The VICC.ORG Directory of Doctors, Healthcare Providers & Researchers

William Pao, M.D., Ph.D.

Cornelius Abernathy Craig Professor of Medical & Surgical Oncology
Professor and Director of Hematology/Oncology
Professor of Cancer Biology and Pathology/Microbiology/Immunology
Director, Personalized Cancer Medicine
VICC Member
Medical Oncologist

  • Appointments
    615-936-8422
    Physicians: 1-877-936-8422
  • Clinical Trials Information
  • Other Telephone Numbers
    Henry-Joyce Cancer Clinic
    615-936-8422 or 1-877-936-8422

    Office
    615-343-9454
  • Faxes
    Henry-Joyce Cancer Clinic Fax
    615-343-8668
    Office Fax
    615-343-7602
  • Addresses
    Henry-Joyce Cancer Clinic
    1301 Medical Center Drive, Suite 1710
    Nashville, Tennessee 37232-7415
    Website

    Office
    2220 Pierce Avenue
    777 Preston Research Building
    Nashville, TN 37232-6307

Profile

Dr. Pao is a physician-scientist with a special interest in thoracic oncology. Dr. Pao's research focuses on identification of genes involved in the pathogenesis of lung tumors and stratifying tumors into clinically relevant molecular subsets. Using information derived from these experiments, Dr.
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Dr. Pao is a physician-scientist with a special interest in thoracic oncology. Dr. Pao's research focuses on identification of genes involved in the pathogenesis of lung tumors and stratifying tumors into clinically relevant molecular subsets. Using information derived from these experiments, Dr. Pao seeks to improve treatment for patients with non-small cell lung cancer. His research has yielded important insights into mechanisms of lung tumor sensitivity and resistance to inhibitors of the epidermal growth factor receptor.

Dr. Pao is the author of over 50 publications, is actively involved innumerous professional associations including the American Association for Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO), and has served as a journal editor for PLoS Medicine, Cancer Research, and the Journal of Clinical Oncology.

Education

  • Ph.D. - Yale University, 1998
  • M.D. - Yale University, 1990
  • Fellowship - Memorial Sloan-Kettering Cancer Center, 2005
  • Fellowship - Memorial Sloan-Kettering Cancer Center, 2004
  • Internship - New York Presbyterian Hospital, 2000
  • Residency - New York Presbyterian Hospital, 2000

 

Research Specialty

The Pao Laboratory aims to perform translational research in the area of solid tumor biology, using lung cancer as a paradigm. The overall goal is to develop molecularly-tailored treatments for patients with lung cancer.

Research Description

Lung cancer is the leading cause of cancer-related death in the U.S and worldwide. Most cases arise in former or current smokers, but about 10% of cases also occur in individuals who smoked less than 100 cigarettes in a lifetime (“never smokers”). Lung cancers are currently classified by histopathological techniques as either small-cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). In North America, adenocarcinoma (a type of NSCLC) is the most frequent type of histological tumor, accounting for 40% of all cases of lung cancer.

New “targeted” epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) like gefitinib (Iressa) and erlotinib (Tarceva) have given us a window of opportunity to elucidate clinically relevant molecular subsets of lung adenocarcinomas. For example, clinical trials have shown that gefitinib has an overall response rate of 10% in American and European populations, and 28% in Japanese patients. Retrospective analyses suggested that gefitinib is most efficacious in “never smokers” with adenocarcinoma histology. Such findings can now be largely accounted for by research from our group and others showing the relatively high incidence of mutations in the gene encoding EGFR in these respective populations and the association of EGFR mutations with increased sensitivity to both gefitinib and erlotinib.

While EGFR mutations are common in tumors from never smokers, mutations in KRAS, which encodes a signaling molecule downstream of EGFR, more commonly occur in individuals with substantial cigarette use. Moreover, EGFR and KRAS mutations appear to be mutually exclusive, suggesting that EGFR and KRAS mutations within lung epithelia are equivalent in their tumorigenic effects. We found that mutations in KRAS are associated with primary resistance to these drugs. This suggests that pre-treatment mutational profiling of both EGFR and KRAS may help guide treatment decisions regarding the use of these agents.

Unfortunately, virtually all patients who initially respond to gefitinib and erlotinib eventually develop acquired resistance. We have shown that tumor cells from patients whose disease progresses after initial responses on therapy with these agents frequently harbor second-site mutations in EGFR. The predominant second mutation substitutes methionine for threonine at position 790 in EGFR, which is predicted to block binding of gefitinib and erlotinib to the ATP-binding pocket of the kinase. Interestingly, the T790M amino acid change is analogous to changes seen in other kinases targeted by a related kinase inhibitor, imatinib (Gleevec), in patients that develop acquired resistance to that drug. Using a genomic approach, we have also recently found that tumor samples from patients with acquired resistance to gefitinib or erlotinib harbor amplification of MET, which encodes another tyrosine kinase. MET amplification appears to occur independently of T790M mutations. Importantly, MET inhibitors are currently being developed in the clinic.

The Pao Laboratory is now focused on the following:

1) Defining further molecular subsets of lung cancers, based primarily upon mutational profiling of the oncogenome in tumor samples.

2) Elucidating other mechanisms of sensitivity and resistance to EGFR inhibitors in lung cancer. For example, we recently showed that in drug-sensitive EGFR mutant lung cancer cells, induction of BIM is essential for apoptosis triggered by EGFR kinase inhibitors. These data imply that the intrinsic pathway of caspase activation may influence sensitivity and/or resistance of EGFR mutant lung tumor cells to EGFR kinase inhibition.

3) Identifying ways to overcome resistance to gefitinib and erlotinib. We have generated mouse lung tumor models driven by EGFR T790M mutants and which are resistant to erlotinib. We are now using these models to uncover agents and strategies that overcome acquired resistance to the T790M amino acid change.

Clinical Research Description

The identification of genetic abnormalities that initiate and sustain cancers has paved the way to a new era of personalized anti-cancer therapies which are more effective than current approaches with fewer side effects. We aim to shape the practice of cancer medicine, envisioning a day when anti-cancer treatment will be assigned according to the genetic makeup of patients' tumors rather than on an empiric basis.

Publications


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