|
Target
|
Incidence
|
Agent
|
|
|
RECEPTOR
PROTEIN KINASES
|
|
|
EGFR
expression
|
50%
|
C225
(Imclone)
|
mAb
(humanized mouse)
|
Y
|
|
EGFR
Overexpression
|
10-35%
|
E7.6.3
|
mAb
(human)
|
|
| |
|
EMD
55 900
|
mAb
(mouse)
|
|
| |
|
ICR62
|
mAb
(rat)
|
|
| |
|
ZD
1839 (Astra Zeneca)
|
Kinase
Inhibitor – responses seen in phase 1 NSCLC patients
|
Y
|
| |
|
CP
358 774 (Pfizer)
|
Kinase
Inhibitor
|
|
| |
|
PD
168 393 (Parke-Davis)
|
Kinase
Inhibitor
|
|
| |
|
CGP
75166/PKI166 (Novartis)
|
Kinase
Inhibitor
|
|
| |
|
CGP
59326A (Novartis)
|
Kinase
Inhibitor
|
|
| |
|
BIBX
1382 (Boehringer
Ingelheim)
|
Kinase
Inhibitor
|
|
|
Her-2/neu
Overexpression
|
13-42%
|
Trastuzumab/Herceptin®
(Genentech)
|
mAb
(humanized mouse)
|
Y
|
|
PDGFR
|
Cell-line
data only
|
SU101
(Sugen)
|
Kinase
Inhibitor
|
|
| |
|
STI-571
(Novartis)
|
Kinase
Inhibitor
|
|
| |
|
SU6668
(Sugen)
|
Kinase
Inhibitor; inhibits PDGFR as wells as VEGFR2 and FGFR
|
Y
|
|
Met/HGF
Overexpression
|
35%
Adenocarcinoma
20%
Large Cell
|
|
|
|
|
Laminin
Receptor
|
86%
|
|
One
study in NSCLC has reported poor prognosis with expression of
laminin receptor
|
|
CYTOPLASMIC
PROTEIN KINASES
|
|
|
K-Ras
mutation
|
15-24%
|
R115777
(Janssen)
|
Tricyclic
FTI
|
|
| |
|
SCH66336
(Schering-Plough)
|
Pyridobenzocycloheptene
FTI
|
|
| |
|
BMS214662
(Bristol Myers Squibb)
|
FTI
|
|
| |
|
L-778123
(Merck)
|
Peptidomimetic
CAAX FTI
|
|
| |
|
ISIS-2503
(ISIS Pharmaceuticals)
|
H-Ras-anti-sense
oligonucleotide
|
|
| |
|
CT-2584HMS
(Cell Therapeutics)
|
|
|
| |
|
Ras
Peptides (NCI)
|
Immunotherapy
|
|
| |
|
|
|
|
|
Downstream
of RAS
|
|
|
|
|
|
Raf
|
|
ISIS
5132/CGP69846A (ISIS
Pharmaceuticals Inc)
|
c-raf-kinase anti-sense oligonucleotide
|
|
|
|
|
L-779,450
(Merck)
|
|
|
|
MEK
|
|
PD
184352 (Parke-Davis)
|
Preclinical
data only
|
|
| |
|
PD
98059 (Parke-Davis)
|
2`-amino-3`-methoxyflavone;
preclinical data
|
|
| |
|
U-0126
(Promega)
|
1,4-diamino-2,3-dicyano-1,4-bis-[aminophenylthio]butadiene;
preclinical only
|
|
|
|
|
ISIS
3521 (ISIS Pharmaceuticals)
|
Oligonucleotide;
Phase III study in NSCLC
|
Y
|
|
|
|
Bryostatin-1
|
|
Y
|
CELL CYCLE
|
|
|
P53
Abnormalities
|
|
|
|
|
|
·
P53 mutations
|
43-60%
|
UCN-01
(Kyowa Hakko Kogyo)
|
Active
regardless of p53 status
|
|
|
|
|
Onyx-015
(Onyx Pharmaceuticals)
|
|
|
|
|
|
|
|
|
|
·
MDM2 Overexpression
|
70%
|
Ad-p53
+ chemotherapy or XRT
|
|
|
|
RB
mutation
|
15-30%
|
UCN-01
+ S phase chemotherapeutics
|
more
active in RB- cells
|
|
|
P16
methylation
|
30-60%
|
5-Aza-2’deoxycytidine/Decitabine
|
DNA
demethylating/hypomethylating agent
|
Y
|
|
|
|
5-Azacytidine
|
DNA
hypomethylating agent; leads to decreased DNA synthesis and
protein synthesis
|
|
|
|
|
Fazarabine
(Ara-AC)
|
Inhibits
DNA methylation and DNA synthesis
|
|
|
|
|
|
Binds
to 3’ untranslated region of DNA MeTase mRNA; Growth inhibition
in NSCLC xenograft
|
|
|
|
|
|
|
Y
|
|
P16
mutation
|
10-40%
|
|
|
|
|
Cyclin
D Overexpression
|
30%-40%
|
Rapamycin
Analog CCI-779 (Wyeth-Ayerst)
|
Decreases
Cyclin D expression – indirectly; response seen in phase 1 NSCLC
patient
|
Y
|
|
|
|
Flavopirodol/HMR-1275
(Aventis)
|
|
|
|
Fhit
expression reduced
|
34%
86%
SCC
10%
Adenocarcinoma
|
|
Candidate
tumor suppressor gene; function of Fhit unknown
|
|
|
P27
Reduced Expression
|
86-100%
|
PS-341
(Millenium)
|
Proteosome
Inhibitor; P27 loss may do to accelerated degradation by ubiquitin-proteosome
|
|
TRANSCRPITION
|
|
|
|
5-10%
50%
|
|
|
|
APOPTOSIS
|
|
|
BCL-2
Expression
|
10-35%
|
G3139
antisense oligonucleotide (Genta)
|
Bcl-2
over- expression has been associated with better expression
in one paper.
|
|
ANGIOGENESIS
|
|
|
VEGF
Over-expression
|
26-46%(Tumor)
39%(Serum)
|
SU5416
(Sugen)
|
|
Y
|
| |
|
SU6668
(Sugen)
|
Inhibition
of autophosphorylation of VEGF-R2 (KDR), FGFR1, PDGFR-B
|
Y
|
| |
|
Bevacizumab
(Genentech)
|
mAb
– humanized;
|
Y
|
| |
|
HuMV833
(PDL)
|
mAb
– humanized
|
|
| |
|
IM-862
(Cytran Inc)
|
peptide
that inhibits VEGF, stimulates IL-12
|
|
|
aVb3
|
|
EMD
121974 (E Merck KgaA)
|
Cyclic
pentapeptide inhibitor of the aVb3
and aVb5 integrin receptors
|
|
|
|
|
Vitaxin
(Medarex)
|
