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. We utilized tissue resources from a 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 indicators of tumor response. A chemotherapy-induced profile was generated by a direct comparison of expression changes between pre-treatment and post-treatment cancerous epithelia from prostate. After excluding genes previously shown to be influenced by the radical prostatectomy procedure, we identified 51 genes with significant transcript level alterations following chemotherapy. This group included several cytokines including GDF15, IL8, CXCL10, IL1B, and CCL2. In vitro analyses confirmed overexpression of GDF15 may confer resistance to chemotherapy in prostate cancer cells. Gene expression changes after chemotherapy were further correlated with clinical outcomes including percentage of PSA decline and PSA-relapse free survival. Several chemokines and chemokine pathways were found to be associated with the percentage of PSA decline. Expression changes of IL8 and CXCL10 measured by qRT-PCR were significantly and negatively associated with the percentage of PSA decline. Further, in vitro tests showed only IL1B influenced chemosensitivity of prostate cancer cells. When correlating expression profiles with PSA-relapse free survival, we found patients with a positive post-chemotherapy change in the expression of monoamine oxidase A (MAOA) have higher risk to have a PSA relapse compared with patients with negative post-chemotherapy MAOA expression change.

Open PDF

Document Details

Document Type
Technical Report
Publication Date
Sep 01, 2008
Accession Number
ADA490413

Entities

People

  • Chung-ying Huang

Organizations

  • Fred Hutchinson Cancer Center

Tags

DTIC Thesaurus Topics

  • Abstracts
  • Apoptosis
  • Biomedical Research
  • Cancer
  • Cell Line
  • Cell Physiological Processes
  • Cells
  • Culture Techniques
  • Data Analysis
  • Gene Expression
  • Neoplasms
  • Nucleotides
  • Prostate Cancer
  • Proteins
  • Regression Analysis
  • Standards
  • Tissues

Fields of Study

  • Biology
  • Medicine

Readers

  • Oncology
  • Oncology (Cancer Research).