TY - JOUR
T1 - Targeting B-cell receptor signaling
T2 - changing the paradigm.
AU - Fowler, Nathan
AU - Davis, Eric
N1 - Copyright:
This record is sourced from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
PY - 2013
Y1 - 2013
N2 - It is well known that signals emanating from the B-cell receptor (BCR) activate downstream pathways to regulate the development and survival of normal B cells. In B-cell malignancies, it is increasingly understood that similar pathways are activated through both tonic and chronic active BCR signaling to promote tumor viability and resistance to therapy. Recently, several active and oral agents have emerged that target key proximal kinases in the BCR pathway, including Bruton tyrosine kinase, PI3K, and spleen tyrosine kinase. In early clinical studies, these agents have shown significant activity across a broad range of B-cell lymphomas and chronic lymphocytic leukemia. Especially impressive responses have been reported in mantle cell lymphoma and chronic lymphocytic leukemia, and many patients remain on treatment with continued disease control. Toxicity profiles have been mild in the majority of early studies, without significant myelosuppression over prolonged dosing. Due to these attractive attributes, several agents targeting the BCR pathway are now entering early combination studies with traditional chemotherapeutics and/or other novel agents. It is clear that agents targeting the BCR pathway will significantly affect the design of future therapeutic regimens for B-cell malignancies. Future research will focus on understanding potential mechanisms of resistance, identifying biomarkers of response, and defining optimal combination regimens.
AB - It is well known that signals emanating from the B-cell receptor (BCR) activate downstream pathways to regulate the development and survival of normal B cells. In B-cell malignancies, it is increasingly understood that similar pathways are activated through both tonic and chronic active BCR signaling to promote tumor viability and resistance to therapy. Recently, several active and oral agents have emerged that target key proximal kinases in the BCR pathway, including Bruton tyrosine kinase, PI3K, and spleen tyrosine kinase. In early clinical studies, these agents have shown significant activity across a broad range of B-cell lymphomas and chronic lymphocytic leukemia. Especially impressive responses have been reported in mantle cell lymphoma and chronic lymphocytic leukemia, and many patients remain on treatment with continued disease control. Toxicity profiles have been mild in the majority of early studies, without significant myelosuppression over prolonged dosing. Due to these attractive attributes, several agents targeting the BCR pathway are now entering early combination studies with traditional chemotherapeutics and/or other novel agents. It is clear that agents targeting the BCR pathway will significantly affect the design of future therapeutic regimens for B-cell malignancies. Future research will focus on understanding potential mechanisms of resistance, identifying biomarkers of response, and defining optimal combination regimens.
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U2 - 10.1182/asheducation-2013.1.553
DO - 10.1182/asheducation-2013.1.553
M3 - Review article
C2 - 24319231
AN - SCOPUS:84902366078
SN - 1520-4391
VL - 2013
SP - 553
EP - 560
JO - Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program
JF - Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program
ER -