1. RESEARCH IN MOLECULAR THERAPI
TRI SETYAWATI
PSPD FKIK UNTAD

2. Tujuan
Meneliti tentang efektifitas suatu terapi pada penyakit tertentu yang dapat diamati secara/dari segi molekulernya

3. New Drug Development: An Algorithm
Phase I w. other agents
XRT
Clinic
Phase I trial
-pk, pd
-assessment of targeting
Phase III
Phase II: defined populations
required correlative studies
Dose ranging
Randomized Phase II
Lab
-preclinical w.other agents
-XRT
-development of assays
-define and redefine mechanism
Imaging
Statistics
Alternative
schedules

4. EGFR Family of Tyrosine Kinases
The EGFR (ErbB) family of receptor tyrosine kinases consists of 4 members that are similar in structure and are activated by various ligands. The exception is HER2/neu (ErbB2), which has no known ligand
Members of the EGFR family have an extracellular ligand binding domain, a transmembrane spanning region, and an intracellular tyrosine kinase domain. The tyrosine kinase domain of HER3/ErbB3 is nonfunctional and expresses its activity by dimerizing with other ErbB receptors
Adapted with permission from Ritter CA, Arteaga CL. Semin Oncol. 2003;30(suppl 1):3-11.0
Ritter CA, Arteaga CL. The epidermal growth factor receptor–tyrosine kinase: a promising therapeutic target in solid tumors. Semin Oncol. 2003;30(suppl 1):3-11.

6. 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 M
Terminal half life days
Human epidermal growth factor receptor 2, also known as HER2 appears to be involved in the regulation of normal cell growth. Gene amplification or protein overexpression stimulates cell growth.
Herceptin is a monoclonal anti-HER2 antibody directed against p185HER2, which is the membrane receptor for the HER2 gene.
The antibody was humanized to avoid the immunogenicity of murine antibodies and to enhance the potential for enlisting endogenous immune anti-tumor effects.
Several mechanisms of action have been proposed, which are not mutually exclusive. Possible mechanisms include inhibition of signaling, down modulation of HER2 receptors, and enhancement of antibody-dependent cellular cytotoxicity.

7. VEGF as a target for the tratment of Lung Cancer:
TUMOR
Ineffective Vasculature
High Interstitial Pressure
VEGF
Effective Vasculature

8. VEGF as a target for the tratment of Lung Cancer:
TUMOR
Ineffective Vasculature
Anti-VEGF
Low Interstitial Pressure
Effective Vasculature
Jain et al, Nature Medicine, 2004

9. EGFR Mutations
NEJM 2004

10. 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

11. The TARGET Trial: Trial to Assess Response to Gefitinib in EGFR-mutated TumorsC R E N I G M U T A I O N
Enroll to Treatment (up to 35)
Positive
Eligible Patients
Enter
Negative
Off-Protocol
Patients eligible to be screened: adenocarcinoma, female, non-smoker, Japanese/Chinese
Primary endpoint: RR (estimate 60%)
Dana Farber/MGH P.Janne

12. Molecular correlates of drug response
Beta-tubulin isoforms predict response to taxanes, vinca alkaloids.
ERCC1 predicts response to platinum agents.

13. Isolation of Circulating Cancer Cells

14. Target Identification in Circulating Cancer Cells
ERCC1
Her2-neu