The relations between PI3K signaling pathway and cancer

PI3K (phosphatidylinositol trikinase) is a cellular signaling molecule that is involved in a range of female cancers, such as breast cancer, ovarian cancer, and endometrial cancer. Recently in a research paper published in Cell, researchers from the Beth Israel Deaconess Medical Center revealed the new role of PI3K in glycolysis, a special metabolic process that can promote the growth of cancer cells by producing biomass and energy. Relevant research confirms the importance of carbohydrates for cancer cell survival and provides new information for the development of PI3K inhibitor drugs as cancer targeted therapies.

Researcher Dr. Gerburg Wulf said that PI3K is a major regulator of the integration of cancer cell architecture and its metabolic processes, but it remains a mystery as to how sugar molecules break down and how cell architectures are coordinated. In normal cells, external signals activate the cytoskeleton, and the cytoskeleton is not fixed. It is dynamically assembled by fiber bundles and undergoes continuous turnover, breaking ATP molecules to maintain cell shape. The researchers found that when PI3K was activated, and when ATP disruption occurs in cancer cells, fibrin fibers are detached and release enzymes called aldolase.

PI3K inhibitor promotes cancer metastasis

PI3K is a protein kinase. Many studies have found PI3K abnormalities in many types of human cancers, which has attracted a wide-spread interest of many scientists. Many kinds of PI3K inhibitor drugs like XL147 have been developed with PI3K as a therapeutic target, but are in different stages of clinical validation. However, based on the current results, the PI3K inhibitor drug is not ideal in clinical application, and has no significant effect on improving the survival rate of cancer patients.

Recently, scientists from the Wistar Institute in the United States conducted a new study and found that cancer treatment with PI3K inhibitor alone may promote the aggressiveness of tumor cells and the spread to other organs, leading to a worsening of the patient's condition. Recently, the results of this research were published in the international academic journal PNAS.

In this study, the researchers focused their research on the "energy plant" of cells, mitochondria, regarding how mitochondria reprogram in tumor cells treated with PI3K inhibitors, and how mitochondrial changes prevent targeted drugs from functioning effectively. The researchers found that cells treated with no inhibitor drugs have mitochondria distributed around the nucleus, while treatment of tumor cells with PI3K inhibitors causes mitochondria to move to specific regions of the cell membrane. The important "strategic" position of mitochondria occupying the surrounding cell skeleton can provide a lot of energy for the migration and invasion of cells, which indicates an increase in cell movement and invasion.

PI3K dual inhibitors proved active in phase 3 clinical trials for the treatment of lymphoma
Verastem today announced an important positive outcome of a Phase 3 clinical trial called DUO. Its dual inhibitor duvelisib of PI3Kδ and PI3Kγ has shown efficacy and safety in the treatment of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

CLL and SLL are cancers that affect the same lymphocytes. They are essentially the same disease, the only difference being where the cancer occurs. When most cancer cells are located in the blood and bone marrow, the disease is called CLL. When cancer cells are mostly located in lymph nodes, it is called SLL. According to the National Cancer Institute, approximately 19,000 people are diagnosed with CLL/SLL each year in the United States. On average, each person has a 0.6% risk of developing CLL/SLL during their lifetime. The disease is rare in people under the age of 40 and the average age at diagnosis is 71 years.

Duvelisib is a dual inhibitor of PI3Kδ and PI3Kγ. These two enzymes help the growth and survival of malignant B cells and T cells. PI3K signaling pathway may lead to the proliferation of malignant B cells and play an important role in the formation and maintenance of the tumor microenvironment. Duvelisib is currently in mid- and late-stage clinical trials, including a phase 3 clinical trial of DUO as a monotherapy for CLL/SLL, and a phase 2 clinical trial of monotherapy for refractory inert non-Hodgkin's lymphoma (iNHL) DYNAMO. In the analysis of the efficacy data, both DUO and DYNAMO reached their respective primary endpoints. Duvelisib has also been evaluated for the treatment of other malignant hematological tumors, including T-cell lymphoma.