Abstract
To identify molecular alterations associating with in vivo exposure of prostate carcinoma to chemotherapy and assess functional roles modulating tumor response and resistance. Patients with high-risk localized prostate cancer (tumor-node-metastasis >or= T(2b) or prostate-specific antigen >or= 15 ng/mL or Gleason glade >or= 4+3) were enrolled into a phase II clinical trial of neoadjuvant chemotherapy with docetaxel and mitoxantrone followed by prostatectomy. Pretreatment prostate tissue was acquired by needle biopsy and posttreatment tissue was acquired by prostatectomy. Prostate epithelium was captured by microdissection, and transcript levels were quantitated by cDNA microarray hybridization. Gene expression changes associated with chemotherapy were determined by a random variance t test. Several were verified by quantitative reverse transcription PCR. In vitro analyses determining the influence of growth differentiation factor 15 (GDF15) on chemotherapy resistance were done. Gene expression changes after chemotherapy were measured in 31 patients who completed four cycles of neoadjuvant chemotherapy. After excluding genes shown previously 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, chemokine (C-X-C motif) ligand 10, and interleukin receptor 1beta. Overexpression of GDF15 or exposure of prostate cancer cell lines to exogenous recombinant GDF15 conferred resistance to docetaxel and mitoxantrone. Consistent molecular alterations were identified in prostate cancer cells exposed to docetaxel and mitoxantrone chemotherapy. These alterations include transcripts encoding cytokines known to be regulated through the nuclear factor-kappaB pathway. Chemotherapy-induced cytokines and growth factors, such as GDF15, contribute to tumor cell therapy resistance and may serve as targets to improve responses.
Highlights
To identify molecular alterations associating with in vivo exposure of prostate carcinoma to chemotherapy and assess functional roles modulating tumor response and resistance
Both trials reported that docetaxel treatment results in improved clinical outcomes based on prostate-specific antigen (PSA) decline and survival, when compared with mitoxantrone chemotherapy
We selected 31 patients that completed the full courses of chemotherapy and that had sufficient tumor tissue in the pretherapy and posttherapy samples to measure gene expression changes associated with chemotherapy
Summary
To identify molecular alterations associating with in vivo exposure of prostate carcinoma to chemotherapy and assess functional roles modulating tumor response and resistance. Correlating the induced profiles with clinical outcomes such as changes in tumor markers, pathologic response, and diseasefree survival may uncover intrinsic differences in tumor susceptibility to cytotoxic drugs and identify predictors of chemotherapy susceptibility for individual patients In this context, studies of breast carcinoma are relevant in view of the common use of neoadjuvant chemotherapy approaches as standard treatment. Comparative analyses of isogenic matched tumor tissue provided a measure of gene expression alterations in the context of pharmacodynamic drug activity Together, these data sets serve as rich resources for exploiting both common and unique determinants of tumor response and resistance. Comparable systematic analyses delineating the effects of chemotherapy on molecular features of localized or disseminated prostate cancer within individual patients have not been reported
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