Prostate cancer (PCa) is the most common cancer in North American males. Conventional, maximum tolerated dose (MTD) chemotherapy with cyclophosphamide (CPA) has been used in the past for PCa treatment, but has been replaced by docetaxel. However, renewed interest in CPA is emerging given its frequent use in low-dose metronomic (LDM) chemotherapy regimens known for their antiangiogenic properties. While therapeutic resistance limits the clinical utility of both LDM and MTD CPA, such resistance appears to occur through at least partially distinct mechanisms.
To investigate the molecular changes contributing to resistance formation, we have generated LDM and MTD CPA resistant PC-3 human prostate cancer cell variants (LCR and MCR, respectively), and corresponding control variants (NS), through in vivo passaging in mice. Using next-generation sequencing and gene expression analysis, we observed 453 differentially regulated genes in LCR vs NS, and 1141 genes in MCR vs NS. An intersecting set of 158 genes found to be differentially expressed in both resistant tumor cell lines was further characterized. The genes most up-regulated (including ALDH1A3, MAGEA2 and ELOVL2) and down-regulated (comprising FN1, IL8 and IGFBP3) were chosen for validation by qRT-PCR studies. We also undertook pathway analysis using the DAVID database and the Reactome FI Cytoscape Plugin.
Collectively, our studies revealed that glycolysis/gluconeogenesis, biosynthesis of unsaturated fatty acids and activated drug metabolism may contribute to resistance to both LDM and MTD CPA. In addition, numerous chemokine signaling pathway-related genes were found to be downregulated. Current studies are focusing on the role of ALDH1A3 in LDM and MTD CPA resistance. ALDH1A3 is amongst the most differentially regulated genes found in our analysis, and it has been associated with chemotherapy resistance, ‘stemness’ and aggressive tumor behaviour.
Despite different mechanisms of action, there are overlapping mechanisms of resistance to LDM and MTD CPA chemotherapy. If our studies confirm an essential role of ALDH13A in such resistance, this could be rapidly clinically translated by repurposing approved pharmacological ALDH inhibitors as anticancer agents.
Citation Format: Van C. Hoang, Annabelle Chow, Amy Wong, Lavarnan Sivanathan, Urban Emmenegger. Identification of ALDH1A3 as a driver of resistance to both low-dose metronomic and conventional cyclophosphamide chemotherapy in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3773. doi:10.1158/1538-7445.AM2014-3773