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Supplementary Figure 3S - Relative mRNA expression of ABCB1 (P-gp) and ABCC1 (MRP-1) in pre- and post-treatment formalin-fixed paraffin-embedded (FFPE) tumor samples. from Nilotinib as Coadjuvant Treatment with Doxorubicin in Patients with Sarcomas: A Phase I Trial of the Spanish Group for Research on Sarcoma

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posted on 2023-03-31, 21:42 authored by Regina Alemany, David S. Moura, Andres Redondo, Javier Martinez-Trufero, Silvia Calabuig, Carlos Saus, Antonia Obrador-Hevia, Rafael Ramos, Victor H. Villar, Claudia Valverde, Maria Angeles Vaz, Javier Medina, Irene Felipe-Abrio, Nadia Hindi, Miguel Taron, Javier Martin-Broto

Relative Expression shows the expression levels of ABCB1 and ABCC1 determined in FFPE samples after treatment (post-treatment) relatively to baseline levels (pre-treatment) in two cases (Relative expression = post-treatment/ pre-treatment). These results are in line with the expression of both genes determined in patient blood samples and with protein expression by immunohistochemistry. Patient 07 (leiomyosarcoma) displayed the highest radiological progression.

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Andalusian Public Health System Biobank and ISCIII-Red de Biobancos

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ARTICLE ABSTRACT

Purpose: Nilotinib plus doxorubicin showed to be synergistic regarding apoptosis in several sarcoma cell lines. A phase I/II trial was thus designed to explore the feasibility of nilotinib as coadjuvant of doxorubicin by inhibiting MRP-1/P-gp efflux activity. The phase I part of the study is presented here.Patients and Methods: Nilotinib 400 mg/12 hours was administered in fixed dose from day 1 to 6, and doxorubicin on day 5 of each cycle. Three dose escalation levels for doxorubicin at 60, 65, and 75 mg/m2 were planned. Cycles were repeated every 3 weeks for a total of 4 cycles. Eligible subtypes were retroperitoneal liposarcoma, leiomyosarcoma, and unresectable/metastatic high-grade chondrosarcoma.Results: Thirteen patients were enrolled: 7 chondrosarcoma, 4 liposarcoma, and 2 leiomyosarcoma. In 46 cycles administered, the most relevant grade 3/4 adverse effects per patient were neutropenia 54%, febrile neutropenia 15%, and asthenia 8%. No cardiac toxicity was observed. Only one dose-limiting toxicity (febrile neutropenia) was reported in the third dose level. With regard to efficacy, 1 partial response (1 liposarcoma), 9 stable diseases (5 chondrosarcoma, 2 liposarcoma, 1 leiomyosarcoma), and 3 progressive diseases (2 chondrosarcoma and 1 leiomyosarcoma) were present. ABCB1 and ABCC1 RNA expression levels decreased by 58.47-fold and 1.47-fold, respectively, on day 5 of the cycle.Conclusions: Combination of MRP-1/P-gp inhibitor, nilotinib, as coadjuvant with doxorubicin is feasible; it appears not to add substantial toxicity compared with doxorubicin alone. Pharmacodynamic study supports this concept. The recommended dose for the phase II part for doxorubicin was 75 mg/m2. Clin Cancer Res; 24(21); 5239–49. ©2018 AACR.

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