Integrin αvβ3 Presents a Possible Therapeutic Target for Patients with T-cell Lymphomas

lecBy Leandro Cerchietti, MD

Malignant T-cell proliferation, survival, and drug resistance are dependent on a combination of external stimuli delivered by the micro-environment. Previous research has shown that the transmembrane receptor integrin αvβ3 plays a crucial role in mediating the interaction of T-cell lymphoma (TCL) cells with external signals. Integrin αvβ3 ligands include extracellular matrix-associated signaling proteins and soluble factors such as thyroid hormones (TH). Having previously shown that TH stimulate the proliferation of TCL through complimentary intracellular pathways involving the αvβ3 integrin, we hypothesized that targeting integrin αvβ3 could represent a novel strategy in treating TCL patients in an abstract presented during ASH.

In determining whether αVβ3 integrin is of therapeutic benefit for TCL, xenografts were developed in SCID mice using CUTLL1 cells transfected with si-control, si-αV and si-β3, and monitored tumor growth and angiogenesis. CUTLL1 was found to transfect with si-αV and si-β3 developed significant smaller tumors than si-control. The translational impact of this strategy was determined through the effect of cilengitide, a selective αVβ3 integrin inhibitor in phase 3 for glioma, in pre-clinical models of PTCL-NOS,  ALCL-ALK+ and  ALCL-ALK-. Similarly to si-αV and si-β3 treated mice, the anti-lymphoma effect of cilengitide correlated with lower levels of angiogenesis and NFkB activation.

This allowed us to elucidate the mechanisms by which integrin αvβ3 activation increases TCL proliferation through the activation of pro-survival pathways in malignant T-cells, while promoting angiogenesis. In the course of our research we also found that the genetic and pharmacological targeting of integrin αvβ3 induces an anti-lymphoma effect in TCL, including ALCL-ALK + and ALCL-ALK- PDT models obtained from treatment refractory patients. Both of these findings present potentially new therapeutic targets for the treatment of patients with T-cell lymphoma.

Author: lymphomaprogram

Located on the Upper East Side of New York City, the Lymphoma Program at Weill Cornell Medical College/NewYork Presbyterian Hospital is internationally recognized for our efforts to enable patients with non-Hodgkin lymphoma, Hodgkin disease and related disorders to have the best possible clinical outcome, including cure when possible.

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