Satraplatin Demonstrates High Cytotoxic Activity Against Genetically Defined Lymphoid Malignancies

Abstract

Background/Aim: Satraplatin is an oral platinum analog with proven clinical efficacy and a more favorable toxicity profile, although with increased hematotoxicity, when compared to cisplatin. Hence, we carried out a systematic biomarker analysis to identify hematological malignancies with high susceptibility to satraplatin. Materials and Methods: Halfmaximal inhibitory concentrations (IC 50 ) for satraplatin and cisplatin were determined for 66 different cancer cell lines by CTG Luminescent Cell Viability Assay. In a second step, whole transcriptome RNA sequencing and whole-exome DNA sequencing technology followed by unbiased analysis of gene expression, gene mutation and copy number levels were performed and correlated with drug efficacy. Results: Satraplatin was significantly more active against hematological malignancies compared to solid organ cancer. In addition, satraplatin showed a significantly more potent antiproliferative activity compared to cisplatin in most lymphoma cell lines achieving sub micromolar IC 50 values. Single BCL2 apoptosis regulator (BCL2) gene mutation and 9p21 copy-number deletions including S-methyl-5'-thioadenosine phosphorylase (MTAP) deficiency were identified as key characteristics for high sensitivity to satraplatin. Conclusion: Satraplatin demonstrated a high cytotoxic activity in genetically welldefined hematological malignancies which is distinct from that of cisplatin. MTAP deficiency was identified as biomarker of enhanced satraplatin efficacy in hematological cancer-derived cell lines. These data in combination with the lipophilicity of satraplatin provide the rationale for targeting specific lymphatic entities such as primary central nervous system lymphoma and cutaneous T-cell lymphoma to improve clinical outcome.Cisplatin, carboplatin and oxaliplatin are platinum-based drugs that are used throughout the world for cancer treatment (1). All three are intravenously administered and primarily hydrophilic, with similar or even overlapping side-effects including nephrotoxicity, ototoxicity, neurotoxicity, cardiotoxicity, hematological toxicity, hepatotoxicity, and gastrointestinal toxicity. Platinum toxicity is usually the main reason for dose adaptations or even treatment suspension. This is particularly true for cisplatin, with the two most common nephrotoxic sideeffects being acute kidney injury and hypomagnesemia, which is reported to affect up to 90% of cisplatin-treated patients (2). Neurotoxicity and ototoxicity (60-90% of all patients) are the second and third most common platinum toxicities experienced with oxaliplatin, primarily causing neurotoxicity, and cisplatin causing ototoxicity.In order to develop better tolerated platinum compounds with less toxicity, platinum(IV) complexes featuring an octahedral geometry with two additional ligand sites were developed. They follow a classical prodrug concept since it is essential for their anticancer activity that they are reduced to the corresponding platinum(II) analogs in the tumor cell, leading to apoptosis (3). Satrap...