Project 1: Biological and Therapeutic Implications of Blockade of EGFR Axis and Src in Colorectal Cancer
- Clinical PI: Nipun B. Merchant, M.D.
- Basic PI: Robert. J. Coffey, M.D.
- Patient Advocate: Nancy Roach
The goal of this project is to translate discoveries in EGFR biology into improved therapies for patients with colorectal cancer (CRC). Two complementary strategies will be employed: combined inhibition of the EGFR axis and inhibition of EGFR and complementary signaling pathways, as exemplified by Src. We previously identified the important role of EGFR signaling in gastrointestinal neoplasia based on genetic and pharmacological studies in the mouse (Roberts RB, Min L, Washington MK, Olsen SJ, Settle SH, Coffey RJ, Threadgill DW. Importance of epidermal growth factor receptor signaling in establishment of adenomas and maintenance of carcinomas during intestinal tumorigenesis. Proc Natl Acad Sci U S A 2002;99:1521-6). A notable translational research accomplishment of our GI SPORE was the design and conduct of a randomized Phase II trial of two dose levels of gefitinib (IressaTM) in patients with advanced CRC recruited through collaboration with the Eastern Cooperative Oncology Group (ECOG) (Rothenberg ML, LaFleur B, Levy DE, Washington MK, Morgan-Meadows SL, Ramanathan RK, Berlin JD, Benson AB, 3rd, Coffey RJ. Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma. J Clin Oncol 2005;23:9265-74). In this trial, gefitinib was clinically inactive and paired tumor biopsies confirmed that gefitinib failed to inhibit key biological targets including phosphorylated EGFR, Akt and MAPK. The concordance of laboratory and clinical findings and the ability to obtain paired tumor biopsies in a cooperative group setting were important accomplishments and provide a foundation upon which current and future translational research studies can - and are - being rationally designed. Although gefitinib alone is not an active drug in this disease, cetuximab (Erbitux, C225) monotherapy has demonstrated modest, but consistent, activity in this setting. We and others have generated preclinical data and championed the notion that one can combine blockade of discrete steps in the activation of the EGFR - cell surface ligand cleavage, ligand uptake by the receptor and receptor tyrosine kinase activity - to achieve cooperative growth inhibition in CRC. (Merchant NB, Voskresensky I, Rogers CM, Lafleur B, Dempsey PJ, Graves-Deal R, Revetta F, Foutch AC, Rothenberg ML, Washington MK, Coffey RJ. TACE/ADAM-17: a component of the epidermal growth factor receptor axis and a promising therapeutic target in colorectal cancer.Clin Cancer Res. 2008 Feb 15;14(4):1182-91). A Phase I/II trial combining cetuximab and erlotinib (TarcevaTM) has been approved by the Cancer Therapy Evaluation Program (CTEP) and is evaluating the biological and clinical effect of this strategy. Should this approach prove promising, we plan to add a selective inhibitor of TACE, the enzyme that cleaves cell surface TGFα and amphiregulin, two EGFR ligands that are frequently upregulated in CRC, to further block the EGFR axis in a translational research trial planned for Years 3-5 of this grant.
Aim 1: To evaluate the clinical and biological effects of inhibiting the EGFR axis in advanced CRC;
Aim 2: To evaluate the clinical and biological effects of inhibiting EGFR and Src in a neoadjuvant trial of CRC patients with liver-limited metastasis prior to surgical resection;
Aim 3: To explore utilizing novel imaging modalities in the mouse that will assess tumor volume, DNA replication, apoptosis, angiogenesis and EGFR status in a non-invasive manner. The most promising of these imaging modalities will be advanced to human application during the course of this funding cycle.