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Tumor-associated carbonic anhydrases IX (CAIX) and XII (CAXII) have long been in the spotlight as potential new targets for anti-cancer therapy. Recently, CAIX/CAXII specific inhibitor SLC-0111 has passed clinical phase I study and showed differential response among patients with colorectal cancer (CRC). CRC can be classified into four different consensus molecular subgroups (CMS) showing unique expression patterns and molecular traits. We questioned whether there is a CMS-related CAIX/CAXII expression pattern in CRC predicting response. As such, we analyzed transcriptomic data of tumor samples for CA9/CA12 expression using Cancertool. Protein expression pattern was examined in preclinical models comprising cell lines, spheroids and xenograft tumors representing the CMS groups. Impact of CAIX/CAXII knockdown and SLC-0111 treatment was investigated in 2D and 3D cell culture. The transcriptomic data revealed a characteristic CMS-related CA9/CA12 expression pattern with pronounced co-expression of both CAs as a typical feature of CMS3 tumors. Protein expression in spheroid- and xenograft tumor tissue clearly differed, ranging from close to none (CMS1) to strong CAIX/CAXII co-expression in CMS3 models (HT29, LS174T). Accordingly, response to SLC-0111 analyzed in the spheroid model ranged from no (CMS1) to clear (CMS3), with moderate in CMS2 and mixed in CMS4. Furthermore, SLC-0111 positively affected impact of single and combined chemotherapeutic treatment of CMS3 spheroids. In addition, combined CAIX/CAXII knockdown and more effective treatment with SLC-0111 reduced clonogenic survival of CMS3 modelling single cells. In conclusion, the preclinical data support the clinical approach of targeted CAIX/CAXII inhibition by showing linkage of expression with response and suggest that patients with CMS3-classified tumors would most benefit from such treatment. [ABSTRACT FROM AUTHOR]

The prognosis for patients with Hodgkin lymphoma (HL) has improved in recent decades. On the other hand, not all patients can be cured with the currently established therapy regimes and this therapy is associated with several adverse late effects. Therefore it is necessary to develop new therapy strategies. After treatment of L-540 HL cells with 5′-azacytidine (5AC), we observed increased expression of the preferentially expressed antigen in melanoma (PRAME). In addition, we detected an increased resistance of 5AC-treated cells against cytotoxic drugs. We analyzed the influence of PRAME on cell survival of HL cells by knocking down PRAME in the chemotherapy resistant cell line L-428, a cell line that express PRAME at a high level. After knock-down of PRAME using vector based RNA interference we observed increased sensitivity for cisplatin, etoposide and retinoic acid. DNA microarray analysis of HL cells after PRAME knock-down indicated regulation of several genes including down-regulation of known anti-apoptotic factors. Increased retinoic acid signaling in these cells was revealed by increased expression of the retinoic acid metabolizing cytochrome P450 (CYP26B1), a transcriptional target of retinoic acid signaling. Our data suggest that PRAME inhibits retinoic acid signaling in HL cells and that the knock-down of PRAME might be an interesting option for the development of new therapy strategies for patients with chemo-resistant HL. [ABSTRACT FROM AUTHOR]

Objective: The prognosis of patients with Hodgkin''s lymphoma (HL) has been significantly improved as a result of combination treatment including chemotherapy. However, some patients are refractory to chemotherapy. Therefore, identification of new targets might be useful for development of alternative treatment strategies. In addition, identification of markers associated with chemoresistance can be used to identify patients with increased risk of relapse. Materials and Methods: By using high-density DNA microarrays, we analyzed the gene-expression profile of HL-cell lines in comparison to a set of normal tissues. Furthermore, we tested the sensitivity of HL cells for cytotoxic drugs (cisplatin, etoposide, melphalan) and compared the gene-expression profile of chemotherapy-resistant and -sensitive cell lines. Differentially expressed genes were validated by polymerase chain reaction and flow cytometry. Results: In addition to genes with high expression in all cell lines, we observed differences between the gene-expression profile of chemotherapy-resistant and -sensitive cells. Genes upregulated in resistant cells include cytokine receptors (IL5RA, IL13RA1), markers expressed on antigen-presenting cells (CD40, CD80), as well as genes with known association to chemoresistance, e.g., myristoylated alanine–rich protein kinase C substrate. In addition, the tumor antigen PRAME (preferentially expressed antigen in melanoma) was expressed in resistant cell lines only. Conclusion: Genes with high expression in HL cells might be potential targets for development of future therapeutic interventions. Expression of tumor antigens together with costimulatory molecules in chemotherapy-resistant HL cells might become targets for cytotoxic T–cell responses against HL cells. [Copyright &y& Elsevier]