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Targeting PI3Kδ: Emerging Therapy for Chronic Lymphocytic Leukemia and Beyond
Author(s) -
Wei Manman,
Wang Xiang,
Song Zilan,
Jiao Mingkun,
Ding Jian,
Meng LingHua,
Zhang Ao
Publication year - 2015
Publication title -
medicinal research reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.868
H-Index - 130
eISSN - 1098-1128
pISSN - 0198-6325
DOI - 10.1002/med.21341
Subject(s) - idelalisib , chronic lymphocytic leukemia , pi3k/akt/mtor pathway , medicine , purine analogue , leukemia , targeted therapy , lymphoma , venetoclax , cancer research , immunology , ibrutinib , cancer , oncology , biology , signal transduction , purine , biochemistry , enzyme
Chronic lymphocytic leukemia (CLL) remains the most incurable leukemia. Early chemotherapeutic treatments, including alkylating agents, purine nucleoside derivatives, and immunotherapeutic antibodies, only show limited benefits for patients but severe off‐target related side effects. Recent advances in understanding of the critical molecular pathways of regulating proliferation and survival of B‐CLL cells have spurred a new therapeutical strategy by selectively targeting phosphoinositide 3‐kinase delta (PI3Kδ). Idelalisib, a first‐in‐class PI3Kδ‐selective small molecule has received the FDA's fast‐track approval in July of 2014 as a new treatment of CLL, indolent B‐cell non‐Hodgkin's lymphoma, and relapsed small lymphocytic lymphoma. Undoubtedly, the success of idelalisib has provided a solid support in the development of PI3Kδ‐specific inhibitors and reformed the concept of treating CLL. However, the number of reported selective inhibitors of PI3Kδ is very limited and very few have advanced into clinical trials. The mechanism of their actions remains elusive. More profound understanding on the modes of action of new PI3Kδ inhibitors will further validate the PI3Kδ‐targeting strategy, and help to identify biomarkers capable of stratifying patients who will most likely benefit from the therapy.