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    Home > Biochemistry News > Biotechnology News > The latest review of nature: targeting cancer stem cells, setting off the upsurge of research and development of anticancer drugs

    The latest review of nature: targeting cancer stem cells, setting off the upsurge of research and development of anticancer drugs

    • Last Update: 2020-06-19
    • Source: Internet
    • Author: User
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    Cancer stem cells (CSCs) < br / > are also known as tumor initiating cellsThey are a small subset of cancer cells, with enhanced self-renewal, metastasis, diffusion and resistance to treatmentThey were first found in acute myeloid leukemia (AML)After that, the assumed cancer stem cells were also isolated from other blood malignancies and various types of solid tumors, < br / > plays an important role in the occurrence, recurrence and metastasis of tumor< br / > at present, it is not clear which kind of cells the cancer stem cells originated fromOne hypothesis is that the cancer stem cells originated from the non stem cells with higher differentiation degreeAfter transformation, the cancer stem cells mainly obtained the stem cell like characteristics after the epithelial mesenchymal transformation (EMT: the process of epithelial cells transforming to the mesenchymal cell phenotype under specific physiological or pathological conditions); the other hypothesis is that, Cancer stem cells originate from non malignant stem cells, which are transformed into cancer stem cells by tumorigenic cell mutationIn addition, some studies have shown that inflammation, especially inflammatory cytokines (such as interferon, tumor necrosis factor, IL-6 and IL-17), may play a role in inducing cancer stem cell status< br / > at present, it is still a challenge to isolate and identify cancer stem cells, because tumors contain a variety of cell groups, and cancer stem cells account for only a small part (usually less than 1% in solid tumors)In addition, although CD133, CD44 and other cell surface markers, epithelial cell adhesion molecules and aldehyde dehydrogenase activity have shown value in identifying cancer stem cells, it is still difficult to distinguish non cancer stem cells from real cancer stem cells, because these markers are not unique to cancer stem cells, And not all cancer stem cells in tumors express these typical markers< br / > in terms of clinical relevance, research has confirmed that cancer stem cells have natural resistance to chemotherapy and radiotherapyIn addition, inhibition of the phenotypic transformation of differentiated cancer cells (i.e., non cancer stem cells) induced by treatment or microenvironment into cancer stem cells is considered to be a key challenge for tumor eradicationAt present, notch, Wnt, hedgehog (Hh) and hippo pathways are the main targets of cancer stem cell therapy< br / > knowledge card: developmental signaling pathways including notch, Wnt, hedgehog (Hh) and hippo are often changed in cancer stem cells, and these pathways do have key regulatory functions to support the maintenance and survival of cancer stem cells< br / > theoretically, targeting cancer stem cells with natural drug resistance with new drugs has the potential to reduce the recurrence rate of cancer and improve the therapeutic effect of cancerBased on the deepening understanding of cancer stem cell biology, a variety of new therapeutic approaches targeting cancer stem cells have been developed and put into clinical testing, of which a few have been approved by the regulatory authoritiesIn addition, some "old drugs" (such as HER2 targeted drugs and CDK4 / 6 inhibitors) that have been approved for treatment of different cancers also show potential activity against cancer stem cells < br / > picture source: nature reviews clinical oncology < br / > on December 2, four scientists from NIH and other institutions in the United States published the latest review entitled "targeting signaling pathways and the immune micro environment of cancer stem cells-a clinical update" on nature reviews clinical oncology, This paper systematically summarizes the clinical development of targeted notch, Wnt, hedgehog and hippo pathways At the same time, the paper also discusses the interaction between cancer stem cells and immune system, and summarizes the new immunotherapy targeting cancer stem cells < br / > first, the Notch signaling pathway is a highly conserved cell fate determining pathway Its function involves many aspects of cancer biology, including the phenotype, angiogenesis, metastasis and tumor immune escape of cancer stem cells The gene change (mutation) of Notch pathway was first seen in T cell acute lymphoblastic leukemia (T-ALL) After that, abnormal Notch signal was found in many types of cancer Interestingly, the pathogenicity of the Notch pathway seems to depend on the type of tumor In T-ALL and most solid tumors, the abnormal activation of Notch signal promotes tumor development However, in myeloid malignancies, this pathway has been found to be tumor suppressive (in AML, the Notch signaling pathway is usually down regulated) < br / > Figure 1 Classic Notch signaling pathway and related in-depth anticancer inhibitors (picture source: Nature Reviews Clinical Oncology) < br / > drug research and development < br / > due to the complexity of Notch signaling pathway, if you want to successfully develop a therapy targeting this pathway, you must have a precise understanding of its mechanism in specific cancer At present, scientists have developed a variety of Notch pathway inhibitors with different targets and mechanisms of action, and various drugs are in different stages of clinical development (Table 1) γ - secretase inhibitors (GSIS, such as mrk-003, pf-03084014, bms-906024) are the largest class of drugs, showing strong antitumor activity in preclinical models The clinical investigation of γ - secretase inhibitors such as pf-03084014, bms-906024 and mk-0752 also obtained good results < br / > using monoclonal antibodies to target notch ligands is another strategy to inhibit abnormal Notch signals, such as DLL antibody demcizumab In addition, other teams have developed antibodies targeting Notch receptors, such as bronticuzumab, a monoclonal antibody against Notch 1, and tarextumab, an all human IgG2 antibody targeting both notch 2 and Notch 3 < br / > Table 1 the clinical trial results of the drugs in research targeting the Notch signaling pathway < br / > data source: nature reviews clinical oncology < br / > 2 The Wnt signaling cascade targeting the Notch signaling pathway is composed of three main pathways: 1) classical (β - Catenin dependent) Wnt pathway, which is related to the activation of a transcriptional reverse activation complex, The complex includes β - Catenin, T cell specific transcription factor (TCF) and lymphoid enhancer binding factor (LEF); 2) nonclassical (β - Catenin independent) planar cell polarity pathway, which is involved in the regulation of cytoskeleton; 3) nonclassical Wnt calcium pathway, This pathway is involved in the regulation of intracellular calcium level < br / > Fig 2 the function of Wnt signaling pathway and related anticancer inhibitors in research (picture source: Nature Reviews Clinical Oncology) < br / > is significantly related to cancer, and Wnt signaling disorder plays an important role in the tumorigenesis of various cancers For example, Wnt signaling pathway is up-regulated in most colorectal cancer (CRC), which is most often attributed to the loss of APC (about 50% of colorectal cancer will have APC mutation) In addition, abnormal Wnt pathway activation (due to overexpression of classical Wnt receptors and ligands) is also present in about half of basal breast cancers and is associated with poor treatment outcomes Wnt signaling disorder also plays an important role in cancer such as acute myeloid leukemia (AML), multiple myeloma (mm), chronic myeloid leukemia (CML), T-ALL, and chronic lymphocytic leukemia (CLL) Therefore, the drugs that inhibit this pathway have attractive anticancer potential < br / > pharmacological antagonists of Wnt pathway can be divided into four categories: 1) drugs targeting transmembrane proteins or ligands in Wnt signaling pathway, including monoclonal antibodies (such as dkn-01, vantictuab, circtuzumab), ADC, small molecules and other types; 2) porcupine inhibitors that interfere with Wnt ligand processing and secretion, For example, wnt974 and etc-1922159; 3) drugs that activate caspases or inhibit tankyrase can promote β - Catenin degradation, such as cwp232291; 4) downstream β - catenin-tcf-lef-dependent transcription inhibitors At present, all of these drugs are candidates for clinical testing (Table 2) < br / > Table 2 results of clinical trials of drugs under development targeting Wnt signaling pathway < br / > data source: nature reviews clinical oncology < br / > 3 Targeting hedgehog (Hh) signaling pathway < br / > Hh signaling pathway plays an important role in the development of embryos The abnormal activity of this pathway in adult tissues has been confirmed to be related to a variety of solid tumors, Such as basal cell carcinoma of skin and Shh subtype of medulloblastoma HH ligand secreting cells can process and release a variety of HH isoforms, including sonic hedgehog (Shh), Indian hedgehog and desert hedgehog These HH isoforms mainly bind to the transmembrane receptors patched 1 (PTCH1) and ptch2 in a paracrine manner, thus inhibiting their inhibitory activity on another transmembrane egg white smoothed (SMO) (Fig 3) Subsequently, this signaling cascade leads to the activation and nuclear localization of Gli transcription factors, which drive the expression of Hh target genes Most of the target genes are related to cell proliferation, survival and angiogenesis < br / > Figure 3 The classical hedgehog signaling pathway and the related in-situ inhibitors for anticancer therapy (picture source: Nature Reviews Clinical Oncology) < br / > abnormal Hh signaling are also related to the maintenance and expansion of leukemia stem cells (LSCs) in a variety of hematologic malignancies For example, abnormal Hh signals have been identified in myeloid LSCs, and the increased expression of Hh pathway components is related to the resistance of AML cell lines to chemotherapy Hh signal is also activated in chronic myeloid leukemia (CML), which promotes the amplification of bcr-abl1-positive LSCs, so it is related to the progress of CML Other hematologic malignancies associated with Hh signal include multiple myeloma (mm), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma, etc < br / > drug research and development < br / > at present, drugs targeting Hh pathway have been approved for marketing, but it is still a hot research field to investigate the potential of such drugs in the treatment of blood tumors and solid tumors The three main targets of Hh pathway antagonists are HH ligands, SMO and Gli transcription factors (Figure 3) The latter two types of drugs have been verified in clinical trials (Table 3) < br / > in 2012, 2015 and 2018, the U.S FDA approved three kinds of SMO inhibitors, vismodegib and sonidegib for the treatment of basal cell carcinoma, glasdegib for the treatment of acute myeloid leukemia (AML) < br / > targeting Gli transcription factors is also an attractive therapeutic option, because the downstream effectors of these HH pathways can induce the up regulation of genes involved in cell proliferation and survival, but they are not dependent on the classical Hh pathway Drugs targeting Gli transcriptional activity (such as gant58, gant61, pirfenidone) are designed to overcome the resistance of tumors to SMO inhibitors Preclinical studies have provided evidence for the antitumor activity of these drugs, in particular the role of gant61 in models of HCC, NSCLC, rhabdomyosarcoma and pancreatic cancer, ovarian cancer and breast cancer Gant61 and gant58 have also been shown to reduce Gli1 mediated transcription and inhibit cell proliferation in HH activated xenotransplantation of pancreatic cancer mice It has also been shown that gant58 can reduce the viability of T-ALL cells by reducing the expression of Gli1 and PTCH1 At present, however, there is no active clinical trial of these drugs < br / > it is worth mentioning that as 2O 3 (ATO) approved by FDA for the treatment of acute promyelocytic leukemia is also an effective inhibitor of Gli1 and Gli2 In preclinical studies, ATO can bind to Gli1 and inhibit its transcriptional activity, thus reducing the expression of Gli1 target gene At present, many trials are investigating ATO monotherapy or combined standard therapy in patients with blood or solid malignancies.
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