Abstract
BackgroundAnthracycline-containing regimens, namely cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or CHOEP (CHOP + etoposide), represent the current standard of care for patients with newly diagnosed peripheral T-cell lymphomas (PTCLs), although responses are unsatisfactory. In this study, we investigated the pathways able to mitigate the sensitivity to CHOP-based regimens in preclinical models of T-cell lymphoma (TCL) to select agents for the development of CHOP-based drug combinations.MethodsWe performed gene expression profiling of malignant T-cell lines exposed to CHOEP; flow cytometry was employed to study the effects of drug combinations on cell viability, cell cycle distribution, apoptosis and mitochondrial membrane depolarisation. Western blot analyses were performed to study cell signalling downstream of the T-cell receptor and apoptosis. The in vivo effect of the drug combination was tested in xenograft models.ResultsWe highlighted a modulation of tyrosine kinases belonging to the T-cell receptor pathway upon chemotherapy that provided the rationale for combining the tyrosine kinase inhibitor dasatinib with CHOEP. Dasatinib improves CHOEP activity and reduces viability in vitro. Furthermore, combination treatment results in tumour growth inhibition in in vivo xenograft mouse models.ConclusionsOur data provide the rationale for clinical testing of the dasatinib–CHOEP combination in patients with T-cell lymphoma.
Highlights
Anthracycline-containing regimens, namely cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or CHOEP (CHOP + etoposide), represent the current standard of care for patients with newly diagnosed peripheral T-cell lymphomas (PTCLs), responses are unsatisfactory
CHOEP treatment induces cell cycle perturbations and apoptosis in preclinical models of TCL We first assessed the sensitivity of a panel of malignant T-cell lines (HH, cutaneous TCL; SUP-T1, lymphoblastic TCL; KARPAS-299, ALCL; JURKAT and HD-MAR-2, T-cell leukaemia) to CHOP, a combination of drugs reflecting the regimen used in patients.[13]
Adding etoposide to CHOP (CHOEP 1 × ) strongly improves the anti-proliferative activity (Fig. S1A) when compared with either CHOP or etoposide treatment alone, responses were heterogeneous among the cell lines (CHOEP IC50 values range 0.32 × −1.12 ×), with HH cells being the most sensitive and HD-MAR-2 the least sensitive (Table S1)
Summary
Anthracycline-containing regimens, namely cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or CHOEP (CHOP + etoposide), represent the current standard of care for patients with newly diagnosed peripheral T-cell lymphomas (PTCLs), responses are unsatisfactory. Mature T-cell lymphomas (TCLs) are a phenotypically heterogeneous group of malignancies representing 10–15% of non-Hodgkin lymphomas (NHL). They comprise different cutaneous, extranodal and nodal entities that are often referred to as peripheral T-cell lymphomas (PTCL) to distinguish them from immature T-cell neoplasms.[1] Nodal forms are the most common and include well-characterised histotypes, such as angioimmunoblastic T-cell lymphoma (AITL) and anaplastic large T-cell lymphoma (ALCL, ALK + or ALK−). Anthracycline-based chemotherapy programs, predominantly cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or CHOEP (CHOP + etoposide), are widely used in the upfront treatment of PTCLs, despite suboptimal results.[4,5,6] Neither intensified/escalated chemotherapeutic approaches[7,8] nor the addition of monoclonal antibodies[9] have demonstrated a clear advantage in response rates and survival
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