MDM4 is a homologue of MDM2, serving cooperatively as the negative regulator of tumor suppressor p53. Under the shadow of MDM2 inhibitors, limited efforts had been put into the discovery of MDM4 modulators. Recent studies of the experimental drug ALRN-6924, a dual MDM4 and MDM2 inhibitor, suggest that concurrent inhibition of MDM4 and MDM2 might be beneficial over only MDM2 inhibition. In view of the present research progress, we summarized published inhibitors of MDM4/p53 interactions including both peptide-based compounds and small molecules. Cocrystal structures of ligand/MDM4 complexes have been examined, and their structural features were compiled and compared in order to show the molecular basis required for high MDM4 binding affinities. Representative examples of small-molecule MDM4 inhibitors were discussed, followed by clinical results of ALRN-6924, together, providing a consolidated reference for further development of MDM4 inhibitors, either dual or selective.

Recent Progress and Clinical Development of Inhibitors that Block MDM4/p53 Protein–Protein Interactions

Doxorubicin is widely used in the treatment of different cancers, and its side effects can be severe in many tissues, including the intestines. Symptoms such as diarrhoea and abdominal pain caused by intestinal inflammation lead to the interruption of chemotherapy. Nevertheless, the molecular mechanisms associated with doxorubicin intestinal toxicity have been poorly explored. This study aims to investigate such mechanisms by exposing 3D small intestine and colon organoids to doxorubicin and to evaluate transcriptomic responses in relation to viability and apoptosis as physiological endpoints. The in vitro concentrations and dosing regimens of doxorubicin were selected based on physiologically based pharmacokinetic model simulations of treatment regimens recommended for cancer patients. Cytotoxicity and cell morphology were evaluated as well as gene expression and biological pathways affected by doxorubicin. In both types of organoids, cell cycle, the p53 signalling pathway, and oxidative stress were the most affected pathways. However, significant differences between colon and SI organoids were evident, particularly in essential metabolic pathways. Short time-series expression miner was used to further explore temporal changes in gene profiles, which identified distinct tissue responses. Finally, in silico proteomics revealed important proteins involved in doxorubicin metabolism and cellular processes that were in line with the transcriptomic responses, including cell cycle and senescence, transport of molecules, and mitochondria impairment. This study provides new insight into doxorubicin-induced effects on the gene expression levels in the intestines. Currently, we are exploring the potential use of these data in establishing quantitative systems toxicology models for the prediction of drug-induced gastrointestinal toxicity.

/pdf/unravelling-mechanisms-of-doxorubicin-induced-toxicity-in-3d-147ybezd.pdf

Unravelling Mechanisms of Doxorubicin-Induced Toxicity in 3D Human Intestinal Organoids

Hepatoblastomas with carcinoma features represent a biological spectrum of aggressive neoplasms in children and young adults

Malignant hepatocellular cancers are the most common primary liver malignancies in children, and hepatoblastomas (HBs) account for more than two-thirds of these cases. While most HBs respond to chemotherapy and have favorable outcomes, the 3-year overall survival rate for high-risk HBs is below 50% and guidelines for their classification and treatment are still evolving. HB risk-stratification efforts using clinical, histological, and molecular parameters have been reported to help identify patients that require more or less aggressive therapies in retrospective studies, and are being validated in clinical trials. However, risk assessment is particularly challenging for cancers with certain histologies, including tumors in the recently proposed provisional hepatocellular neoplasm not otherwise specified (HCN NOS) category. HCN NOSs exhibit either intermediate or combined HB and hepatocellular carcinoma (HCC) histological features, and while neoplasms with such features were observed over a decade ago, only a handful have been characterized and little is known about their biology and clinical features. Here, we molecularly characterized a series of clinically annotated HCN NOSs that demonstrated either intermediate HB/HCC histology or distinct coexisting areas with HB and HCC histological features. In addition, molecular profiling of HBs demonstrating focal pleomorphism or anaplasia (HB FPA) after chemotherapy revealed underlying biological features previously observed in HCCs. Our study suggested that HCN NOSs and HB FPAs are aggressive tumors, irrespective of patient age or resectability. Consequently, we designated them collectively as HBs with carcinoma features (HBCs) and outlined histological and molecular characteristics for their diagnosis and treatment. In our single-institution study, transplanted HBC patients were significantly and more than twice as likely to have good outcomes, highlighting the importance of molecular testing and aggressive early intervention.

https://www.biorxiv.org/content/biorxiv/early/2021/07/16/2021.07.15.445600.full.pdf

Hepatoblastomas with carcinoma features (HBCs) represent a biological spectrum of aggressive neoplasms in children and young adults

Approximately 90% of pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC). PDAC is the fourth leading cause of cancer death world-wide. Therapies for PDAC are largely ineffective due to the dense desmoplastic tumor microenvironment which prevents chemotherapeutic drugs and small molecule inhibitors from exerting effective anti-cancer effects. In this review, we will discuss the roles of TP53 and miRs on the PDAC tumor microenvironment and how loss of the normal functions of TP53 promote tumor progression. The TP53 gene is mutated in approximately 50% of pancreatic cancers. Often, these TP53 mutations are point mutations which confer additional functions for the TP53 proteins. These are called gain of function (GOF) mutations (mut). Another class of TP53 mutations are deletions which result in loss of the TP53 protein; these are referred to TP53-null mutations. We have organized this review into various components/properties of the PDAC microenvironment and how they may be altered in the presence of mutant TP53 and loss of certain miR expression.

/pdf/effects-of-tp53-mutations-and-mirs-on-immune-responses-in-flklz2ni.pdf

Effects of TP53 Mutations and miRs on Immune Responses in the Tumor Microenvironment Important in Pancreatic Cancer Progression

Hepatoblastoma (HB) is the most common pediatric liver malignancy High-risk patients have poor survival, and current chemotherapies are associated with significant toxicities Targeted therapies are needed to improve outcomes and patient quality of life Most HB cases are TP53 wild-type; therefore, we hypothesized that targeting the p53 regulator Murine double minute 4 (MDM4) to reactivate p53 signaling may show efficacy MDM4 expression was elevated in HB patient samples, and increased expression was strongly correlated with decreased expression of p53 target genes Treatment with NSC207895 (XI-006), which inhibits MDM4 expression, or ATSP-7041, a stapled peptide dual inhibitor of MDM2 and MDM4, showed significant cytotoxic and antiproliferative effects in HB cells Similar phenotypes were seen with short hairpin RNA (shRNA)-mediated inhibition of MDM4 Both NSC207895 and ATSP-7041 caused significant upregulation of p53 targets in HB cells Knocking-down TP53 with shRNA or overexpressing MDM4 led to resistance to NSC207895-mediated cytotoxicity, suggesting that this phenotype is dependent on the MDM4-p53 axis MDM4 inhibition also showed efficacy in a murine model of HB with significantly decreased tumor weight and increased apoptosis observed in the treatment group This study demonstrates that inhibition of MDM4 is efficacious in HB by upregulating p53 tumor suppressor signaling

/pdf/mdm4-inhibition-a-novel-therapeutic-strategy-to-reactivate-f7yo9goyls.pdf

D. Allen Annis

Papers

MDM4 inhibition: a novel therapeutic strategy to reactivate p53 in hepatoblastoma.