Treatment-Related Protein Biomarker Expression Differs between Primary and Recurrent Ovarian Carcinomas

Abstract

The molecular characteristics of recurrent ovarian cancers following chemotherapy treatment have been poorly characterized. Such knowledge could impact salvage therapy selection. Since 2008, we have profiled 168 patients' ovarian cancers to determine the expression of proteins that may predict chemotherapy response or are targets for drugs that are in clinical trials for ovarian cancer treatment. Expression of epidermal growth factor receptor (EGFR), HER2, VEGF, ER, c-Met, IGF1R, Ki67, COX2, PGP/MDR1, BCRP, MRP1, excision repair complementation group 1 (ERCC1), MGMT, TS, RRM1, TOPO1, TOP2A, and SPARC was measured by immunohistochemical analyses at Clinical Laboratory Improvement Amendmentscertified laboratories. Our univariate analysis of 56 primary and 50 recurrent tumors from patients with advanced stage ovarian serous carcinoma revealed that PGP and ERCC1 were significantly upregulated in recurrent lesions (P < 0.05). To determine whether these or any of the other markers were differentially expressed in specimens obtained from the same individual at diagnosis and at recurrence, we analyzed 43 matched tumor specimens from 19 advanced stage ovarian carcinoma patients. We confirmed the expression differences in PGP and ERCC1 that were observed in the cohort analysis but discovered that the expression levels of BCRP, RRM1, and COX2 were also discordant in more than 40% of the matched tumor specimens. These results may have implications both for the use of biomarkers in therapy selection as well as for their discovery and validation. Expression of these and other candidate response biomarkers must be evaluated in much larger studies and, if confirmed, support the need for profiling of recurrent tumor specimens in future clinical trials. Mol Cancer Ther; 11(2); 492-502. Ó2011 AACR.

Reversal of Chemoresistance in Ovarian Cancer by Co-Delivery of a P-Glycoprotein Inhibitor and Paclitaxel in a Liposomal Platform

“…However, the number of patients in these studies was small (19–22). We, therefore, interrogated two publicly available datasets to determine whether P-gp mRNA expression is associated with the survival of OvCa patients (Fig.…”

“…P-gp was the first ABC member found to confer chemoresistance and is still seen as one of the most promising targets for the reversal of chemoresistance (17). The overexpression of P-gp is associated with reduced progression-free and overall survival in several cancer types, including OvCa (19–22), most probably because it contributes to the cellular exclusion of a broad spectrum of chemotherapeutic drugs, including taxanes, doxorubicin, and vinca alkaloids (8). The energy-dependent efflux of the chemotherapeutic drugs out of the cancer cell reduces the intracellular accumulation of otherwise effective therapies, requiring a higher dose to achieve an anti-cancer effect.…”

Analysis and Comparison of Somatic Mutations in Paired Primary and Recurrent Epithelial Ovarian Cancer Samples

“…In ovarian cancer, some studies have shown discordant expression of genes or protein biomarkers in paired primary and relapsed ovarian cancer tissue samples, as measured by immunohistochemical analyses [28]–[30]. Recently, however, the opposite data has been reported that no new mutations arose from diagnosis to relapse after chemotherapy by exome sequencing of matched samples from one patient, suggesting that mutations already present in the primary tumor contributed to metastasis and chemotherapy resistance [31].…”

Cell-Penetrating, Guanidinium-Rich Molecular Transporters for Overcoming Efflux-Mediated Multidrug Resistance

“…19,20 It has additionally been shown that recurrent ovarian cancers have higher levels of Pgp expression on a population basis. 17 …”

“…89 Because less drug gets into the cell and thus to its target, Taxol shows reduced activity against MDR tumors. 17,18,20 Increasing the dose of Taxol to offset efflux loss and force more intracellular accumulation is not an option, as that would cause greater off-target toxicities. However, a releasable Taxol–transporter conjugate that is not a substrate for Pgp export would evade export and release free Taxol in a cell at a concentration and rate determined by linker design (Figure 4).…”