Preclinical efficacy of tasquinimod-based combinations in advanced myeloproliferative neoplasms (MPN) in blastic phase.

The alarmins, S100A8 (A8) and S100A9 (A9), are low molecular weight proteins belonging to the S100 protein family. A8 and A9 are secreted into the extracellular space and plasma, where they interact with TLR4 (Toll like receptor 4), RAGE (receptor for advanced glycation end products) and CD33. In present studies, we determined the preclinical efficacy of tasquinimod (TQ) against advanced MPN cell lines and patient-derived (PD) CD34+ blastic phase (BP, >5% blasts in PB) MPN cells. TQ induced loss of viability in cell lines and PD MPN-BP cells, but not in normal CD34+ progenitor cells. In TQ-treated PD MPN-AML cells, RNA-Seq analysis showed negative enrichment of the gene-sets of MYC and E2F targets, IL6-JAK-STAT3 signaling, and of inflammatory response. In phenotypically defined, PD, CD34+ MPN-BP stem progenitor cells, CyTOF analysis showed that TQ reduced expression of proteins including A8, A9, and MPO, while increasing expression of GFI1, p21 and cleaved PARP. Co-treatment with TQ and ruxolitinib or BET inhibitor induced synergistic lethality in advanced MPN-BP cells. Monotherapy with TQ significantly improved survival of immune-depleted NSG mice engrafted with PDX cells of MPN-AML. Notably, cotreatment with TQ and ruxolitinib or OTX015 induced significantly greater survival than treatment with single agents in the NSG mice engrafted with the PDX cells. These findings clearly demonstrate the preclinical efficacy of TQ in advanced MPN-BP cells and create the rationale to further interrogate the efficacy of TQ-based combinations with the current, front-line therapies or novel agents in advanced MPNs with excess blasts.