RESEARCH IN MOLECULAR THERAPI

TRI SETYAWATI
PSPD FKIK UNTAD
 Tujuan
• Meneliti tentang efektifitas suatu terapi
pada penyakit tertentu yang dapat diamati
secara/dari segi molekulernya
 New Drug Development: An Algorithm

Phase I w. other agents

Clinic XRT
Phase I trial
-pk, pd Phase III
-assessment of targeting
Phase II: defined populations
-required correlative studies
-Dose ranging
-Randomized Phase II

Alternative Lab
schedules -preclinical w.other agents
-XRT
-development of assays
-define and redefine mechanism
Imaging
Statistics
 EGFR Family of Tyrosine Kinases

Adapted with permission from Ritter CA, Arteaga CL. Semin Oncol. 2003;30(suppl 1):3-11.0
rhuMAb VEGF (Recombinant Humanized
Monoclonal Antibody to VEGF)

• Humanized to avoid
immunogenicity (93%
human, 7% murine).

• Recognizes all isoforms of

vascular endothelial
growth factor, Kd = 8 x
10-10 M

• Terminal half life 17-21

days
VEGF as a target for the tratment of
Lung Cancer:
Ineffective Vasculature TUMOR

High
VEGF Interstitial
Pressure

Effective Vasculature
VEGF as a target for the tratment of
Lung Cancer:
Ineffective Vasculature TUMOR

Anti-VEGF Low
Interstitial
Pressure

Effective Vasculature

Jain et al, Nature Medicine, 2004

 EGFR Mutations

NEJM 2004
 CALGB 30406 Randomized Phase II
Study: Trial Design
Chemotherapy naive patients with stage III/IV
adenocarcinoma or BAC who are never or “light” former smokers*
ECOG PS 0-1

Daily oral erlotinib +

Daily oral erlotinib
6 cycles carboplatin/paclitaxel

Daily oral erlotinib Daily oral erlotinib

• Patients can continue therapy until evidence of

disease progression or toxicity
*never smoker:  100 cigarettes/lifetime; “light” former smoker: quit  1 year ago and  10 pack years
 The TARGET Trial: Trial to Assess
Response to Gefitinib in
EGFR-mutated Tumors
S
M Enroll to
C Positive
U Treatment
R
Eligible T (up to 35)
E
Patients A
T E
Enter N
I Negative
I Off-Protocol
O
N
N
G
Patients eligible to be screened: adenocarcinoma, female, non-smoker,
Japanese/Chinese
Primary endpoint: RR (estimate 60%)
Dana Farber/MGH P.Janne
 Molecular correlates of drug
response
• Beta-tubulin isoforms
100% Median
N Deaths in Months
A 24 24 7
N 8 8 18
80%

predict response to 60%

taxanes, vinca 40%

20%

alkaloids. 0%
0 12 24 36
Months After Registration

• ERCC1 predicts
response to platinum
agents.
Isolation of Circulating Cancer
Cells
Target Identification in
Circulating Cancer Cells

Her2-neu ERCC1