On March 18, the first new oral PI3K dual inhibitor was approved by the my country Food and Drug Administration. According to the priority review announcement of the Center for Drug Evaluation (CDE) of the China State Food and Drug Administration, the drug was approved for indications this time. For: Indicated for the treatment of relapsed or refractory follicular lymphoma that has received at least two prior systemic therapies. It is expected to bring new treatment options to patients with follicular lymphoma.
What exactly are PI3K inhibitors? Let’s find out together.
What is PI3K?
Phosphatidylinositol-3-kinase (PI3K) is an intracellular phosphatidylinositol kinase, which is an important signal transduction molecule in cells and is involved in the regulation of cell proliferation and apoptosis. Physiological processes such as death and differentiation. The PI3K-dependent signaling pathway plays a key role in tumorigenesis, and when it is overexpressed due to genetic and epigenetic mutations in major components of the pathway or upstream regulators, it contributes to the initiation and persistence of tumor cells.
The mechanism of action of PI3K inhibitors
PI3K can be divided into three types: I, II and III according to its encoding gene, structural characteristics and substrate specificity Type, a total of 8 subtypes. Among them, the four subtypes in type I are most closely related to tumors, namely PI3Ka, PI3Kβ, PI3Kγ, and PI3Kδ. A common mechanism of PI3K activation in cancer is mutation of the PIK3CA gene. PIK3CA mutations are most commonly found in gynecologic malignancies, breast and head and neck cancers, and other tumor types include lung, bladder, and colorectal adenocarcinomas.
PI3K inhibitors have cell-autonomous effects in cancer cells. These include activation of intrinsic apoptosis, reduction of glucose metabolism, translational repression, and regulation of activity through FOXO transcription factors. In addition to these effects, PI3K inhibitors can also exert non-cell-autonomous effects in vivo and in the tumor microenvironment, which can significantly promote antitumor effects.
Application of PI3K inhibitors
At present, a total of 5 PI3K inhibitors (Idelalisib, Copanlisib, Duvelisib, Alpelisib, Umbralisib) have been approved by the US FDA It is used for the treatment of lymphoma and breast tumors, and clinical trials related to PI3K inhibitors are being carried out in many other tumors.
1. Application in lymphoid and hematological tumors
In 2014, the first PI3K inhibitor Idelalisib was approved for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) . Copanlisib, approved in 2017, is used for relapsed follicular lymphoma above second-line.
Duvelisib, an oral PI3Kδ and γ inhibitor, was approved in 2018 for three types of lymphomas in patients with relapsed/refractory chronic lymphoma who have received at least two prior therapies Adults with relapsed/refractory follicular lymphoma who have received at least two prior therapies. Basic studies have shown that PI3Kδ inhibitors can slow tumor cell proliferation, while inhibition of the γ subunit can reduce myeloid cells associated with immune escape from the tumor microenvironment.
2. Application in breast tumors
In May 2019, the US FDA approved alpelisib in combination with fulvestrant for the treatment of HR with disease progression during or after endocrine therapy Patients with advanced or metastatic breast cancer positive, human epidermal growth factor receptor 2 (HER-2) negative, and PIK3CA mutated.
Challenges and Prospects of PI3K Inhibitors
Although PI3K is an effective target for the treatment of cancer, However, 4 of the 5 approved drugs for hematology PI3K products were investigated by the US FDA or their marketing applications were withdrawn. The development and progression of PI3K inhibitors remains challenging—poor drug tolerance, intrinsic resistance, acquired resistance, and compensatory mechanisms that neutralize the effects of PI3K inhibitors are all hurdles. It is believed that with the continuous deepening of research work, PI3K inhibitors will bring new hope and provide new methods for tumor treatment.
References:
1. Cai Tiantian, Zhao Min, Wang Jianping. Research progress of PI3K inhibitors in anti-tumor [J]. Zhejiang Journal of Integrated Traditional Chinese and Western Medicine, 2018, 28(08): 709-714.
2. Castel P, Toska E, Engelman JA, Scaltriti M. The present and future of PI3K inhibitors for cancer therapy. Nat Cancer. 2021;2(6):587-597.
3. Gong Yuanhe, Ma Jinzhu. Application status of PI3K inhibitors in the treatment of breast cancer[J].Chinese Journal of Oncology,2021,13(03):251-254.