Predicting Response to Methotrexate, Vinblastine, Doxorubicin, and Cisplatin Neoadjuvant Chemotherapy for Bladder Cancers through Genome-Wide Gene Expression Profiling

Abstract

Purpose: Neoadjuvant chemotherapy for invasive bladder cancer, involving a regimen of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC), can improve the resectability of larger neoplasms for some patients and offer a better prognosis. However, some suffer severe adverse drug reactions without any effect, and no method yet exists for predicting the response of an individual patient to chemotherapy. Our purpose in this study is to establish a method for predicting response to the M-VAC therapy. Experimental Design: We analyzed gene expression profiles of biopsy materials from 27 invasive bladder cancers using a cDNA microarray consisting of 27,648 genes, after populations of cancer cells had been purified by laser microbeam microdissection. Results: We identified dozens of genes that were expressed differently between nine “responder” and nine “nonresponder” tumors; from that list we selected the 14 “predictive” genes that showed the most significant differences and devised a numerical prediction scoring system that clearly separated the responder group from the nonresponder group. This system accurately predicted the drug responses of 8 of 9 test cases that were reserved from the original 27 cases. Because real-time reverse transcription–PCR data were highly concordant with the cDNA microarray data for those 14 genes, we developed a quantitative reverse transcription–PCR–based prediction system that could be feasible for routine clinical use. Conclusions: Our results suggest that the sensitivity of an invasive bladder cancer to the M-VAC neoadjuvant chemotherapy can be predicted by expression patterns in this set of genes, a step toward achievement of “personalized therapy” for treatment of this disease.

CD147 overexpression allows an accurate discrimination of bladder cancer patients’ prognosis

“…Xue et al have recently reported that CD147 immunoexpression is as an independent prognostic factor for bladder cancer patients, playing an important role in tumour progression [14]. Takata et al identified, in non-responder patients with invasive bladder cancer treated by M-VAC regimen, a gene (SLC16A3) that is closely associated with CD147 [9]. Als et al identified CD147 as a strong independent prognostic factor for response and survival M A N U S C R I P T…”

“…The treatment of UBC may be improved if we understand the molecular events that occur in tumour progression, identifying potential targets to, ultimately, achieve "personalized therapy". In this line of investigation, Takata and colleagues [9] observed that SLC16A3 (solute carrier family 16 -monocarboxylic acid transporter 4 -MCT4, member 3) is up-regulated in patients that do not respond to neoadjuvant M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) therapy. SLC16A3 (MCT4) is closely associated with CD147 [10], a highly glycosylated cell surface transmembrane protein which stimulates matrix metalloproteinases synthesis and angiogenesis in tumour local environment [11].…”

UHRF1 is a novel molecular marker for diagnosis and the prognosis of bladder cancer

“…However, the levels of upregulation of UHRF1 in bladder tumours were much higher than that in kidney tumours (Po0.0001), suggesting that UHRF1 might be a sensitive tool for detection of bladder tumours, especially the upper tract TCCs, which are currently often found in advanced stages. Overexpression of UHRF1 was further confirmed in bladder tumours from 36 Japanese patients by microarray analysis (Takata et al, 2005(Takata et al, , 2007. Expression of UHRF1 in these bladder tumours was compared with the corresponding adjacent normal tissues from the same patients, and tumour/normal ratio was obtained.…”

CDC20, a potential cancer therapeutic target, is negatively regulated by p53

“…After amplified RNAs (aRNAs) were labeled with Cy3 or Cy5, respectively, we carried out hybridization between labeled aRNAs and cDNA microarray slides containing 36 864 spots and detected the signals. Expression of CDC20 in various cancer tissues and their corresponding normal tissues were examined by using data sets that were analysed previously (Ono et al, 2000;Kitahara et al, 2001;Okabe et al, 2001;Hasegawa et al, 2002;Kaneta et al, 2002;Kitahara et al, 2002;Nagayama et al, 2002;Okutsu et al, 2002;Kikuchi et al, 2003;Okada et al, 2003;Ashida et al, 2004;Jinawath et al, 2004;Nakamura et al, 2004;Nishidate et al, 2004;Ochi et al, 2004;Obama et al, 2005;Takata et al, 2005;Hirota et al, 2006;Taniwaki et al, 2006;Yamabuki et al, 2006). To select genes that were suppressed by p53 and upregulated in various cancer tissues, the following two criteria were used: (1) genes whose expression were more than threefold decreased by Ad-p53 and (2) genes whose expression were more than threefold increased in various cancer tissues compared with its corresponding normal tissues.…”

“…Extracted RNAs were reverse-transcribed using oligo(dT) 12-18 primer and SuperScript II reverse transcriptase (Invitrogen, Carlsbad, CA, USA). cDNAs of colorectal and bladder cancer tissues were prepared as described previously Takata et al, 2005). CDC20 was quantified by real-time RT-PCR that was performed in an Applied Biosystems 7700 sequence detector system with SYBR Premix Ex Taq (Takara, Tokyo, Japan).…”