Palifosfamide Tromethamine

MRP-1 is implicated in multidrug resistance and was described as prognostic in high-risk patients with soft-tissue sarcoma (STS) in a previous study. The current research aimed to validate MRP-1 prognostic/predictive value in localized sarcomas treated with anthracyclines plus ifosfamide within the ISG-1001 phase III study. In addition, the inhibitory activity on MRP-1 was investigated in preclinical studies to identify new combinations able to increase the efficacy of standard chemotherapy in STS. MRP-1 expression was assessed by IHC in tissue microarrays from patients with STS and tested for correlation with disease-free survival (DFS) and overall survival (OS). In vitro studies tested the efficacy of MRP-1 inhibitors (nilotinib, ripretinib, selumetinib, and avapritinib) in sarcoma cell lines. The effect of combinations of the most active MRP-1 inhibitors and chemotherapy was measured on the basis of apoptosis. MRP-1 was evaluable in 231 of 264 cases who entered the study. MRP-1 expression (strong intensity) was independently associated with worse DFS [HR, 1.78; 95% confidence interval (CI), 1.11–2.83; P = 0.016], in the multivariate analysis, with a trend for a worse OS (HR, 1.78; 95% CI, 0.97–3.25; P = 0.062). In vitro studies showed that the addition of MRP-1 inhibitors (nilotinib or avapritinib) to doxorubicin plus palifosfamide, significantly increased cell death in SK-UT-1 and CP0024 cell lines. MRP-1 is an adverse predictive factor in localized high-risk patients with STS treated with neoadjuvant anthracyclines plus ifosfamide followed by surgery. In vitro findings support the clinical assessment of the combination of chemotherapy and MRP-1 inhibitors as a promising strategy to overcome the drug ceiling effect for chemotherapy.

In this study, we investigated the effect of ABCB1 on the cytotoxicity of anti-myeloma drugs in carfilzomib-resistant myeloma model representing a double class-refractory disease relevant in the era of novel anti-MM drugs.To study the effect of ABCB1 activity on the cytotoxicity of anti-MM drugs in carfilzomib-refractory (CFZ-R) MM in vitro, two isogenic clones of CFZ-R subline of MM cell line AMO1 (AMO-CFZ-R) were obtained using CRISPR/Cas9 technol.A broad panel of anti-MM drugs was systematically tested for their cytotoxicity in both ABCB1+ and ABCB1- CFZ-R cells. The panel included immunomodulatory drugs (pomalidomide and iberdomide), chemotherapy drugs (doxorubicin, vincristine, paclitaxel), alkylators (melphalan, bendamustine, palifosfamide), and a novel peptide-drug conjugate melphalan flufenamide (hereafter, melflufen).