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. The chemotherapy induced profile was further correlated with clinical outcome including percentage of PSA decline and PSA-relapse free survival. Cytokines and cytokine pathways were found to be associated with immediate clinical outcome measured by percentage of PSA decline. Four cytokines including ILS CXCL10 IL1B and CCL2 were included for further analysis. Expression changes ofthese4 cytokines by qRT-PCR were correlated with percentage of PSA decline. Expression changes of ILS and CXCL10 were significantly and negatively associated with percentage of PSA decline. Further in vitrotests showed only CXCL10 but not ILS conferring chemoresistance to prostate cancer cells. When using longer term clinical outcome we found genes correlated with PSA-relapse free survival.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2007
- Accession Number
- ADA475749
Entities
People
- Chung-ying Huang
Organizations
- Fred Hutchinson Cancer Center