Supplementary Table 1 | Novel strategies for the treatment of patients with HER2-positive breast cancer*
Strategies and examples
Optimization of trastuzumab antibody
IgE homolog of (IgG) trastuzumab
Trastuzumab with modified oligosaccharides in Fc region
(afucosylated)
MDX-H210 (bispecific mAb targeting HER2 and FcγRI)
2B1 (bispecific mAb targeting HER2 and FcγRIII)
C6.5xscFv (bispecific mAb without an Fc domain,
targeting HER2 and FcγRIII [CD16])
Conjugation of HER2-targeted agents with toxins
ScFv(FRP5)–ETA (single-chain antibody fragment
targeting HER2 and fused to truncated Pseudomonas
exotoxin)
GrB–scFv(FRP5) (single-chain antibody targeting HER2
and fused to granzyme B, an apoptosis-inducing serine
protease)
Affitoxin (HER2-specific affibody molecule [smaller than
most antibody fragments] fused to truncated
Pseudomonas exotoxin)
Pegylated immunoliposomes bearing trastuzumab and
containing melittin
Single-chain antibody targeting HER2 and fused to
recombinant gelonin
Ec-LDP–Hr-AE (bispecific fusion protein targeting HER1
and HER2, conjugated to lidamycin)
Trastuzumab conjugated to nanoparticles (loaded with
paclitaxel, doxorubicin, or cisplatin
Targeting HER1
Cetuximab (HER1-targeted mAb)
Panitumumab (HER1-target mAb)
Targeting HER3
AMG-888 (HER3-targeted mAb)
Targeting HER2
Arry 380 (potent, reversible HER2 TKI)
Broad-spectrum TKIs
JNJ-2887 1063 (HER1/HER2/HER4 TKI)
Inhibition of PI3K (class I)
GDC-0941 (pan-PI3K inhibitor [all class I isoforms])
BKM120 (pan-PI3K inhibitor [all class I isoforms])
PX-866 (pan-PI3K inhibitor [all class I isoforms])
Stage of development
Reference or ClinicalTrials.gov
identifier
Preclinical
Preclinical
Karagiannis et al. (2009)1
Mori et al. (2007),2 Suzuki et al.
(2007)3
Repp et al. (2003)4
Weiner et al. (1995)5
McCall et al. (1999),6 McCall
et al. (2001)7
Phase I (NAD)
Phase I (terminated)
Preclinical (NAD)
Phase I (NAD)
Azemar et al. (2003),8
von Minckwitz et al. (2005)9
Preclinical
Dalken et al. (2006)10
Preclinical
Zielinski et al. (2009)11
Preclinical
Barrajón-Catalán et al. (2010)12
Preclinical
Cao et al. (2009)13
Preclinical
Guo et al. (2010)14
Preclinical
Dilnawaz et al. (2010),15
Colombo et al. (2010)16
Phase I in HER2+ BC
Phase I
NCT00367250
NCT00894504
Phase I
NCT00730470
Phase I
Lee et al. (2009),17
NCT00650572
Preclinical
Emanuel et al. (2008)18
Phase I
Raynaud et al. (2009),19
Wagner et al. (2009),20
NCT00928330, NCT00960960
NCT01068483
Jimeno et al. (2009),21
NCT00726583
Phase I
Phase I
Dual PI3K–mTOR inhibition
SF1126 (vascular targeted pan-PI3K inhibitor [all class I
isoforms] and inhibitor of mTORC1/2, DNA-PK, PLK-1,
CK2, ATM and PIM-1)
XL765 (PI3K–mTOR inhibitor)
PF-04691,502 (PI3K–mTOR inhibitor)
BEZ235 (reversible inhibitor of PI3K–mTOR)
Inhibition of Akt
MEKK-2206 (allosteric Akt1/2 inhibitor)
Phase I
Chiorean et al. (2009),22
NCT00907205
Phase I
LoRusso et al. (2009)23
NCT00485719, NCT00777699
NCT00927823
NCT00620594
Phase I
Phase I
Phase I
Tolcher et al. (2009),24
NCT00963547
Inhibition of mTOR
Temsirolimus
Phase II (NAD for BC)
Ridaforolimus
Phase II (NAD for BC)
Chan et al. (2005),25 Chow et al.
(2006),26 NCT00699491
Sessa et al. (2009),27 Hartford
et al. (2009),28 Mita et al.
(2008),29 Rizzieri et al. (2008),30
Di Cosimo et al. (2010)31
Inhibition of IGF-1R pathway
BIIB022 (mAb targeting IGF-1R)
Phase I
1
NCT00555724
RO1507 (IGF-1R inhibitor)
AXL1717 (IGF-1R inhibitor)
XL228 (multitarget protein-kinase inhibitor)
Inhibition of HSP90
Tanespimycin
Phase I
Phase I
Phase I
NCT00811993 (12 agents)
NCT01062620
NCT00526838
Phase II (NAD for BC)
SNX-5,422
STA-9,090
AT13387
Vaccines and immunotherapy
Chimeric HER2 peptide epitopes fused to T-cell epitope
HER2-derived p369-377 peptide incorporated into
polylactide-co-glycolide microspheres
MUC1 and HER2 combined peptide vaccines
9 peptides from HER2 CEA and CTA and a class II
MHC-restricted tetanus helper peptide
MVA-BN-HER2 (vaccinia viral vector encoding modified
HER2)
V930 (plasmid-based DNA vaccine)
pNGVL3-hICD (plasmid-based DNA vaccine encoding
intracellular HER2 domain)
Adenovector vaccine expressing rat HER2
MVF-HER-2(628-647)-CRL 1005 (chimeric peptide
consisting of a mutated HER2 B-cell epitope and a
promiscuous T-cell epitope from the measles virus fusion
protein, coated with poloxamer CRL-1005 to form
microparticles)
CHP-HER2 (cholesterol-bearing hydrophobized pullulan
HER2 protein vaccine)
Co-stimulatory gene (CD80)-modified, HLA-A2-matched,
allogeneic, breast-cancer cell line
Lapuleucel-T (autologous peripheral blood mononuclear
cells cultured ex vivo with a recombinant fusion protein
derived from HER2)
Ex vivo expansion and adoptive transfer of HER2specific T cells
Multitarget kinase and angiogenesis inhibitors
Sorafenib (inhibitor of VEGFR, PDGFR, RET, FLT3, and
c-KIT)
Axitinib (selective inhibitor of VEGFRTK1, VEGFRTK2
and VEGFRTK3)
Vandetanib (dual inhibitor of VEGFR and HER1 RTK)
Phase I
Phase I
Phase I
Erlichman et al. (2009),32 Modi
et al. (2008),33 Modi et al.
(2006)34
NCT00506805
NCT01193364
NCT01246102
Phase I
Phase I
Kaumaya et al. (2009)35
NCT00005023
Phase I
Phase I
NCT00640861
NCT00892567
Phase I
NCT00485277
Phase I
Phase I
NCT00250419
NCT00436254
Phase I
Phase I
NCT00307229
NCT00017537
Phase I
Aoki et al. (2009),36 Kageyama
et al. (2008),37 NCT00291473
Dols et al. (2003),38 Dols et al.
(2003)39
Peethambaram et al. (2009)40
Phase I
Phase I
Phase I
Bernhard et al. (2008),41
NCT00228358
NAD for HER2+ BC
Bianchi et al. (2003),42 MorenoAspitia et al. (2009)43
Kelly et al. (2010)44
Phase I–II (NAD for
HER2+ BC
Phase I–II (NAD for
Morabito et al. (2009)45
HER2+ BC
BMS-690,514 (oral, pan-HER and VEGFR2 inhibitor)
Phase I-II
NCT01068704
*At the preclinical stage, in phase I clinical trials, or NAD for the treatment of patients with BC. Abbreviations: BC,
breast cancer; CEA, carcinoembryonic antigen; CTA, cancer-testis antigen; FLT3, Fms-like tyrosine kinase 3; HLA-A2,
human leukocyte antigen A2; HSP90, heat-shock protein 90; IGF-1R, insulin-like growth factor-1 receptor; mAb,
monoclonal antibody; mTOR, mammalian target of rapamycin; NAD, not in active development; PI3K,
phosphatidylinositol-3-kinase; PDGFR, platelet-derived growth factor receptor; VEGFR, VEGF receptor; VEGFRTK,
VEGFR tyrosine kinase; TKI, tyrosine kinase inhibitor.
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