Target

Incidence

Agent

Comments

NSCLC Trials

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

  

PKC

  

ISIS 3521 (ISIS Pharmaceuticals)

Oligonucleotide; Phase III study in NSCLC

Y

 

Bryostatin-1

Phase 2 study of bryostatin in combination with paclitaxel

Y

CELL CYCLE

 

P53 Abnormalities

 

 

 

·         P53 mutations

43-60%

UCN-01 (Kyowa Hakko Kogyo)

Active regardless of p53 status

 

 

 

Onyx-015 (Onyx Pharmaceuticals)

Recombinant virus replicates in p53 deficient cells Phase 1 IV study ongoing

 

 

Ad-p53 + chemotherapy or XRT

 

 

·         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

 

MG-98 oligonucleotide (MethylGene)

Binds to 3’ untranslated region of DNA MeTase mRNA; Growth inhibition in NSCLC xenograft

Depsipeptide (Fujisawa Pharmaceutical Co. Ltd.)

Histone deacetylase inhibitor, induction of p16 expression

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)

CDK 4 inhibitor, decrease of cyclin D1 by repressing the cyclin D1 promoter

  

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

 

MYC Amplification

MYC Expression

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)

Inhibition of the autophosphorylation of VEGF-R2, KDR, (KDR specific)

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)

mAb – humanized

 

PD-ECGF

32%

      

“Angiogenesis - Other”

 

Carboxy-Amino-Imidazole (CAI)

Inhibits Ca2+ influx through non-voltage-gated Ca2+ channels

  
   

Endostatin (EntreMed)

Inhibition of endothelial cell function,

 
   

Thalidomide (Celgene)

Inhibition of angiogenesis and TNF production

Y
   

Neovastat

Inhibition of MMP activity; inhibition of VEGF activity, angiogenesis inhibitor

Y
   

Squalamine/MSI-1256F (Magainin Pharmaceuticals Inc),

angiogenesis inhibitor originally derived from the liver of the dogfish shark; 7-24-dihydroxylated-24-sulfated cholestane steroid conjugated to a spermidine at C3

   

ABT-627 (Abbott Laboratories)

Endothelin A receptor antagonist

  
   

2-Methoxy Estradiol  (EntreMed)

Inhibition of cellular proliferation, inhibit tubulin function, up-regulate DR5

  
   

AE-941 (Aeterna)

Shark cartilage extract

Y
   

PNU-145156E (Pharmacia & Upjohn)

PNU-145156E up to MTD level induces short-lasting and unpredictable decrease in AT III levels

(Withdrawn?)
   

DMXAA

5, 6-Dimethylxanthenone-4-Acetic Acid; antivascular effects and cytokine (TNF) induction

  

MATRIX METALLOPROTEINASES:

  

MMP-2 Gelatinase A 

MMP-3 Stromelysin-1

MMP-9 Gelatinase B

MMP-11 Stromelysin-3

MMP-13 Collagenase-3

MMP-14 MT1-MMP 

41-66%

73%

21-48%

61%

68%

56%

Batimastat BB-94 (British Biotech)

Inhibition of MMP 1,2,9,3,7 activity in nM concentrations

(Withdrawn?)
   

Marimastat BB-2516 (British Biotech)

Inhibition of MMP 1,2, 3, 7,9,12 activity in nM concentrations

Y
   

BMS-275291 (Bristol Myers Squibb)

Inhibition of MMP 1, 2, 9, 14

   

Prinomastat/AG 3340 (Agouron)

Inhibition of MMP-1, 7 in nM ranges

Inhibition of 2,3,9,13,14 in pM ranges

Y
   

BAY 12-9566 (Bayer)

Inhibition of MMP 2,3,9, in nM ranges

(Withdrawn)
   

MMI 270B CGS27023A (Novartis)

Inhibition of MMP 1,2,3,7,9,13,14 activity in nM concentrations

  
   

COL 3

Inhibition of MMP 2 activity and expression in microM concentration ranges

  

ANTIGENS

Tag72 Antigen

90%

Radiolabeled CC49 NCI

Radiolabeled mAb –

 

CD44

32%

Metastatic adhesion factor

  

CEA-mono

CEA-poly

34%

90%

CEA-Cide (Immunomedics)

MAb humanized mouse

  
   

CEA-Vac (Titan)

 

MUC-1

90%

BLP25 (Biomira)

Liposomal  formulation of a 25-amino acid sequence of MUC-1 peptide chain

Y

TELOMERASE ACTIVITY

60-80%

Rhodacyanine (MKT077)

Telomerase erosion, chromosome abnormalities, senescence

  
   

FJ5002

Only preclinical data available for this agent