American Association for Cancer Research
10780432ccr180851-sup-198599_2_supp_4874818_pbflr4.pdf (221.51 kB)

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.


Andalusian Public Health System Biobank and ISCIII-Red de Biobancos



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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