Grant Recipient: Dr.
David E. Kozono
Title of Project: Biomarkers for NSCLC radiosensitization by proteasome inhibition
Sponsoring Institution: Dana-Farber Cancer Institute, Boston, MA
Lung cancer is frequently diagnosed after it has spread beyond the original tumor but not outside the chest. Patients with these “locally advanced” cancers can be treated with radiation therapy, chemotherapy and/or surgery, but unfortunately only 25% of the 60,000 patients diagnosed each year in the US are cured. The poor outcomes are largely due to an inability to give sufficient radiation to destroy the tumor without damaging surrounding vital organs. Efforts have therefore focused on increasing the ability of radiation to kill cancer cells selectively by combining radiation with specialized drugs. Unfortunately, for most patients, the available drugs increase cure rates by only about 5%. We examined the effect of deactivating each of nearly 18,000 genes on the survival of cultured lung cancer cells. The gene whose suppression resulted in the most reproducible effect was PSMA1. PSMA1 is a core component of the proteasome, the cellular machinery responsible for the recycling of proteins. Bortezomib, a drug that suppresses the proteasome, is already FDA-approved for multiple myeloma. It has been tested in lung cancer patients, but not extensively with radiation. In preparation for further clinical studies, we propose studies to determine which genetic types of lung cancer are the most resistant to radiation, and which of these may be best treated with bortezomib. Specifically, we propose to test treatment in mice that develop tumors of various genetic types commonly found in patients, and to study gene patterns in these and patient samples that may predict need for better therapies.