Targeting the crosstalk between tumor cells and microenvironment: a new therapeutic approach for the treatment of lymphoid neoplasms
In this thesis we have focused on two novel therapeutic strategies that target the crosstalk between the tumor cells and the microenvironment. Chronic lymphocytic leukemia (CLL) remains an incurable disease where high CD38 expression is associated with poor prognosis and identifies cells that are pr...
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| Formato: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2017 |
| País: | España |
| Recursos: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/587142 |
| Acesso em linha: | http://hdl.handle.net/10803/587142 |
| Access Level: | acceso abierto |
| Palavra-chave: | Ciències de la salut Ciencias biomédicas Medical sciences Oncologia Oncología Oncology Tumors Tumores Limfomes Linfomas Lymphomas Farmacologia Farmacología Pharmacology Ciències de la Salut 616 |
| Resumo: | In this thesis we have focused on two novel therapeutic strategies that target the crosstalk between the tumor cells and the microenvironment. Chronic lymphocytic leukemia (CLL) remains an incurable disease where high CD38 expression is associated with poor prognosis and identifies cells that are prone to proliferate. CD38 cooperates in migration, adhesion and invasion through its molecular association with CXCR4, MMP9 and CD49d. The human anti-CD38 monoclonal antibody daratumumab has shown efficient cell killing and a good safety profile in clinical trials in multiple myeloma. In this thesis, we demonstrate that daratumumab also exerts significant cytotoxicity against patient-derived CLL cells, via ADCC and ADCP in vitro and in vivo. Furthermore, daratumumab interferes with CD38 signaling and reduces CLL cell adhesion, migration and homing. Moreover, daratumumab shows therapeutic activity in two mouse models. Thus, daratumumab improves overall survival in a systemic CD38+ MEC2 cell line mouse model and reduces tumor burden in CLL-patient derived xenografts. These results provide scientific rationale for the clinical development of daratumumab in poor prognosis CD38+CLL. Despite unprecedented activity of ibrutinib in mantle cell lymphoma (MCL), acquired or induced resistances appear in association with dismal prognosis. CC-292 (spebrutinib) is a novel, highly specific covalent BTK inhibitor that binds irreversibly to the Cys481 in the BTK active site, with demonstrated preclinical activity in several B-cell malignancies, and initial encouraging results in a phase 1 trial in relapsed/refractory chronic lymphocytic leukemia. We have characterized CC-292 activity in a panel of MCL cell lines (n=5) and primary cases (n=11) with different mutational status of NF-κB pathway genes. CC-292 shows a similar anti-proliferative profile than ibrutinib, conditioned by the existence of activating mutations in alternative NF-κB pathway genes such as TRAF2/3 and BIRC3. Noteworthy, CC-292 blocks B-cell receptor activation, independently of the presence of mutations on TRAF2/3 or BIRC3 genes. However, CC-292 interferes with CXCL12-induced migration mostly in MCL cells without activation of alternative NF-κB pathway. In sensitive cell lines, CC-292 activity was significantly enhanced by co-treatment with the immunomodulatory agent lenalidomide, maintaining its efficacy in co-culture with mesenchymal stromal cells (MSC). For MCL cases bearing mutations in the alternative NF-κB pathway, inhibitors of NIK, a central kinase promoting processing of p100 to p52, engaged cytostatic and cytotoxic responses in MCL cell lines and primary cultures. This effect was maintained in MSC-MCL co-cultures and was further enhanced by CC-292 leading to a complete impairment of NF-κB pathway. These substantial effects of CC-292 on MCL, especially in combination regimens, warrant further investigation in the clinical setting. All in all, the findings of the present thesis support the importance of developing strategies to target the microenvironment and its interaction with neoplastic cells. |
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