Targeting Mechanisms of Resistance to Taxane-Based Chemotherapy
Abstract
Patients with high-risk localized prostate cancer have a high recurrence rate following primary therapy. Neoadjuvant chemotherapy has been shown to be beneficial in reducing recurrence rates in some tumor types, but has yet to be of proven benefit in prostate cancer. Further, current clinical, pathological and molecular markers poorly predict the response and resistance of chemotherapy, and the molecular mechanisms of chemotherapy resistance are largely unknown. We utilized tissue resources from a unique prospective phase II clinical trial of neoadjuvant chemotherapy with docetaxel and mitoxantrone in patients with high-risk localized prostate cancer to identify molecular alterations after chemotherapy, and correlated these alterations with clinical and pathological indicators of tumor response. We hypothesized that this approach may identify molecular signatures of chemotherapy resistance and uncover mechanisms or pathways suitable for targeting with the objective of improving tumor responses to chemotherapy. Gene expression changes after chemotherapy were measured in 31 patients who completed 4 cycles of docetaxel and mitoxantrone neoadjuvant chemotherapy. After excluding possible ischemia-related genes, the expression of 53 genes were significantly altered after chemotherapy. Several cytokines were significantly up-regulated including IL-8, CCL2, GDF15, CXCL10, and IL1B. Overexpression of GDF15 or treatment with GDF15 protein in DU145 cells conferred resistance to docetaxel and mitoxantrone. Using PSA decline greater than 40% as a cut-point to distinguish good from poor responders, we were able to identified 33 significantly-altered genes. IL8 was not only shown to be activated after chemotherapy but also have higher expression levels in the group of poor responders compared with good responders. Alterations of molecular signatures after administration of docetaxel and mitoxantrone in patients with high-risk localized prostate cancer were recognized.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2006
- Accession Number
- ADA462817
Entities
People
- Chung-yung Huang
Organizations
- Fred Hutchinson Cancer Center