Rational combination of EGFR and Hedgehog inhibitors in head and neck cancer

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Epidermal growth factor receptor (EGFR) inhibition improves survival of head and neck squamous cell carcinoma (HNSCC) patients, but the overall efficacy is limited, and particularly when given in one of its indications (cetuximab single-agent in chemotherapy-refractory HNSCC) responses are low and prognosis is dismal. Cancer stem cells (CSC) have been implicated in resistance to anticancer therapies. Using an advanced patient-derived xenograft HNSCC model we have documented accumulation of CSC subpopulations after EGFR inhibitors, and have hypothesized that CSC are thus responsible for tumor recurrence. These CSC showed 500-fold over expression of the Hedgehog pathway compared with the non-CSC, proliferating cells. In addition, we observed that cetuximab induced SIP1/ZEB2 and TWIST that are promoters of epithelial to mesenchymal transition (EMT), also associated to resistance to EGFR inhibitors in HNSCC. Finally, we determined in vivo that a combination of EGFR and Hedgehog inhibitors decreased the CSC population, blocked EMT, and prevented re-growth of HNSCC tumors. The goal of this proposal is to conduct a rationally- driven combination Phase 1 study of EGFR and Hedgehog inhibitors in refractory HNSCC patients. The trial will include a cetuximab lead-in period of two weeks, followed by the combination of cetuximab plus IPI-926 starting in week 3. By conducting three seriated tumor biopsies (pre-treatment [d0], post-lead-in [C1D14], and post-combination [C1D28]) we will test our hypotheses that 1) CSC accumulate after conventional therapy, 2) EGFR inhibitors induce EMT, and 3) the combination of EGFR and Hedgehog inhibitors induces an antitumor effect by inhibiting both proliferating cells and CSC, and preventing EMT. The candidate is ideally positioned to drive this translation from the bench to the clinic given his involvement as principal investigator in the first-in- human study of IPI-926, his experience in the field of CSC and his unique expertise in conducting studies with multiple tumor testing with pharmacodynamic endpoints. PUBLIC HEALTH RELEVANCE: Our goal is to conduct a translational Phase 1 study combining EGFR and Hedgehog inhibitors in patients with head and neck cancer. We propose to investigate the molecular events in sequential biopsies taken from these patients, which will elucidate the variations induced by therapy in proliferating and cancer stem cells. This project is based on preclinical work conducted in the applicant's laboratory that identified cancer stem cells as responsible for resistance to anti-EGFR therapy. For this he utilized a novel direct patient tumor model he has devised implanting patient head and neck cancers in mice. These stem cells were then characterized molecularly and compared to non-progenitor cells, which led to the identification of the Hedgehog pathway as 500-fold more expressed in these progenitor cells. A combination containing a drug inhibiting this pathway (IPI- 926) achieved tumor cures and a reduction in the number of precursor cells in animal models. This supports translating these findings to the clinic. The first unique feature of this proposal is the utilization of a direct patient tumor model that allows the preservation of all the compartments that constitute a tumor. The second is the integration of laboratory observations and clinical research, since the applicant works with IPI-926 in his laboratory as well as leading the first-in-human Phase 1 study of IPI-926 in patients with solid tumors. It is that integration that permits an efficient translation such as this cancer stem cell-specific therapy. This proposed clinical trial represents truly hypothesis-driven drug development and applied translational science.