CN-113018430-B - Cancer therapeutic target and uses thereof

Abstract

The present invention relates to the use of cytarabine, inhibitors of mitochondrial metabolism and agents that down-regulate the expression or activity of CDA in the treatment of cancer.

Inventors

• ZHAO YUZHENG
• ZHENG JUNKE
• YANG GE
• Chen Chiqi
• LI XIE
• LI TING
• ZHANG ZHUO

Assignees

• 华东理工大学

Dates

Publication Date

20260505

Application Date

20210310

Claims (1)

1. 1. Use of cytarabine and valnemulin in the preparation of a medicament for treating B-cell acute lymphoblastic leukemia.

Description

Cancer therapeutic target and uses thereof Technical Field The invention belongs to the field of cancer treatment, relates to a cancer treatment target point and application thereof, and in particular relates to a novel method for treating B cell acute lymphoblastic leukemia evolution and chemotherapy drug resistance. Background B-cell acute lymphoblastic leukemia (B-ALL) is a serious malignant hematopoietic disease that can cause clonal expansion of hematopoietic stem/progenitor cells, commonly seen in childhood/adolescents. Several treatment regimens have been shown to achieve efficacy in the treatment of B-ALL, including chemotherapy, bone marrow transplantation, CAR-T therapy. However, in the case of CAR-T treatment, the effectiveness of current strategies is hampered by resistance, lack of MHC matched donor HSC sources, patient anergy, or induced toxicity. Although chemotherapy is considered one of the most effective methods of treating B-ALL, 20% of patients relapse after treatment with cytarabine (Ara-C), anthracyclines or other chemotherapeutic agents. There is growing evidence that a small fraction of leukemic cells, known as Leukemic Initiating Cells (LICs), may lead to drug resistance or leukemia recurrence. For example, the immunophenotype CD34+CD19+LICs may be closely related to leukemia progression and drug resistance in human B-ALL. However, the mechanism leading to chemotherapy resistance remains unclear. In recent years, metabolism has been found to play a key role in the development and progression of many different types of cancer, including hematological tumors and solid cancers. For example, mutations in isocitrate dehydrogenase 1/2 (IDH 1/2) are effective in eliciting a variety of cancers, such as acute myelogenous leukemia, glioblastoma, and colon cancer. Acute/chronic myeloid leukemia mainly uses glycolysis as an energy source, fructose metabolism enhances the proliferation of Ph+ -B-ALL cells, and fasted food can effectively induce the early and late B-ALL differentiation of diseases. However, it is unclear whether cellular metabolism and resistance develop in B-ALL. Currently, resistance of B-ALL cells is thought to be caused by changes in many endogenous factors (e.g., transcription factors or epigenetic modifications) and exogenous factors (e.g., tissue microenvironment). For example, mutations in the transcription factor IKZF1 lead to a significant decrease in B-ALL cell sensitivity to tyrosine inhibitor therapy, and down-regulation of TWIST2 also leads to resistance to the chemotherapeutic drugs etoposide, daunorubicin and dexamethasone. Furthermore, the Bone Marrow (BM) microenvironment has been found to play a key role in the development of leukemia and chemotherapy resistance. The remodeled leukemia microenvironment may comprise different types of cells (e.g., endothelial cells, osteoblasts, and mesenchymal stem cells) and their secreted proteins/cytokines/growth factors (e.g., SDF1, IL3, IL6, and hyaluronic acid), which may be different from those secreted under physiological conditions to enhance the distension or chemotherapy resistance of the leukemia cells. Although most recent studies have focused on the microenvironment components during the development and drug resistance of Acute Myeloid Leukemia (AML), some evidence suggests that microenvironment factors also support the initiation and drug resistance of B-ALL. For example, GDF15 secreted by nestin+ cells remodels the BM microenvironment after Ara-C treatment and results in chemotherapy resistance. However, which specific cellular metabolic pathways lead to resistance of B-ALL cells remains to be studied further. There remains a need in the art for mechanisms and therapeutic targets for Ara-C resistance, and methods for efficiently screening therapeutic target drugs. Disclosure of Invention The present invention provides in a first aspect the use of an inhibitor of mitochondrial metabolism in the manufacture of a medicament for the treatment of cancer. In one or more embodiments, the cancer is a cancer in which the tricarboxylic acid cycle (TCA) or Electron Transport Chain (ETC) is enhanced. In one or more embodiments, the cancer is a cancer in which PDHX and/or CREB expression or activity is increased. In one or more embodiments, the cancer is leukemia, including but not limited to lymphoblastic leukemia, myelogenous leukemia, mixed-cell leukemia. In one or more embodiments, the cancer is a B-cell acute lymphoblastic leukemia, preferably a B-cell acute lymphoblastic leukemia in which expression or activity of PDHX and/or CREB is increased. In one or more embodiments, the mitochondrial metabolism inhibitor includes an agent that attenuates the tricarboxylic acid cycle (TCA) or the Electron Transport Chain (ETC). In one or more embodiments, the mitochondrial metabolism inhibitor includes an agent that down-regulates the expression or activity of PDHX and/or CREB. In one or more embodiments, the agent that down regul