mkorn@cc.ucsf.edu
(415) 476-0137 (lab); (415) 502-2844 (office); (415) 502-4787 (fax)

Box 0128, UCSF; San Francisco, CA 94143-0128

deliveries: 2340 Sutter Street, N-361; San Francisco, CA 94115

Full Biosketch

Christine Christian; Deborah Keller; Markus Lacher, PhD; Marisa Shiina; Jing Zhang

Rational Design of Targeted Combination Therapies for Gastrointestinal and Breast Cancer
Our translational research program aims at the rational development of novel combination therapies for gastrointestinal and breast cancer based on the analysis of relevant cellular signal transduction pathways. We have applied this approach to improve the cytotoxicity of oncolytic adenoviruses by combining these agents with small molecule signal transduction inhibitors. In particular, we were the first to propose pharmacological interventions that enhance virus entry into target cells in order to increase viral anti-tumor activity. In a complementary line of investigation, we are investigating novel strategies of improving the efficacy of inhibitors of the EGF receptor family in esophageal and breast cancer.

Our previous studies aimed at elucidating the role of the p53 pathway in determining replication of the adenovirus mutant Onyx-015 (Ries et al., Nat. Med., 2000). We then examined how the anti-tumor efficacy of oncolytic viruses is affected by alterations of the Coxsackievirus and Adenovirus Receptor (CAR), the main receptor for adenovirus. We found frequent loss of CAR protein expression in a variety of tumor types, in particular in those that were poorly differentiated (Anders et al., PNAS, 2003, and manuscript submitted). This observation suggested that some tumors might be intrinsically resistant to adenovirus infection. We discovered that the Ras-MEK-ERK pathway regulate CAR, in analogy to other cell-adhesion molecules, and that CAR expression can be restored by treating cells with small-molecule signal transduction inhibitors of MEK, which are currently in clinical trials as anti-cancer agents. The increased levels of CAR rendered cells significantly more susceptible to infection with and killing by oncolytic adenoviruses (Anders et al., Cancer Res., 2003). The underlying mechanisms of CAR-regulation by this and additional pathways in cancer cells are currently being examined.

We are currently conducting extensive studies of the molecular responses of esophageal and breast cancers to targeted inhibitors of the EGF-receptor family and downstream pathways. These studies are conducted as part of a large collaborative study (lead investigator Dr. Joe Gray, Lawrence Berkeley National Laboratory). Large-scale gene expression analyses and cell biological studies are performed to develop computer models of relevant signal transduction models and identify targets for combination therapies.

Our laboratory efforts are directly linked to clinical studies conducted at the UCSF Helen Diller Family Comprehensive Cancer Center, which aim at improving the therapy of upper gastrointestinal cancer and its precursors. There is particularly great need for improved therapies of adenocarcinoma of the esophagus since this is currently the cancer type with the greatest increase in incidence in the Western world and it is fatal in the vast majority of patients. It is believed that most adenocarcinomas of the esophagus arise from Barretts esophagus, which is characterized by an intestinal metaplasia of the esophageal squamous mucosa resulting from chronic acid reflux (review article: W.M. Korn, Curr Treat Options Oncol. 2004). To further our understanding of the mechanisms leading to resistance to novel treatments, Dr. Korn co-developed (together with Dr. A. Ko) a clinical trial of the EGF receptor antagonist ZD1839 (IRESSA) in combination with chemoradiation therapy before operative tumor resection in patients with locally advanced esophageal cancer. Correlative studies are being performed to validate our results obtained in cell line models.