A Novel Pharmacodynamic Approach To Predict Tumor Response to Targeted Drugs in Sarcoma Patients
M Bui, W Brazelle, J Gemmer, D Noyes, D Reed, S Altiok. Moffitt Cancer Center, Tampa, FL
Background: Molecularly targeted therapeutics are designed to interfere with the function of a biological pathway within the cancer cell that is critical to its growth or survival. The optimal development of molecularly targeted anticancer agents is limited by the lack of clinically applicable tools to predict drug effects. This study aimed to develop methods that might be useful in predicting the efficacy of targeted agents in sarcoma cells obtained from patient tumors.
Design: All tissue studies were conducted in accordance with IRB requirements. Tumor cells were exposed to drugs targeting IGFR, Met, PDGFR, MEK, AKT and mTOR in short-term cell culture conditions (ex vivo). Cellular extracts were prepared and the expression levels and phosphorylation status of intracellular signaling proteins as well as markers of apoptotic cell death (PARP cleavage and caspase 3 activation) and cell proliferation (phospho-histone H3) were analyzed in triplicate by using the Luminex® xMAP system.
Results: Tumor cells obtained from patients with malignant peripheral nerve sheath tumor, osteosarcoma, undifferentiated sarcoma, malignant gastrointestinal stromal tumor and dedifferentiated liposarcoma provided sufficient amount of viable tumor cells to perform short term ex vivo pharmacodynamic assays. The quantitative multiplex assays enabled the simultaneous analysis of the activation status of the membrane tyrosine kinase receptors, their downstream intracellular signaling pathways as well as drug-mediated changes in the cell proliferation and apoptotic cell death in sarcoma cells. Multiplex analysis demonstrated significant variation in the molecular response of tumor cells collected from sarcoma patients to the targeted drugs where target inhibition frequently did not correlate with inhibition of the downstream signaling pathways, suggesting the existence of additional compensatory mechanisms.
Conclusions: Multiplex approach is versatile and highly sensitive for the simultaneous analysis of the multiple components of intracellular signaling pathways in small tumor samples to predict and assess the pharmacodynamic efficacy of targeted agents in tumor samples. This approach may offer a means of enriching clinical trials to better identify effective candidate regimens for patients with given tumor types. Ultimately, if validated in clinical trials, tools such as these may afford a means of tailoring the most efficient therapeutic regimen for individual patients.
Category: Bone & Soft Tissue
Monday, March 22, 2010 1:00 PM
Poster Session II # 11, Monday Afternoon