Mayo Clinic laboratory and pathology research roundup: November 9
The research roundup provides an overview of the past week’s research from Mayo Clinic Laboratories consultants, including featured abstracts and a complete list of published studies and reviews.
CRM1 Inhibitor Anti-Tumor Activity is Enhanced with Salicylates by S-Phase Arrest and Impaired DNA-Damage Repair.
Chromosome region maintenance protein1 (CRM1) mediates protein export from the nucleus and is a new target for anti-cancer therapeutics. Broader application of KPT-330 (selinexor), a first in class CRM1 inhibitor recently approved for relapsed multiple myeloma and diffuse large B-cell lymphoma, have been limited by substantial toxicity. We discovered that salicylates markedly enhance the anti-tumor activity of CRM1 inhibitors by extending the mechanisms of action beyond CRM1 inhibition. Using salicylates in combination enables targeting of a range of blood cancers with a much lower dose of selinexor, thereby potentially mitigating prohibitive clinical adverse effects. Choline salicylate (CS) with low-dose KPT-330 (K+CS) had potent, broad activity across high-risk hematological malignancies and solid organ cancers ex vivo and in vivo. The K+CS combination was not toxic to non-malignant cells as compared to malignant cells and was safe without inducing toxicity to normal organs in mice. Mechanistically, compared to KPT-330 alone, K+CS suppresses the expression of CRM1, Rad51 and thymidylate synthase proteins, leading to more efficient inhibition of CRM1-mediated nuclear export, impairment of DNA-damage repair, reduced pyrimidine synthesis, cell cycle arrest in S-phase, and cell apoptosis. Moreover, the addition of PARP inhibitors further potentiates the K+CS anti-tumor effect. K+CS represents a new class of therapy for multiple types of blood cancers and will stimulate future investigations to exploit DNA-damage repair and nucleocytoplasmic transport for cancer therapy in general. Via Blood
Published to PubMed This Week
- Racial and Ethnic Differences in Multigene Hereditary Cancer Panel Test Results for Women with Breast Cancer.
Journal of the National Cancer Institution
- Th17-Inducing Autologous Dendritic Cell Vaccination Promotes Antigen-Specific Cellular and Humoral Immunity in Ovarian Cancer Patients.
- Return-to-Play Guidelines for Athletes After COVID-19 Infection.
- Impact of Integrated Translational Research on Clinical Exome Sequencing.
- Functional Analysis of Low-Grade Glioma Genetic Variants Predicts Key Target Genes and Transcription Factors.
Neurology and Oncology
- Mechanisms of Vascular Dysfunction in the Interleukin-10-Deficient Murine Model of Preeclampsia Indicate Nitric Oxide Dysregulation.
- Is It Time to Remove Total Calcium from the Basic and Comprehensive Metabolic Panels? Assessing the Effects of American Medical Association-Approved Chemical Test Panels on Laboratory Utilization.
- Executive Summary of the American Radium Society Appropriate Use Criteria for Radiation Treatment of Node-Negative Muscle Invasive Bladder Cancer.
International Journal of Radiology, Oncology, Biology, and Physics
- Germline Genetic Testing in Breast Cancer: Rationale for the Testing of all Women Diagnosed by the Age of 60 Years and for Risk-Based Testing of those Older than 60 Years.
- Challenges and Controversies to Testing for COVID-19.
Journal of Clinical Microbiology