedStates}

be_{UniversityofIllinoisatUrbanaChampaign,Champaign,IL,UnitedStates} bf_{CharlesUniversityinPrague,ThirdFacultyofMedicine,Prague,CzechRepublic}

bg_{SchoolofMedicalLaboratoryandRadiationSciences,OldDominionUniversity,Norfolk,VA,UnitedStates} bh_{CollegeofPharmacy,UniversityofSouthCarolina,Columbia,SC,UnitedStates}

DepartmentofLifeSciences,Tzu-ChiUniversity,Hualien,Taiwan

bk_{AlbertEinsteinCollegeofMedicineandMontefioreMedicalCenter,Bronx,NY,UnitedStates} bl_{DepartmentofMedicalandHealthSciences,LinköpingUniversity,Linköping,Sweden} bm_{DepartmentofMicrobiology,TumorandCellBiology,KarolinskaInstitutet,Stockholm,Sweden} bn_{CardiffUniversitySchoolofMedicine,HeathPark,Cardiff,UnitedKingdom}

bo_{DepartmentofMedicine,MemorialSloan-KetteringCancerCenter,NewYork,NY,UnitedStates} bp_{UniversityofWindsor,Windsor,Ontario,Canada}

bq_{LaboratoryMedicineandPathology,MayoClinic,Rochester,MN,UnitedStates} br_{HenryFordHospital,Detroit,MI,UnitedStates}

bs_{InflammationandCancerResearch,NationalCancerInstitute(Retired),NationalInstitutesofHealth,Bethesda,MD,UnitedStates} bt_{UniversityofMarylandBioPark,InnovationCenter,KoDiscovery,Baltimore,MD,UnitedStates}

bu_{MoffittCancerCenter,UniversityofSouthFloridaCollegeofMedicine,Tampa,FL,UnitedStates} bv_{DepartmentofSurgery,St.Luke’sRooseveltHospital,NewYork,NY,UnitedStates}

bw_{DepartmentofMedicine,TulaneUniversityHealthSciencesCenter,NewOrleans,LA,UnitedStates}

bx_{TheSolGoldmanPancreaticCancerResearchCenter,DepartmentofPathology,JohnsHopkinsUniversitySchoolofMedicine,Baltimore,MD,UnitedStates} by_{NewJerseyMedicalSchool,RutgersUniversity,Newark,NJ,UnitedStates}

bz_{CollegeofPharmacy,SeoulNationalUniversity,SouthKorea}

ca_{DepartmentofNeurosurgery,RushUniversityMedicalCenter,Chicago,IL,UnitedStates}

cb_{DepartmentofMicrobiologyandImmunology,SchoolofMedicine,CollegeofMedicine,TaipeiMedicalUniversity,Taipei,Taiwan} cc_{DivisionofNutritionalSciences,CornellUniversity,Ithaca,NY,UnitedStates}

cd_{DepartmentofMedicine,GeorgiaRegentsUniversityCancerCenter,Augusta,GA,UnitedStates}

ce_{AndrusGerontologyCenter,DivisionofBiogerontology,UniversityofSouthernCalifornia,LosAngeles,CA,UnitedStates}

cf_{DepartmentofMolecularandIntegrativePhysiologyandDepartmentofInternalMedicine,DivisionofGastroenterology,UniversityofMichigan,}

AnnArbor,MI,UnitedStates

cg_{Children’sCancerInstituteAustralia,Kensington,NewSouthWales,Australia} ch_{DepartmentofBiomedicalEngineering,McGillUniversity,Montréal,Canada} ci_{DepartmentofScience,UniversityRomaTre,Rome,Italy}

cj_{MetabolomicUnit,CentrodeInvestigaciónBiomédicaenReddeEnfermedadesHepáticasyDigestivas,TechnologyParkofBizkaia,Bizkaia,Spain} ck_{BiodonostiaInstitute,Gipuzkoa,Spain}

cl_{DepartmentofPathology,JohnsHopkinsUniversitySchoolofMedicine,Baltimore,MD,UnitedStates}

cm_{FieldofGenetics,Genomics,andDevelopment,DepartmentofMolecularBiologyandGenetics,CornellUniversity,Ithaca,NY,UnitedStates} cn_{DepartmentofExperimentalTherapeutics,UniversityofTexasMDAndersonCancerCenter,Houston,TX,UnitedStates}

co_{DepartmentofComparativePathobiology,PurdueUniversityCenterforCancerResearch,WestLafayette,IN,UnitedStates} cp_{Mor-NuCo,Inc,PurdueResearchPark,WestLafayette,IN,UnitedStates}

cq_{Harvard-MITDivisionofHealthSciencesandTechnology,HarvardMedicalSchool,Boston,MA,UnitedStates} cr_{KochInstituteforIntegrativeCancerResearch,MassachusettsInstituteofTechnology,Cambridge,MA,UnitedStates} cs_{MRCMitochondrialBiologyUnit,WellcomeTrust-MRCBuilding,HillsRoad,Cambridge,UnitedKingdom} ct_{UniversityofFlorence,Florence,Italy}

cu_{MedicalScientistTrainingProgram,MayoGraduateSchool,MayoMedicalSchool,MayoClinic,Rochester,MN,UnitedStates} cv_{LaboratoryofInflammatoryMediators,StateUniversityofWestParaná,UNIOESTE,Paraná,Brazil}

cw_{MedicalOncologyDepartment,UniversityCampusBio-Medico,Rome,Italy} cx_{CenterforMedicalResearch,UniversityofTübingen,Tübingen,Germany}

cy_{DepartmentsofBiologicalChemistryandOncology,MemberatLarge,SidneyKimmelComprehensiveCancerCenter,JohnsHopkinsUniversity,SchoolofMedicine,Baltimore,MD,}

UnitedStates

cz_{DepartmentofOtolaryngology-HeadandNeck,MedicalSchool,UniversityofMichigan,AnnArbor,MI,UnitedStates} da_{LaboratoryofOncology,IstitutoGianninaGaslini,Genoa,Italy}

db_{CenterforClinicalandExperimentalPhotodermatology,ClinicforDermatology,VenerologyandAllergology,TheSaarlandUniversityHospital,Homburg,Germany} dc_{DepartmentofBiology,UniversityofRochester,Rochester,NY,UnitedStates}

dd_{DepartmentofBasicMedicalSciences,NeurosciencesandSensoryOrgans,UniversityofBariMedicalSchool,Bari,Italy&NationalCancerInstituteGiovanniPaoloII,Bari,Italy} de_{DepartmentofMedicalandSurgicalSciences,UniversityofBologna,Bologna,Italy}

df_{WhiteRiverJunctionVeteransAffairsMedicalCenter,WhiteRiverJunction,VT,UnitedStates} dg_{GeiselSchoolofMedicineatDartmouth,Hanover,NH,UnitedStates}

dh_{CentredeRechercheduCentreHospitalierdel’UniversitédeMontréalandInstitutduCancerdeMontréal,Montréal,Quebec,Canada} di_{UniversitédeMontréal,DépartementdeRadiologie,Radio-OncologieetMédicineNucléaire,Montréal,Quebec,Canada}

dj_{DepartmentofEnvironmentalSciences,FacultyofAgricultureandDepartmentofPathology,FacultyofMedicine,DalhousieUniversity,Halifax,}

NovaScotia,Canada

dk_{InstituteofFoodSciencesNationalResearchCouncil,Avellino,Italy}

dl_{DepartmentofEnvironmentalandRadiologicalHealthSciences,ColoradoStateUniversity,FortCollins,CO,UnitedStates} dm_{SanusBiosciences,SanDiego,CA,UnitedStates}

dn_{ExperimentalTherapeuticsandTranslationalOncologyProgram,InstitutodeBiologíaMolecularyCelulardelCáncer,CSIC-UniversidaddeSalamanca,Salamanca,Spain} do_{DepartmentofBiology,UniversityofMiami,Miami,FL,UnitedStates}

dp_{DepartmentofImmunology,KurumeUniversitySchoolofMedicine,Kurume,Fukuoka,Japan} dq_{DepartmentofMedicine,UniversityofMarylandSchoolofMedicine,Baltimore,MD,UnitedStates} dr_{DepartmentofPathology,LouisianaStateUniversity,HealthShreveport,Shreveport,LA,UnitedStates}

ds_{DepartmentofOncology,JohnsHopkinsUniversitySchoolofMedicineandtheSidneyKimmelComprehensiveCancerCenteratJohnsHopkins,Baltimore,MD,UnitedStates} dt_{DepartmentofOtolaryngology-HeadandNeckSurgery,JohnsHopkinsUniversitySchoolofMedicine,Baltimore,MD,UnitedStates}

du_{DepartmentofPathologyandCellBiology,ColumbiaUniversityMedicalCenter,NewYork,NY,UnitedStates} dv_{NationalResearchCouncil,InstituteofTranslationalPharmacology,Rome,Italy}

dw_{AdvancedMolecularScienceResearchCentre(CentreforAdvancedResearch),KingGeorge’sMedicalUniversity,Lucknow,UttarPradesh,India} dx_{DepartmentofCancerBiology,PerelmanSchoolofMedicine,UniversityofPennsylvania,Philadelphia,PA,UnitedStates}

dy_{DSTestLaboratories,PurdueResearchPark,Indianapolis,IN,UnitedStates}

dz_{DepartmentofBiomedicalScience,SheffieldCancerResearchCentre,UniversityofSheffield,Sheffield,UnitedKingdom} ea_{HuntsmanCancerInstituteandDepartmentofInternalMedicine,UniversityofUtah,SaltLakeCity,UT,UnitedStates}

eb_{CentredeRechercheduCentreHospitalierdel’UniversitédeMontréal,FacultédePharmacieetInstitutduCancerdeMontréal,Montréal,Quebec,Canada} ec_{DepartmentofMedicine,UniversityofMiamiMillerSchoolofMedicine,Miami,FL,UnitedStates}

ed_{DepartmentofMolecularDiagnostics,SentaraHealthcare,Norfolk,VA,UnitedStates} ee_{DepartmentofClinicalPharmacyandTherapeutics,AppliedScienceUniversity,Amman,Jordan}

DepartmentofSurgery,RoyalAdelaideHospital,Adelaide,Australia

eg_{DepartmentsofRadiationOncology&MolecularRadiationSciences,OncologyandUrology,JohnsHopkinsSchoolofMedicine,Baltimore,MD,}

UnitedStates

eh_{DepartmentofSurgery,UniversityofToronto,DivisionofUrology,SunnybrookHealthSciencesCentre,Toronto,Ontario,Canada} ei_{DepartmentofInternalMedicine,NewYorkUniversityLutheranMedicalCenter,Brooklyn,NewYork,NY,UnitedStates} ej_{DepartmentofUrology,MassachusettsGeneralHospital,HarvardMedicalSchool,Boston,MA,UnitedStates}

ek_{DepartmentofRadiationOncology,UniversityofAlabamaatBirminghamSchoolofMedicine,Birmingham,AL,UnitedStates} el_{TheSchoolofLifeScienceandTechnology,HarbinInstituteofTechnology,Harbin,Heilongjiang,China}

em_{LifeSciencesDivision,LawrenceBerkeleyNationalLab,Berkeley,CA,UnitedStates} en_{DepartmentofBiology,JacksonStateUniversity,Jackson,MS,UnitedStates} eo_{WashingtonStateUniversityCollegeofPharmacy,Spokane,WA,UnitedStates} ep_{AtlantaVeteransAdministrationMedicalCenter,Atlanta,GA,UnitedStates}

eq_{DepartmentofDermatology,EmoryUniversitySchoolofMedicine,EmoryUniversity,Atlanta,GA,UnitedStates} er_{LancasterEnvironmentCentre,LancasterUniversity,Bailrigg,Lancaster,UnitedKingdom}

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Articlehistory:

Received19November2014

Receivedinrevisedform12August2015 Accepted14September2015 Keywords: Multi-targeted Cancerhallmarks Phytochemicals Targetedtherapy Integrativemedicine

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Targetedtherapiesand theconsequent adoptionof“personalized” oncologyhaveachievednotable

successesinsomecancers;however,significantproblemsremainwiththisapproach.Manytargeted

therapiesarehighlytoxic,costsareextremelyhigh,andmostpatientsexperiencerelapseafterafew

disease-freemonths.Relapsesarisefromgeneticheterogeneityintumors,whichharbortherapy-resistant

immortalizedcellsthathaveadoptedalternateandcompensatorypathways(i.e.,pathwaysthatarenot

reliantuponthesamemechanismsasthosewhichhavebeentargeted).Toaddresstheselimitations,an

internationaltaskforceof180scientistswasassembledtoexploretheconceptofalow-toxicity

“broad-spectrum”therapeuticapproachthatcouldsimultaneouslytargetmanykeypathwaysandmechanisms.

Usingcancerhallmarkphenotypesandthetumormicroenvironmenttoaccountforthevariousaspects

ofrelevantcancerbiology,interdisciplinaryteamsreviewedeachhallmarkareaandnominatedawide

rangeofhigh-prioritytargets(74intotal)thatcouldbemodifiedtoimprovepatientoutcomes.Forthese

targets,correspondinglow-toxicitytherapeuticapproacheswerethensuggested,manyofwhichwere

phytochemicals.Proposedactionsoneachtargetandalloftheapproacheswerefurtherreviewedfor

knowneffectsonotherhallmarkareasandthetumormicroenvironment.Potentialcontraryor

procar-cinogeniceffectswerefoundfor3.9%oftherelationshipsbetweentargetsandhallmarks,andmixed

evidenceofcomplementaryandcontraryrelationshipswasfoundfor7.1%.Approximately67%ofthe

relationshipsrevealedpotentiallycomplementaryeffects,andtheremainderhadnoknownrelationship.

Amongtheapproaches,1.1%hadcontrary,2.8%hadmixedand62.1%hadcomplementaryrelationships.

Theseresultssuggestthatabroad-spectrumapproachshouldbefeasiblefromasafetystandpoint.This

novelapproachhaspotentialtoberelativelyinexpensive,itshouldhelpusaddressstagesandtypesof

cancerthatlackconventionaltreatment,anditmayreducerelapserisks.Aproposedagendaforfuture

researchisoffered.

©2015TheAuthors.PublishedbyElsevierLtd.ThisisanopenaccessarticleundertheCCBYlicense

(http://creativecommons.org/licenses/by/4.0/).

1. Introduction

Cancerisasourceofsignificantandgrowingmortality world-wide,withanincreaseto19.3millionnewcancercasesperyear projectedfor2025.Morethanhalfofcancercasesandmortality occurinlow-andmiddle-incomecountries,andtheseproportions areexpectedtoincreaseby2025[1].Currenttreatmentsforcancer includesurgery,radiotherapyandsystemictreatments compris-ingcytotoxicchemotherapy,hormonaltherapy,immunotherapy, and targeted therapies [2]. Cancer continues tostymie clinical treatmentefforts,however,andthesearchforeffectivetherapies continues.

Thiscapstonepaperdescribesthemethodsandresultsofa sub-stantialeffortbyalargeinternationalgroupofbiochemicaland medical researchers,operating under thename of “The Halifax Project,”sponsoredbyanon-profitorganization,GettingToKnow Cancer.Itsummarizesanddrawstogethermaterialfromaseriesof reviewsonthehallmarksofcancer,presentedinthisspecialissue ofSeminarsinCancerBiology,topresentaconceptualframework fora newapproach tocancerpreventionandtherapeutics.This approachinvolvesthetargetingofmanyspecifichigh-priority anti-cancermechanismsandpathwayswithinamorecomprehensive modeloftreatmentandcare.Werefertothisasa“broad-spectrum”

approach(i.e.,anapproachaimedatabroadspectrumof impor-tantmechanismsandpathways)[3].Thebroad-spectrumapproach involvescombinationsofmultiplelow-toxicityagentsthatcan col-lectivelyimpactmanypathwaysthatareknowntobeimportant forthegenesisandspreadofcancer.Bymakingextensiveuseof chemicalsfromplantsandfoodsthathavealreadybeenstudiedor utilizedforcancerpreventionandtreatment,thisapproachoffersa compellingrationaleforaddressingtheunderlyingbiologyof can-cerwhilebeingefficacious,non-toxicandcost-effective.Wecome togetherinthebeliefthatabroad-spectrumapproachofthistype, inthecontextofatherapeuticenvironmentincludingconventional treatmentandattentivetooptimalhealth,wouldprovidegenuine benefitinclinicaloutcomesforcancerpatients.Inthispaperwe describetherationaleforbroad-spectrumtherapeutics,detailthe methodsoftheHalifaxProject,summarizepotentialtargetsand agents related toelevenhallmarkfeatures of cancer,propose a researchmodelforthedevelopmentofbroad-spectrumtherapies, andcallforactiontoadvancethisresearchmodel.

1.1. Rationaleforbroad-spectrumapproach

Primarymotivationsforthedevelopmentofabroad-spectrum approach stemfrom thedistinctlimitations thatare evidentin

Fig.1.Diagrammaticrepresentationofremovalofsusceptiblecellsbyatargetedcancertherapyresultingindiseaseremission,whichleavesgeneticallyheterogeneous resistantcellstoproliferate,resultinginrelapse.

manycurrenttargetedtherapies andthepersonalizedmedicine paradigm. Molecular target therapies represent a significant advanceinthetreatmentof cancer.Theyincludedrugssuchas imatinib, an inhibitor of the tyrosine kinase enzyme BCR-ABL, whichhasmadechronicmyelogenousleukemiaamore manage-abledisease,andinhibitorsofvascularendothelialgrowthfactor receptor(VEGFR),suchassunitinib,sorafeniband bevacizumab, usedinrenalandcoloncancers[2].Otherimportanttreatments basedontumor-specifictargetsarenowinuse,including exam-plessuchasepidermalgrowthfactorreceptor(EGFR)inhibitors (gefitinib,erlotinib)usedinlung cancer,and theHer2inhibitor trastuzumabusedinbreastcancer.Anotherapproachisthe syn-theticlethalmodel[4]exemplifiedbyresearchonpolyADPribose polymerase(PARP) inhibition, in which mutational loss of one or more redundant components of a cell survival pathway in tumorigeniccellsconfersselectivesensitivitytodrugsthattarget remainingpathwaycomponents.

Thesedrugstargetcellsbearingone,oratmostafewmutated geneproductsorotherabnormalitiesnotfoundonnormalcells. Inthetherapeuticcontext,theactionofthetargetedagentscan efficientlyaddressmalignantcells,withoutsomeoftheeffectson normalcells notorious in cytotoxicchemotherapy.Thisenables therapeuticresponses and remissions.Over time, however, the geneticheterogeneityoftumorsincreases,engenderingresistance totreatment.Resistantcellsdrivetheemergenceofincreasingly aggressivedisease, through clonal expansion and clonal evolu-tion(Fig.1).Epigeneticmodifications,heritablecellularchanges notcaused by alterationstoDNA sequences,but by alterations suchasmethylationofDNAormodificationofthehistoneprotein associated withDNA, may also affect patternsof gene expres-sionanddrivecancers[5].Relapsesoftenoccurafteronlyafew months,andtumorsreappear,sometimesinexactlythesameareas inwhichtheyoriginated[6].Moreover,targetedagents arenot withoutserioussideeffects,suchastreatment-relatedmortality withbevacizumaband cardiopulmonaryarrest withcetuximab. Meta-analysisoftrialsofrecentlyapprovedcancerdrugs includ-ingtargetedtherapiesversusolderdrugsshowedincreasedrates ofgrades3and4toxicity(OR=1.52),treatmentdiscontinuation (OR=1.33) and toxic deaths (OR=1.40) [7]. This worsening of adverseeffectshasgoneinlargepartunacknowledged.

The efficacy shown to date with targeted therapies, aside from now-established treatments such as bevacizumab and trastuzumab,isneverthelessstilllimited.Sunitinib,forinstance, extendsoverallsurvivalby4.6monthsinrenalcancercompared withtheprevioustreatmentofinterferon-_␣[8].Whilestatistically significant,thisdegreeofimprovementissmallcomforttoafflicted patients,andchallengestheextraordinarymonetaryinvestment indrugdevelopmentaswellascoststothemedicalsystemthat targetedtherapiesrepresent.TheMOSCATO01trialofmolecular triagewasabletotreat25of111patientswithavarietyofadvanced cancersusingtherapiestargetedtogenomicalterationsassessed fromtumorbiopsies[9].Of these,5 patients(20%) experienced partialresponseand56%hadstabledisease.Basedontheentire

populationof111patients,thisisapartialresponseoflessthan5%, suggestinglimitedefficacytodate,anoutcomealsoseeninsome otherstudies[10].Onamorehopefulnotehowever,a combina-tionofpertuzumabwithtrastuzumabandthechemotherapyagent docetaxelwasrecentlyfoundtoextendoverallsurvivalamongthe subsetofbreastcancerpatientswhosetumorsexpressHer-2by 15.7months[11].

Interestingly,harnessingthebody’simmuneresponseagainst thetumorcanalsoresultinimpressivedurableclinicalresponses, perhapsbecausetheimmunesystemisa paragonof adaptabil-ity and can deal with changes in the mutational landscape of cancertopreventescapefromthetherapeuticeffect. Immunomod-ulatoryantibodiesrecentlylicensedintheUnitedStatesinclude ipilimumabaswellasnivolumabandpembrolizumab, neutraliz-ingtwodifferentinhibitorypathwaysthatblockantitumorTcell responses.Theseagentshaveachievedsomesuccessesintreating latestagecancersrefractorytoessentiallyanyothertreatments

[12].Butevenwiththeseagents,responseratesarestilllowand predictingwhowillrespondisanunsolvedchallenge[13,14].

Manyofthesetherapiesaresomewhatnarrowlydescribedas “personalized”becausepatients’tumorsmustbetestedfor spe-cificmutationstostratifypatientstothecorrecttherapy.Viewed inthelargercontextofindividualbiologicalvariation,ofcourse, specific mutationsdriveonly the smallestdegree of personali-zation.Trulypersonalizedtreatmentapproachescanbeseento includeamuch morecomprehensiveassessmentofgeneticand even lifestyle factors, such as nutritional, biobehavioral (stress management) strategies, and exercise habits, along with other hostvariablessuchasinflammationandimmunestatus.Suchan approachtopersonalizingtreatmentcanbefoundinthesystematic practiceofintegrativemedicine,whichplayedasignificantrolein thedevelopmentofthismodelofbroad-spectrumcancertherapy. Somedefinitionsofintegrativemedicinestresssimplytheinclusion ofcomplementaryand alternativetherapies alongsideorthodox treatment[15].Amorerelevantdefinitionemphasizesa patient-centered,multi-interventiontreatmentparadigmthataddresses thefullrangeofphysical,mental,emotionaland environmental influences,utilizinganarrayofdisciplinesincludingdiet, mind-bodyandphysicalactivitytherapiesinadditiontoconventional therapiesanddietarysupplementstosupportoptimalhealth[16], basedonlaboratorytestingthatenablescomprehensive persona-lization.

The stratification of patientsfor these targeted and person-alizedtherapies poses practical challenges.Asindicated earlier, over50%oftheincreaseincancerincidenceby2025isprojected tooccurinthedeveloping world[1].Asindustrialization devel-opsinlower-incomecountries,occupationalcancersareexpected to increase, potentially aggravating this situation [17]. Cancer treatmentinmanyofthesecountriesisalreadybecominga social-economicchallengeduetotheexpenseandmedicalinfrastructure required[18],andthenewgenerationoftreatmentsmayfurther strain localresources. Currently, theplatformsused for testing topersonalizeregimensincludewholeexomeorwholegenome

sequencing, whole transcriptome sequencing, and comparative genomichybridizationwithstillothersindevelopment.Itislikely thatsuchtests,andrelatedexpense,willproliferateinthefuture. Managingtreatmenttoxicityisalsoataxingandcomplexproblem, asthesetoxicitiesnecessitateadditionalmedicalinterventions.

Theexpenseofthenewtargetedtherapiesisalsoconcerning. ElevenoftwelvedrugsapprovedbytheUSFoodandDrug Admin-istration(USFDA)in2012werepricedabove$100,000USperyear perpatient–perhapsnotsurprisinglyinviewoftheaccelerating costsofdrugdevelopment[19].Clinicianshavedrawnattention tothese highcosts:in 2013 morethan 100expertsin chronic myeloid leukemia coauthored a paper calling for lower prices andbroaderaccesstothesedrugs[20].Theexcessivecostshave resultedindrugsnotbeingapprovedforusebynationalorregional governmentswherecost-benefitanalysesfigureinapproval pro-cesses[21].Whilecostsareexpectedtodecreaseafterexpiration ofpatentsonthedrugs,thecostsfortreatmentinlow-or middle-incomecountriesmaycontinuetobeproblematic.Thepotential forunsupportablefinancialstressonhealthsystemschallengesthe researchcommunitytoexploreothertreatmentmodelsthatcan bemoresustainableinthefaceoftheworldwideincreaseincancer incidence.

Thebroad-spectrumapproachthatwedescribehereisprimarily intended toaddress the two major issues of therapeutic resis-tanceand cost. It is basedonmany of theinsightsof genomic sequencingincancers.Wenowknowthatcancersharbor signif-icantgeneticheterogeneity,evenwithinasinglepatient[6].Based onthisheterogeneity,cancersroutinelyevolveresistanceto treat-mentthroughswitchingfromonegrowthpathwaytoanother[22]. Theproposedstrategyemploysthebasicprinciplesofrationaldrug design,butaimstostemcancergrowthbypreciselytargetingmany growthpathwayssimultaneously.Someeffortisnowbeingmade incombiningtargetedagentssothatmorethanonepathwaycan beaffected,butlackoftherapeuticsuccess,significanttoxicityand costsmakethisachallenge[23–26].

Weseethebroad-spectrum approachasonethatis comple-mentarytoexistingtherapies,preferablywithinthecontextofa genuinelyintegrativeclinicalsystem.Clinicalsituationsinwhich suchanapproachmightproveusefulinclude(a)asa follow-up maintenanceplantoconventionaladjuvanttreatment;(b)in sit-uationsofrarecancersanddiseasestagesforwhichnoaccepted treatments exist; (c) for patients who do not tolerate conven-tionalchemotherapy,hormonaltherapyortargetedtherapies;(d) forpatientswhoexperiencerelapseorprogressionaftertargeted treatment;(e)inhospiceorpalliativecarepatientswherelow-or non-invasivestrategiesarealegitimateandhumaneoption;and(f) insituationsinwhichhigh-costagentscannotbeobtained.Because ofcontinuousheterogeneityamongcancercells,andtheir propen-sityforgenomic instability,even a broad-spectrumapproach is unlikelytocausecompleteremission.However,thedesignofthis approachposedasubstantialtheoreticalchallenge,forwhichwe chosetousethehallmarksofcancerasabroadorganizing frame-work.

1.2. Hallmarksofcancerasaframeworkfordeveloping broad-spectrumtherapeutics

Hanahan and Weinberg first published theirconcept of the hallmarks of cancer in 2000 [27]. The hallmarks “constitute an organizing principle that provides a logical framework for understandingtheremarkable diversity ofneoplastic diseases.” This framework encompasses the biological capabilities that cells acquire during the development of cancers that allow themtobecomemalignancies asweknow them.Sixhallmarks were proposedin the 2000publication: sustainedproliferative signaling, evading growth suppressors, activating invasion and

metastasis,enabling replicativeimmortality,inducing angiogen-esisandresistingcelldeath.Theconceptofthehallmarksbecame widelyrecognizedandinfluential.In2011,HanahanandWeinberg expandedontheinitialhallmarkstoincludeotherareasofcancer biologythattheyfeltwereequallyimportant[28].Theypointedout twoenablingcharacteristicscriticaltotheabilityofcellstoacquire thesixhallmarks,andtwonewhallmarkcapabilities.Theyalso sin-gledoutthecrucialnatureofthecomplextumormicroenvironment intheappearanceofthecancerphenotype.Theenabling character-isticsaregenomicinstabilityandtumor-promotinginflammation; thenewhallmarksarederegulatingcellularenergeticsand avoid-ingimmunedestruction.

Thehallmarksframeworkhelpstodefinedomainsinwhichhigh prioritytargetscanbeidentifiedfortherapeutictargeting.Hanahan andWeinbergpointoutthatagentsareindevelopmentthattarget eachofthehallmarks.Theyalsonote,however,thatinresponseto targetedtherapy,cancersmayreducetheirrelianceonaparticular hallmarkcapability,suchasangiogenesis,andinsteadheightenthe activityofanothercapability,suchasinvasionandmetastasis[29]. Thisreactionhasbeenclinicallyverifiedinthecaseofglioblastoma

[30].

Anothermodel, which wasproposedby Vogelstein et al. in 2013 [6], alsoattempts to describe themechanisms and path-ways thatare relevanttomanycancers. Inthis model,“driver” genesthatdrivecancergrowtharedistinguishedfrom“passenger” mutations foundin cancercells that impart nogrowth advan-tage.Twelvemajorsignalingpathwaysthatdrivecancergrowth havebeenelucidated,includingsignaltransducersandactivators oftranscription(STAT),Notch,DNAdamagecontroland9others. Thesepathwaysareclassifiedintothreecellularprocesses underly-ingtumorgrowth:cellsurvival,cellfateandgenomemaintenance. Individualpatientswiththesamecancercanhavemutationson dif-ferentpathways,leadingtointer-patientheterogeneity.Yetwithin eachpatientthereisalsosubstantialheterogeneity,both within eachpatient’sprimarytumor,andamongandwithinmetastases, withsignificancefortreatmentstrategies.Forinstance,the small-estmetastasesvisiblethroughmedicalimagingmayalreadyhave thousandsofcellsthatharbormutationsrenderingthemresistant tocurrentdrugs[31].

Cancermutations,moreover,arenotsimplyaseriesofisolated targets.Beneath thesurface ofthe cancergenomeis a notably complexcellularsignalingnetwork,filledwithredundancies.The elucidationofrationaltherapeuticcombinationsrequiresdynamic mechanisticmodelsthatreachbeyondsimpletargeting[32].What propelsgrowth,disseminationandthusineffectivetreatmentand drugresistanceactuallyappearsnottobepathwaysactingin iso-lationbutinterconnected,multidirectionalanddynamicnetworks

[33].Evensorafenib,whichinhibitsmultiplekinases,issusceptible totherapiddevelopmentofresistancederivingfromcrosstalkin pathwayssuchasphosphatidylinositide3-kinase/proteinkinaseB (PI3K/Akt)andJanuskinase(JAK)-STAT,hypoxia-inducedsignaling ortheepithelial-to-mesenchymaltransition(EMT)[34]. Conven-tionaldrugdiscoveryprogramsarenowcontemplatingsystems biology approaches aimed at furtheringthe network approach topharmacology.Theinterdependenceofcytokines,chemokines, growthfactors,transcriptionfactors,andtheirresultingproteomes, togetherwiththeirrelevancetocancerpreventionandtreatment

[35],makessystemsbiologyapproachesmostattractive[36].This realizationmakesthesignificanceofabroad-spectrumapproach tocancerofevengreaterimportance.

Cliniciansaswellasresearchersrecognizetheimportanceof heterogeneity in cancer. A least one clinical center recognizes thesignificanceofthisheterogeneity,andinterveneswith broad-spectrumapproaches torespondtoit.In a2009book,LifeOver Cancer,basedonaclinicinoperationsince1980,Blocklaysout a model of nutraceutical-based targeting of nine “pathways of

progression”and sixmetabolicfactorsimpactingthechallenges faced byallcancerpatients[3]. Thenine growthpathwaysare proliferation, apoptosis, treatment resistance, immune evasion, angiogenesis,metastasis,cell-to-cellcommunication, differentia-tionandimmortality.Multipletargetingofthesepathwayswith naturalproductsisusedtosimultaneouslyaddressmultiple inter-connectedgrowthpathways.Comprehensivemolecularprofiling mapspatients’growthpathwaysand providesfor relevant nat-uralproductintervention.Thesixmetabolic“terrainfactors”are oxidation,inflammation,glycemia, bloodcoagulation,immunity andstress chemistry. Terrain-focusedinterventionsaretailored topatients’laboratorytestresults,whicharemonitoredregularly toguidetherapeuticmodification.Interventionsinclude elimina-tionof maladaptivelifestyle patterns,adjusting exercisehabits, improvingdiet,implementingbiobehavioralstrategiesto dimin-ishadverse consequencesof unabatedstress/distress, andusing naturalproductsandmedicationsthataffectspecifictargetssuch asC-reactiveprotein(CRP)[37],interleukin-6(IL-6),nuclear fac-tor␬-beta(NF-␬B)[38],prostaglandinE2andleukotrieneB4[39]

forinflammation.Clinicalobservationsandliteraturereview sug-gestpotentialefficacyforthissysteminbreastcancer(includinga near-doublingofsurvivaltimeofbreastcancerpatientsin integra-tivecare)andpotentiallyothercancers[40,41].Essentially,Block’s clinicalmodelsystematicallyaddressesmultipletargetsand path-waysthroughaspecificandselectivebroad-spectrumapproachto treatment.Whilethissystemwasdevelopedinclinicalpractice, quiteindependentlyfromthediscussionofhallmarksandenabling characteristicsbyHanahanandWeinberg,theconceptualoverlap isobvious.Thattheseconceptshavealreadybeenusedinclinical treatmentprovidespowerfulsupportfortheviabilityofacarefully designedbroad-spectrumapproach.

Themodelweproposetousetodevelopasoundframework fora broad-spectrum approach recognizesthesebroadareas of conceptualoverlapandagreement,andcanbeconsideredtobest alignwiththehallmarksofcancerframework[27].Ourframework encompassesthemolecularandmetabolicdiversityofmalignancy recognizedinHanahanandWeinberg’shallmarks,Vogelstein’s12 growthpathways,Block’spathwaysofprogressionandterrain fac-tors,andotheremergingresearch.Forthepurposesofthisproject, wetreatthe6hallmarks,2enablingcharacteristics,2emerging hallmarks,andthetumormicroenvironmentequallyashallmarks ofmalignancy.Fromadesignstandpoint,eachoftheseindividual areasencompassesanimportantaspectofcancer’sbiology,soeach wasseenasimportanttoconsiderforatherapeuticapproachaimed atawiderangeofhighprioritytargets.

Inmid-2012,theframeworkforthisprojectandapproachwere sharedwithDouglasHanahan.Helaterindependently provided supportforthistypeofapproachinapaper,“Rethinkingthewar oncancer”[42].Usingamilitarymetaphor,hesuggestsa three-dimensional cancer“battlespace” plan that attackscancer in a full-scalewarratherthanindividuallytargetedskirmishes.Thefirst dimensionisdisruptionofcancer’smanycapabilities,specifically thosefiguringinthehallmarks.Ratherthanjustremovingone capa-bility,astargetedtherapiesdo,heexplainsthatanidealapproach shouldtargetallthehallmarkcapabilities.Theseconddimensionis defenseagainstcancer’sarmedforces,implyingspecifictargeting oftheaccessorycelltypesinthetumormicroenvironment,such astumor-promotinginflammatorycells.Thethirddimension rep-resentsthemultiplebattlefieldsofcancer:primarytumor,tumor microenvironment,lymphandbloodvesselsthroughwhichtumors disseminate,draininglymphnodesanddistantorgans.This dimen-sionsuggestsstillmoretargets.

Arapidlydevelopingsub-disciplinein oncologyisthe appli-cationof geneticandimmune analysisof tumortissue andthe concomitantuseofpersonalizedtherapiesandprescriptions.These analysesallowbetterstratificationofpatientstotreatmentsand

clinicaldecision-making[43].Inthecaseofbreastcanceralone, testsrangefromHer-2testing,thebasisoftrastuzumabtreatment tosophisticatedsuitesofteststhatanalyzedozensofgenes.These complexanalysesassistintreatmentdecisionsbasedon correla-tionswithclinicaloutcomesbypredictingtreatmentresponse,risk ofrecurrenceandoutcome.Theysuggestthesizeofthenetworkof genesthataffectjustonecancer,andemphasizethesignificanceof abroad-spectrumattack.Clinicalutilityofthesetestsisstillunder review[44].

Despiteimpressiveprogressingenomicandgeneexpression profiling,however,itisoftenimpossibletofullycharacterizethe rangeofimmortalizedcellvariantswithinanygivencancer.The perspectivesofferedbyHanahan,VogelsteinandBlock,aswellasby therecognitionofthenetworkaspectsofsignalingpathways, how-ever,suggestalargernumberoftargetsmayneedtobereached. Sothe138drivergenes,togetherwiththe12signalingpathways thatcomprisethem,inadditiontothemolecularcontributorstothe hallmarks,andBlock’sninepathwaysofprogressionandsixterrain factors,helpusdelineatesomeofthemostsignificanttargetsthat shouldbetakenintoaccountindevelopmentofabroad-spectrum approach.

2. Methods

Theefforttodeveloptheconceptofbroad-spectrumtargeting ofcancerthrough a complexcombination ofagents, emphasiz-ingnaturallyoccurringchemicals,wasdevelopedbyanon-profit organization,GettingToKnowCancer,andimplementedwithin aninitiativecalled“TheHalifaxProject.”Theaimoftheproject wastoproduceaseriesofreviewsofthecancerhallmarksthat couldcollectivelyassess and prioritizethe manytarget choices thatexist,andalsoidentifynon-toxicchemicals(primarilyfrom plantsorfoods)thatcouldsafelybecombinedtoproducean opti-mizedbroad-spectrumapproach thathasbothprophylacticand therapeuticpotential.Tothatend,itwasenvisionedthateleven teamsofresearchers wouldproduce reviewsonthetencancer hallmarksplusthetumormicroenvironment,whichwastreated asahallmark forthepurposesofthis project.Eachreview was todescribethehallmark, itssystemicandcellulardysfunctions, anditsrelationshipstootherhallmarks.Aprioritylistofrelevant therapeutictargetsandcorrespondingapproachessuitedtothose targetswasrequested,alongwithadiscussionofresearchneeded inthecontextof goalsof theproject.Naturalcompoundswere emphasizedbecauseofthegrowingbodyofliteraturethat sup-portsthelowtoxicityandinterestingpotentialthatmanyofthese substanceshavedemonstrated(i.e.,astargetedtherapeuticsorin cancerprevention),whilerecognizingthevariableeffectivenessof thesecompoundsin humantrialsaswellastheundocumented safetyorfranktoxicityconcernswithmanynaturalproducts[45]. Inrecognitionofthenetworkofsignalingpathwaysinvolvednot onlyindrugresistancebuttheinterconnectionandmaintenanceof allthehallmarks,theprojectimplementedacross-validationstep intheevaluationoftargetsandapproaches.Becauseofthediversity ofthetargetsinvolvedinthe11hallmarkareas,itisnot unreason-abletosuspectthatinhibitingorstimulatingatargetrelevanttoone hallmarkmayhaveanadversegrowtheffectorclinicallyadverse effectonatargetinanotherhallmark.Forinstance,reducingDNA damageisapotentialtargetfor counteractinggenomic instabil-ity.ActivationoftheimmunesystemcancounterDNAdamageby eliminatingdamagedcells.However,activationoftheimmune sys-tem,whilereducingoveralllevelsofDNAdamage,cancontribute tochronicinflammation[46].

Similar considerations apply to therapeutic approaches. For instance,triptolide,acomponentoftheChineseherbTripterygium wilfordii,isknowntocauseapoptosisincancercells[47].Extracts