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

Designing a broad-spectrum integrative

approach for cancer prevention and treatment

Keith I. Block, Charlotte Gyllenhaal, Leroy Lowe, Amedeo Amedei, A. R. M. Ruhul Amin,

Amr Amin, Katia Aquilano, Jack Arbiser, Alexandra Arreola, Alla Arzumanyan, S. Salman

Ashraf, Asfar S. Azmi, Fabian Benencia, Dipita Bhakta, Alan Bilsland, Anupam Bishayeen,

Stacy W. Blain, Penny B. Block, Chandra S. Boosani, Thomas E. Carey, Amancio Carnero,

Marianeve Carotenuto, Stephanie C. Casey, Mrinmay Chakrabarti, Rupesh Chaturvedi,

Georgia Zhuo Chen, Helen Chenx, Sophie Chen, Yi Charlie Chen, Beom K. Choi, Maria

Rosa Ciriolo, Helen M. Coley, Andrew R. Collins, Marisa Connell, Sarah Crawford, Colleen

S. Curran, Charlotta Dabrosin, Giovanna Damia, Santanu Dasgupta, Ralph J. DeBerardinis,

William K. Decker, Punita Dhawan, Anna Mae E. Diehl, Jin-Tang Dong, Q. Ping Dou, Janice

E. Drew, Eyad Elkord, Bassel El-Rayes, Mark A. Feitelson, Dean W. Felsher, Lynnette R.

Ferguson, Carmela Fimognari, Gary L. Firestone, Christian Frezza, Hiromasa Fujii, Mark M.

Fuster, Daniele Generali, Alexandros G. Georgakilas, Frank Gieseler, Michael Gilbertson,

Michelle F. Green, Brendan Grue, Gunjan Guha, Dorota Halicka, William G. Helferich, Petr

Heneberg, Patricia Hentosh, Matthew D. Hirschey, Lorne J. Hofseth, Randall F. Holcombe,

Kanya Honoki, Hsue-Yin Hsu, Gloria S. Huang, Lasse D. Jensen, Wen G. Jiang, Lee W.

Jones, Phillip A. Karpowicz, W. Nicol Keith, Sid P. Kerkar, Gazala N. Khan, Mahin

Khatami, Young H. Ko, Omer Kucuk, Rob J. Kulathinal, Nagi B. Kumar, Byoung S. Kwon,

Anne Le, Michael A. Lea, Ho-Young Lee, Terry Lichtor, Liang-Tzung Lin, Jason W.

Locasale, Bal L. Lokeshwar, Valter D. Longo, Costas A. Lyssiotis, Karen L. MacKenzie,

Meenakshi Malhotra, Maria Marino, Maria L. Martinez-Chantar, Ander Matheu, Christopher

Maxwell, Eoin McDonnell, Alan K. Meeker, Mahya Mehrmohamadi, Kapil Mehta, Gregory

A. Michelotti, Ramzi M. Mohammad, Sulma I. Mohammed, D. James Morre, Irfana Muqbil,

Vinayak Muralidhar, Michael P. Murphy, Ganji Purnachandra Nagaraju, Rita Nahta, Elena

Niccolai, Somaira Nowsheen, Carolina Panis, Francesco Pantano, Virginia R. Parslow,

Graham Pawelec, Peter L. Pedersen, Brad Poore, Deepak Poudyal, Satya Prakash, Mark

Prince, Lizzia Raffaghello, Jeffrey C. Rathmell, W. Kimryn Rathmell, Swapan K. Ray, Joerg

Reichrath, Sarallah Rezazadeh, Domenico Ribatti, Luigi Ricciardiello, R. Brooks Robey,

Francis Rodier, H. P. Vasantha Rupasinghe, Gian Luigi Russo, Elizabeth P. Ryan, Abbas K.

Samadi, Isidro Sanchez-Garcia, Andrew J. Sanders, Daniele Santini, Malancha Sarkar,

Tetsuro Sasada, Neeraj K. Saxena, Rodney E. Shackelford, H. M. C. Shantha Kumara, Dipali

Sharma, Dong M. Shin, David Sidransky, Markus David Siegelin, Emanuela Signori, Neetu

Singh, Sharanya Sivanand, Daniel Sliva, Carl Smythe, Carmela Spagnuolo, Diana M.

Stafforini, John Stagg, Pochi R. Subbarayan, Tabetha Sundin, Wamidh H. Talib, Sarah K.

Thompson, Phuoc T. Tran, Hendrik Ungefroren, Matthew G. Vander Heiden, Vasundara

Venkateswaran, Dass S. Vinay, Panagiotis J. Vlachostergios, Zongwei Wang, Kathryn E.

Wellendx, Richard L. Whelan, Eddy S. Yang, Huanjie Yang, Xujuan Yang, Paul Yaswen,

Clement Yedjou, Xin Yin, Jiyue Zhu and Massimo Zollo

Linköping University Post Print

N.B.: When citing this work, cite the original article.

Original Publication:

Keith I. Block, Charlotte Gyllenhaal, Leroy Lowe, Amedeo Amedei, A. R. M. Ruhul Amin,

Amr Amin, Katia Aquilano, Jack Arbiser, Alexandra Arreola, Alla Arzumanyan, S. Salman

Ashraf, Asfar S. Azmi, Fabian Benencia, Dipita Bhakta, Alan Bilsland, Anupam Bishayeen,

Stacy W. Blain, Penny B. Block, Chandra S. Boosani, Thomas E. Carey, Amancio Carnero,

Marianeve Carotenuto, Stephanie C. Casey, Mrinmay Chakrabarti, Rupesh Chaturvedi,

Georgia Zhuo Chen, Helen Chenx, Sophie Chen, Yi Charlie Chen, Beom K. Choi, Maria Rosa

Ciriolo, Helen M. Coley, Andrew R. Collins, Marisa Connell, Sarah Crawford, Colleen S.

Curran, Charlotta Dabrosin, Giovanna Damia, Santanu Dasgupta, Ralph J. DeBerardinis,

William K. Decker, Punita Dhawan, Anna Mae E. Diehl, Jin-Tang Dong, Q. Ping Dou, Janice

E. Drew, Eyad Elkord, Bassel El-Rayes, Mark A. Feitelson, Dean W. Felsher, Lynnette R.

Ferguson, Carmela Fimognari, Gary L. Firestone, Christian Frezza, Hiromasa Fujii, Mark M.

Fuster, Daniele Generali, Alexandros G. Georgakilas, Frank Gieseler, Michael Gilbertson,

Michelle F. Green, Brendan Grue, Gunjan Guha, Dorota Halicka, William G. Helferich, Petr

Heneberg, Patricia Hentosh, Matthew D. Hirschey, Lorne J. Hofseth, Randall F. Holcombe,

Kanya Honoki, Hsue-Yin Hsu, Gloria S. Huang, Lasse D. Jensen, Wen G. Jiang, Lee W. Jones,

Phillip A. Karpowicz, W. Nicol Keith, Sid P. Kerkar, Gazala N. Khan, Mahin Khatami, Young

H. Ko, Omer Kucuk, Rob J. Kulathinal, Nagi B. Kumar, Byoung S. Kwon, Anne Le, Michael

A. Lea, Ho-Young Lee, Terry Lichtor, Liang-Tzung Lin, Jason W. Locasale, Bal L.

Lokeshwar, Valter D. Longo, Costas A. Lyssiotis, Karen L. MacKenzie, Meenakshi Malhotra,

Maria Marino, Maria L. Martinez-Chantar, Ander Matheu, Christopher Maxwell, Eoin

McDonnell, Alan K. Meeker, Mahya Mehrmohamadi, Kapil Mehta, Gregory A. Michelotti,

Ramzi M. Mohammad, Sulma I. Mohammed, D. James Morre, Irfana Muqbil, Vinayak

Muralidhar, Michael P. Murphy, Ganji Purnachandra Nagaraju, Rita Nahta, Elena Niccolai,

Somaira Nowsheen, Carolina Panis, Francesco Pantano, Virginia R. Parslow, Graham Pawelec,

Peter L. Pedersen, Brad Poore, Deepak Poudyal, Satya Prakash, Mark Prince, Lizzia

Raffaghello, Jeffrey C. Rathmell, W. Kimryn Rathmell, Swapan K. Ray, Joerg Reichrath,

Sarallah Rezazadeh, Domenico Ribatti, Luigi Ricciardiello, R. Brooks Robey, Francis Rodier,

H. P. Vasantha Rupasinghe, Gian Luigi Russo, Elizabeth P. Ryan, Abbas K. Samadi, Isidro

Sanchez-Garcia, Andrew J. Sanders, Daniele Santini, Malancha Sarkar, Tetsuro Sasada, Neeraj

K. Saxena, Rodney E. Shackelford, H. M. C. Shantha Kumara, Dipali Sharma, Dong M. Shin,

David Sidransky, Markus David Siegelin, Emanuela Signori, Neetu Singh, Sharanya Sivanand,

Daniel Sliva, Carl Smythe, Carmela Spagnuolo, Diana M. Stafforini, John Stagg, Pochi R.

Subbarayan, Tabetha Sundin, Wamidh H. Talib, Sarah K. Thompson, Phuoc T. Tran, Hendrik

Ungefroren, Matthew G. Vander Heiden, Vasundara Venkateswaran, Dass S. Vinay,

Panagiotis J. Vlachostergios, Zongwei Wang, Kathryn E. Wellendx, Richard L. Whelan, Eddy

S. Yang, Huanjie Yang, Xujuan Yang, Paul Yaswen, Clement Yedjou, Xin Yin, Jiyue Zhu and

Massimo Zollo, Designing a broad-spectrum integrative approach for cancer prevention and

treatment, 2015, Seminars in Cancer Biology, (35), S276-S304.

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

Copyright: Elsevier

http://www.elsevier.com/

Postprint available at: Linköping University Electronic Press

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}

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

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

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