Esophageal adenocarcinoma (EAC) is a major global health burden and its incidence has risen considerably. The patient outcome is often very poor with the 5-year cure rate remaining <20%. Preoperative chemo radiation provides the strongest Level 1 evidence for treating localized EAC, however, this is an empiric approach with unpredictable outcomes. In summary, none of the current approaches to localized EAC are based on fundamental understanding of molecular biology. We have generated compelling data supporting the central role of hedgehog (Hh) pathway in conferring resistance to therapy. Our data document that in EAC cells, inhibition of Hh can overcome resistance to cytotoxics and radiation. We have also developed a validated 3- biomarker (sonic Hh, NF-kB, and Gli-1) signature for predicting pathologic complete response (pathCR) to chemoradiaiton in EAC patients. Thus Hh signaling and the NF-kB pathway appear very important in mediating resistance in EAC. In this Project we focus on Hh signaling. Our hypothesis is that inhibition of Hh signaling during chemoradiation in patients with localized nuclear Gli-1 expressing EAC would result in a e40% pathCR rate. GDC-0449 (a smo inhibitor of Hh pathway) down regulates nuclear Gli-1 in vitro and in vivo and has efficacy in vivo. GDC-0449 has antitumor activity but no dose-limiting toxicity (150, 270, and 540 mg). In this project, we propose an elaborate translational clinical trial and other non-clinical experiments to uncover molecular mechanisms of EAC resistance despite the inhibition of Hh signaling. We propose 3 Specific Aims as follows:
Aim 1 : To conduct a phase IB/II trial of GDC-0449 (NSC 747691) plus preoperative chemoradiation in enriched patients with localized nuclear Gli-1+ EAC. A: Conduct a phase IB trial to establish safety of GDC-0449 plus chemoradiation. B: Conduct a phase II trial to estimate the rate of pathCR and establish pharmacodynamic effects of GDC-0449 (compare with historical controls). C: Carry out a prospective validation of 3-biomarker pathCR-predicting signature.
Aim 2 : To identify the molecular pathways of GDC-0449 drug resistance in cell lines and patients in Aim 1. A: Determine the change in activation and expression status of proteins in cell signaling pathways after GDC-0449 treatment and identify key molecules of GDC-0449 resistance (Cell lines and patients). B: Determine the change of gene expression profiles after GDC-0449 treatment and establish biomarkers for GDC response and resistance.
Aim 3 : To identify the GDC-0449/chemoradiation resistance/response-related microRNA signature. A: To determine the microRNA profile changes in the EAC cell lines before or after biochemoradiation and find the resistance-related microRNA signature. B: To determine the microRNA profile changes in the chemo/radio resistant EAC patients' specimens before or after biochemoradiation and identify the GDC-0449-related microRNA signature of response/resistance.

Public Health Relevance

Number of patients diagnosed with adenocarcinoma of the esophagus has been increasing, however, our understanding of this disease is quite limited. Treatments are generally not effective and are associated with considerable toxic effects. We propose detailed study of this cancer and want to improve the outcome of patients by using a rational approach and novel target in the cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA172741-03
Application #
8911281
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Timmer, William C
Project Start
2013-09-01
Project End
2016-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Hospitals
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Mizrak Kaya, Dilsa; Nogueras-González, Graciela M; Harada, Kazuto et al. (2018) Risk of peritoneal metastases in patients who had negative peritoneal staging and received therapy for localized gastric adenocarcinoma. J Surg Oncol 117:678-684
Harada, Kazuto; Mizrak Kaya, Dilsa; Baba, Hideo et al. (2018) Immune checkpoint blockade therapy for esophageal squamous cell carcinoma. J Thorac Dis 10:699-702
Harada, Kazuto; Wang, Xuemei; Shimodaira, Yusuke et al. (2018) Early Metabolic Change after Induction Chemotherapy Predicts Histologic Response and Prognosis in Patients with Esophageal Cancer: Secondary Analysis of a Randomized Trial. Target Oncol 13:99-106
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Harada, Kazuto; Pool Pizzi, Melissa; Baba, Hideo et al. (2018) Cancer stem cells in esophageal cancer and response to therapy. Cancer 124:3962-3964
Harada, Kazuto; Song, Shumei; Ajani, Jaffer A (2018) Attenuation of YAP1 can potentially target cancer stem cells to overcome drug resistance. Oncoscience 5:214-215
Harada, Kazuto; Mizrak Kaya, Dilsa; Shimodaira, Yusuke et al. (2017) Translating genomic profiling to gastrointestinal cancer treatment. Future Oncol 13:919-934
Elimova, Elena; Slack, Rebecca S; Chen, Hsiang-Chun et al. (2017) Patterns of relapse in patients with localized gastric adenocarcinoma who had surgery with or without adjunctive therapy: costs and effectiveness of surveillance. Oncotarget 8:81430-81440

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