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 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

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.

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 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.

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

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

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 C 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

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

Isolation of Circulating Cancer Cells

Target Identification in Circulating Cancer Cells ERCC1 Her2-neu