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Previously Funded Research

2005 UALC

William Pao

William Pao, MD, PhD

Memorial Sloan Kettering Cancer Center

Research Project:

Acquired Resistance to Targeted Therapy


Unfortunately, most patients whose tumors initially respond to EGFR inhibitors (Tarceva and Iressa) eventually develop progression of disease and become resistant to treatment. In some patients with “acquired resistance,” tumors contain a second mutation in the EGFR gene after disease progression that blocks binding of either Iressa or Tarceva to EGFR. The overall goal of this project is to use human tumor specimens, lung tumor models, and various molecular and biochemical techniques to enhance knowledge about the subset of cancers that develop acquired resistance to Iressa and Tarceva. Ultimately, Dr. Pao hopes to use the knowledge gained from these studies to determine the most effective way to both treat progressive disease and suppress the development of acquired resistance in patients.

More Content:

Final Report
The T790M mutation is common in patients with acquired resistance. Collectively, data suggest that the type and nature of kinase inhibitor resistance mutations may be influenced by both anatomical site and mode of binding to the target (EGFR). Much of this work was published. Importantly, partly based upon this work, multiple new phase II trials are being performed (HKI-272) or planned (XL647, BIBW2992) for patients with acquired resistance. Dr. Pao showed from biopsy of more than 100 patients with acquired resistance to EGFR TKIs that more than half have a second-site mutation in EGFR (Balak et. al. 2006; Bean et. al. 2008; Arcila et. al. 2011; Oxnard et. al. 2011), and that up to 20% have amplification of MET (Bean et. al. 2007). Dr. Pao and his lab have also generated preclinical models of drug sensitive (Politi et. al. 2006) and drug-resistant lung tumor models (Regales et. al. 2007). Additionally, the team showed in drug-resistant tumor models that the combination of afatinib plus cetuximab could overcome T790M-mediated resistance. A follow-up clinical trial based upon this work showed that the combination in humans induced a 40% response rate (Janjigian et. al. ASCO, 2011). Dr. Pao and his lab are actively working to identify such mechanisms and also elucidating mechanisms of acquired resistance to the combination of afatinib/cetuximab.

Notable Accomplishments
Dr. Pao has garnered over $2.5 million is additional follow on funding to continue his work on acquired resistance and published numerous peer-reviewed articles. Some if this funding includes a large multi-million dollar grant in collaboration with Memorial-Sloan Kettering Cancer Center. Since his initial funding at Memorial Sloan Kettering, Dr. Pao has taken a position at Vanderbilt University as the Professor of Medicine, Cancer Biology, & Pathology/Microbiology/Immunology, Director, Division of Hematology and Oncology, and Director, Personalized Cancer Medicine. He joined the UALC Medical Committee in 2009.

William Pao