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Cardiac Tumours
Published in Mary N. Sheppard, Practical Cardiovascular Pathology, 2022
PD-L1 is a key immune checkpoint protein that plays a significant role in sarcomagenesis. Upregulation of PD-L1 is associated with increased tumour aggressiveness. PD-L1+ sarcomas can be targeted with single-agent immunotherapy such as pembrolizumab. MDM2 is a proto-oncogene, which is one of the most frequently mutated genes in cardiac intimal sarcomas. Upregulation of MDM2 results in loss of p53-dependent activities, such as apoptosis and cell-cycle arrest. There are no established guidelines for chemotherapy targeting MDM2. Newer agents such as olaratumab, a monoclonal antibody that targets platelet-derived growth factor receptor (PDGFR)-α, combined with doxorubicin has limited data to show drug efficacy against soft-tissue sarcomas. Pazopanib, which has been used in metastatic non-adipocytic soft-tissue sarcomas, is a multi-kinase inhibitor that targets the tyrosine kinase activity of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and stem-cell factor receptor. Intimal sarcomas can have PDGF and VEGF expression. A case with a moderate to strong expression of PDGFR-α and -β presented a long-term stable disease when treated with pazopanib while a case with weak expression of PDGFR-α and -β did not respond. The level of PDGFR expression in the tumour tissue may therefore be predictive of pazopanib efficacy.28
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Idasanutlin (RG7388; RO5503781) is an orally available small-molecule MDMA inhibitor developed by Roche based on their nutlin family of agents. It binds to the MDM2 protein blocking interaction with p53, thus facilitating cell-cycle arrest and apoptosis, and slowing tumor growth. A Phase 1b study of idasanutlin in combination with ARA-C in AML patients showed a complete remission (CR) rate of 29% irrespective of TP53 mutation status. The prognosis for patients with relapsed or refractory AML is poor, with 3-year overall survival rates of ~10–30% after intensive chemotherapy-based therapies. Based on these encouraging Phase I results, RG7388 in combination with ARA-C is now being studied in a 440-patient double-blind, randomized Phase 3 trial (MIRROS), with encouraging interim results reported in 2019.
Tumor Growth
Published in John Melford, Pocket Guide to Cancer, 2017
A major barrier to uncontrolled cell division is triggering the death of cells with damaged DNA. There are mechanisms inside cells that continually monitor the integrity of DNA. Where possible, repairs are carried out, but failing that, once damage has accumulated beyond a certain point, cell death is triggered by apoptosis. Transforming cells need to find ways of cutting the wires that set off alarms that trigger cell death. This can be readily achieved by the inactivation of sensor proteins by mutations, a reduction in their levels of expression, or deactivating a protein named P53. Studies have shown the protein mdm2 negatively regulates p53 activity through the induction of its degradation. The role of p53 is illustrated in Figure 4.1.
The roles of TPL in hematological malignancies
Published in Hematology, 2023
Tingyun Xu, Yiwei Zhu, Shuaishuai Ge, Song-Bai Liu
Apoptosis is the main antitumor mechanism of TPL. Multiple signaling pathways and mechanisms are involved in mediating the proapoptotic effect of TPL (Figure 1). XIAP (X-linked inhibitor of apoptosis protein) is a natural intracellular caspase inhibitor and is highly expressed in a variety of leukemia cell lines and acute myelocytic leukemia (AML) blasts [10, 11]. TPL can induce caspase-dependent apoptosis in several AML cell lines and AML blasts by reducing the expression of XIAP and MCL-1 [12], and promoting cytochrome C release to upregulate caspase-dependent apoptotic pathways [13, 14]. The p53 signaling pathway is also involved in this process [15]. MDM2 is an intracellular negative regulator of p53. TPL induces AML cell apoptosis by reducing MDM2 expression to disrupt MDM2-p53 homeostasis [16], thereby promoting p53 activation and upregulating the expression of the downstream death receptor DR5 [17]. AML cells are relatively resistant to tumor necrosis factor α-related apoptosis-inducing ligand (TRAIL), which can be overcome by TPL by downregulating XIAP and activating the P53 signaling pathway [18, 19]. Therefore, TPL combined with TRAIL may achieve a better effect in treating AML.
Immunosuppressive tumor microenvironment modulation by chemotherapies and targeted therapies to enhance immunotherapy effectiveness
Published in OncoImmunology, 2022
Robby Barnestein, Loïck Galland, Laura Kalfeist, François Ghiringhelli, Sylvain Ladoire, Emeric Limagne
In order to potentiate anti-tumor immunity, it is also possible to target the cell cycle of tumors cells and apoptosis, with interesting effects on the TME. For example, the protein p53 is controlled by mouse double minute 2 homolog (MDM2), an ubiquitin E3 ligase, which regulates p53 levels and proteasomal degradation. The MDM2 protein is overexpressed in many cancers, causing disruption of the p53-MDM2 axis, and linked to tumorigenesis. It represents a novel target for cancer therapy. Several MDM2 antagonists have been developed, such as APG 115. This molecule can change the polarization of macrophages, in favor of an anti-tumor M1 phenotype state, and could activate CD4+ T cells. Furthermore, inhibiting MDM2 upregulates PD-L1 expression on tumor cells and may lead to high immunogenicity, confirmed by an improvement in the cytotoxic activity of CD8+ T cells when an anti PD-1 is added to APG 115.215
Akt Phosphorylation Orchestrates T11TS Mediated Cell Cycle Arrest in Glioma Cells
Published in Cancer Investigation, 2021
Sagar Acharya, Sirshendu Chatterjee, Suhnrita Chaudhuri, Manoj Kumar Singh, Debanjan Bhattacharya, Malabika Bhattacharjee, Anirban Ghosh, Swapna Chaudhuri
The Mdm2 gene is frequently over-expressed in many cancers. Figure 5(A) shows the flow cytometric analysis of Mdm2 protein. In ENU induced glioma, Mdm2 expression was significantly (p < .0001) elevated compared to normal. After 1st dose of T11TS, the Mdm2 level decreased considerably (p < .0001) compared to glioma. Mdm2 level further decreased well below (p < .0001) normal level after 2nd dose of T11TS, but with the 3rd dose, the level reverted to near normal. Similar results were obtained when Mdm2 levels were visualized by western blotting. Finally, protein loading was checked by re-probing the same membrane with an actin antibody (Figure 5(C)). Since ENU induction leads to a high level of Mdm2 production, the next aim of the study was to find out whether any functional binding with Akt occurred between Mdm2 and Akt. In that context, co-immunoprecipitation (Figure 5(C)) with Mdm2 and Akt revealed that in ENU induced glioma state, heightened binding of Mdm2 and Akt was observed. In addition, a considerable change in binding was observed in T11TS treated groups.