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A double blinded, placebo-controlled pilot study to examine reduction of CD34+/CD117+ lymphoma progenitor cells and duration of remission induced by neoadjuvant valspodar in dogs with large B-cell lymphoma

ABSTRACT: We previously described a population of lymphoid progenitor cells (LPCs) in canine B-cell lymphoma defined by retention of the early progenitor markers CD34 and CD117 and slow proliferation molecular signatures that persist in the xenotransplantation setting. We examined whether valspodar, a selective inhibitor of the ATP-binding cassette B1 transporter (ABCB1, a.k.a., p-glycoprotein/multidrug resistance protein-1) used in the neoadjuvant setting would sensitize LPCs to doxorubicin and extend the length of remission in dogs with therapy-naive large B-cell lymphoma. Twenty dogs were enrolled into a double-blinded, placebo controlled study where experimental and control groups received oral valspodar (7.5 mg/kg) or placebo, respectively, twice daily for five days followed by five treatments with doxorubicin 21 days apart with a reduction in the first dose to mitigate the potential side effects of ABCB1 inhibition. Lymph node and blood LPCs were quantified at diagnosis, on the fourth day of the neoadjuvant period, and 1-week after the first chemotherapy dose. Valspodar therapy was well tolerated. There were no significant differences between groups in total LPCs in lymph nodes or peripheral blood, nor in event-free survival or overall survival. Overall, we conclude that valspodar can be administered safely in the neoadjuvant setting for canine B-cell lymphoma; however, its use to attenuate ABCB1+ cells does not appear to alter the composition of lymph node or blood LPCs, and it is not sufficient to prolong doxorubicin-dependent remissions in this setting.

ORGANISM(S): Canis lupus familiaris

PROVIDER: GSE93516 | GEO | 2017/04/06

SECONDARY ACCESSION(S): PRJNA360981

REPOSITORIES: GEO

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Project description:In this study, we present the first comparison of global transcriptional changes taking place in canine lymphoma and human diffuse large B-cell lymphoma (DLBCL), with particular reference to the nuclear factor-kappaB (NF-?B) pathway. Microarray data generated from lymph nodes diagnosed with canine DLBCL and healthy lymph nodes were used for differential expression analysis, co-expression analysis and pathway analysis, and compared with analysis of publicly available microarray data from human healthy and DLBCL lymph nodes. The comparisons between species at gene level were performed by mapping the probesets in canine microarrays to orthologous genes in humans and vice versa. A considerable number of differentially expressed genes between canine lymphoma and healthy lymph node samples were also found differentially expressed between human DLBCL and healthy lymph node samples. Principal component analysis (PCA) using a literature derived 120 NF-?B target gene set mapped to 199 orthologous canine array probesets and 259 human array probesets clearly separated the healthy and cancer samples in both canine and human datasets. The analysis demonstrated that for both human and canine DLBCL there is activation of the NF-?B/p65 canonical pathway rather than the alternative pathway. This has therapeutic implications for the use of specific pathway inhibitors for the treatment of DLBCL for both species and also indicates that naturally occurring canine lymphoma could be used as a model to study therapeutic strategies for human lymphoma. The model was further validated by the identification of molecular signatures that could sub-classify canine DLBCL into activated B-cell-like (ABC) or germinal centre B-cell-like (GCB) types equivalent to human subtypes. Canine DLBCL patients were recruited via the clinical oncology service of the University of Edinburgh Royal (Dick) School of Veterinary Studies (DJA), and the University of Wisconsin-Madison School of Veterinary Medicine (DMV). Lymph node biopsy samples were taken, as part of normal diagnostic procedures, from dogs newly diagnosed with lymphoma (naïve) and samples from dogs that had relapsed following standard of care CHOP chemotherapy. Only dogs with confirmed DLBCL after pathological grading were used in this study. This included standard histopathological grading by two independent pathologists and CD3/PAX5 marker analysis. Normal lymph node samples were obtained from canines that were euthanized for non-lymphoma conditions. Microarray data were generated from 35 canine samples (25 DLBCL and 10 healthy) in total. However, data from 2 canine DLBCL samples did not meet our required quality and were removed from further analysis. Only data from 33 (23 DLBCL and 10 healthy) samples were used for analysis. The generated data were used for differential expression analysis, co-expression analysis and pathway analysis, and compared with analysis of publicly available microarray data (GSE12195) from human healthy and DLBCL lymph nodes. The comparisons between species at gene level were performed by mapping the probesets in canine microarrays to orthologous genes in humans and vice versa.

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A double blinded, placebo-controlled pilot study to examine reduction of CD34+/CD117+ lymphoma progenitor cells and duration of remission induced by neoadjuvant valspodar in dogs with large B-cell lymphoma

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