MDM2- an indispensable player in tumorigenesis

Zafar, Asim; Khan, Muhammad Jawad; Naeem, Ayesha

doi:10.1007/s11033-023-08512-3

Cited by 11 publications

(3 citation statements)

References 120 publications

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“…MDM2 is renowned for its pivotal role in regulating cellular growth, apoptosis, DNA repair, and metastasis in cancer cells ( Oliner et al, 2016 ; Shaikh et al, 2016 ; Zafar et al, 2023 ). However, it has recently garnered attention for its involvement in cancer metabolism, further emphasizing the diversity of its biologic roles in cancer.…”

Section: The Rationale For Targeting Mdm2 For Molecular Targeted Therapymentioning

confidence: 99%

MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future

Wang,

Albadari,

et al. 2024

Pharmacol Rev

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Since its discovery over 35 years ago, MDM2 has emerged as an attractive target for the development of cancer therapy. MDM2's activities extend from carcinogenesis to immunity to the response to various cancer therapies. Since the report of the first MDM2 inhibitor more than 30 years ago, various approaches to inhibit MDM2 have been attempted, with hundreds of small-molecule inhibitors evaluated in preclinical studies and numerous molecules tested in clinical trials. Although many MDM2 inhibitors and degraders have been evaluated in clinical trials, there is currently no Food and Drug Administration (FDA)-approved MDM2 inhibitor on the market. Nevertheless, there are several current clinical trials of promising agents that may overcome the past failures, including agents granted FDA orphan drug or fast-track status. We herein summarize the research efforts to discover and develop MDM2 inhibitors, focusing on those that induce MDM2 degradation and exert anticancer activity, regardless of the p53 status of the cancer. We also describe how preclinical and clinical investigations have moved toward combining MDM2 inhibitors with other agents, including immune checkpoint inhibitors. Finally, we discuss the current challenges and future directions to accelerate the clinical application of MDM2 inhibitors. In conclusion, targeting MDM2 remains a promising treatment approach, and targeting MDM2 for protein degradation represents a novel strategy to downregulate MDM2 without the side effects of the existing agents blocking p53-MDM2 binding. Additional preclinical and clinical investigations are needed to finally realize the full potential of MDM2 inhibition in treating cancer and other chronic diseases where MDM2 has been implicated. Significance Statement Overexpression/amplification of the MDM2 oncogene has been detected in various human cancers and is associated with disease progression, treatment resistance, and poor patient outcomes. This article reviews the previous, current, and emerging MDM2-targeted therapies and summarizes the preclinical and clinical studies combining MDM2 inhibitors with chemotherapy and immunotherapy regimens. The findings of these contemporary studies may lead to safer and more effective treatments for patients with cancers overexpressing MDM2.

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Section: The Rationale For Targeting Mdm2 For Molecular Targeted Therapymentioning

confidence: 99%

MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future

Wang,

Albadari,

et al. 2024

Pharmacol Rev

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“…Vascular endothelial growth factor (VEGFA), a key protein in tumor angiogenesis [31], is a critical downstream target of HIF1α signaling and plays an important role in tumor invasion and metastasis [32]. Mouse double minute 2 homolog (MDM2), an E3 ubiquitin-protein ligase, is a negative regulator of p53 and promotes cell growth, angiogenesis, metabolic reprogramming, metastasis, and immune suppression [33]. Breast cancer type 1 susceptibility protein (BRCA1), a tumor suppressor gene commonly mutated in breast and ovarian cancer, plays a critical role in maintaining genomic integrity [34].…”

Section: Validation Of Downregulated Genes Upon Iso Treatment In T24 ...mentioning

confidence: 99%

Transcriptome Analysis Reveals Anti-Cancer Effects of Isorhapontigenin (ISO) on Highly Invasive Human T24 Bladder Cancer Cells

Li,

Park,

et al. 2024

IJMS

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Bladder cancer, the most common malignancy of the urinary tract, has a poor overall survival rate when the tumor becomes muscle invasive. The discovery and evaluation of new alternative medications targeting high-grade muscle invasive bladder cancer (MIBC) are of tremendous importance in reducing bladder cancer mortality. Isorhapontigenin (ISO), a stilbene derivative from the Chinese herb Gnetum cleistostachyum, exhibits a strong anti-cancer effect on MIBCs. Here, we report the whole transcriptome profiling of ISO-treated human bladder cancer T24 cells. A total of 1047 differentially expressed genes (DEGs) were identified, including 596 downregulated and 451 upregulated genes. Functional annotation and pathway analysis revealed that ISO treatment induced massive changes in gene expression associated with cell movement, migration, invasion, metabolism, proliferation, and angiogenesis. Additionally, ISO treatment-activated genes involved in the inflammatory response but repressed genes involved in hypoxia signaling, glycolysis, the actin cytoskeleton, and the tumor microenvironment. In summary, our whole transcriptome analysis demonstrated a shift in metabolism and altered actin cytoskeleton in ISO-treated T24 cells, which subsequently contribute to tumor microenvironment remodeling that suppresses tumor growth and progression.

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“…MDM2 (Murine double minute 2) is widely known for its significant contributions to cancer development, including promoting sustained angiogenesis, metabolic reprogramming, growth stimulation, apoptosis evasion, metastasis, and immunosuppression. Genetic variation in MDM2 promotes its increased expression levels, which leads to uncontrolled proliferation in many cancer types [ 146 ].…”

Section: Panel Of Genes For Screeningmentioning

confidence: 99%

Genomic Newborn Screening for Pediatric Cancer Predisposition Syndromes: A Holistic Approach

Linga,

Mohammed,

Farrell

et al. 2024

Cancers

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As next-generation sequencing (NGS) has become more widely used, germline and rare genetic variations responsible for inherited illnesses, including cancer predisposition syndromes (CPSs) that account for up to 10% of childhood malignancies, have been found. The CPSs are a group of germline genetic disorders that have been identified as risk factors for pediatric cancer development. Excluding a few “classic” CPSs, there is no agreement regarding when and how to conduct germline genetic diagnostic studies in children with cancer due to the constant evolution of knowledge in NGS technologies. Various clinical screening tools have been suggested to aid in the identification of individuals who are at greater risk, using diverse strategies and with varied outcomes. We present here an overview of the primary clinical and molecular characteristics of various CPSs and summarize the existing clinical genomics data on the prevalence of CPSs in pediatric cancer patients. Additionally, we discuss several ethical issues, challenges, limitations, cost-effectiveness, and integration of genomic newborn screening for CPSs into a healthcare system. Furthermore, we assess the effectiveness of commonly utilized decision-support tools in identifying patients who may benefit from genetic counseling and/or direct genetic testing. This investigation highlights a tailored and systematic approach utilizing medical newborn screening tools such as the genome sequencing of high-risk newborns for CPSs, which could be a practical and cost-effective strategy in pediatric cancer care.

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MDM2- an indispensable player in tumorigenesis

Cited by 11 publications

References 120 publications

MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future

MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future

Transcriptome Analysis Reveals Anti-Cancer Effects of Isorhapontigenin (ISO) on Highly Invasive Human T24 Bladder Cancer Cells

Genomic Newborn Screening for Pediatric Cancer Predisposition Syndromes: A Holistic Approach

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