Unraveling BOLD‑100 synergistic potential in pleural mesothelioma treatment - an in vitro study

Sep 24, 2026

Uploaded by Aran

Pleural mesothelioma (PM) is a rare, long-latency asbestos-associated cancer with limited effectiveness of surgery and poor outcomes with standard systemic therapies. Chemotherapy and immune checkpoint inhibitor strategies have improved care for some subtypes, yet additional lines and globally available options remain insufficient. This in vitro study investigates BOLD-100, a GRP78-targeting ruthenium-based small molecule, by assessing cellular responses of multiple PM cell lines to regimens combining BOLD-100 with commonly used treatments. The work focuses on identifying synergistic therapeutic potential and underlying mechanisms involving GRP78 and apoptosis.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

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Summary

Introduction

Materials and methods

Investigational New Drugs (2025) 43:634–645 [https://doi.org/10.1007/s10637-025-01540-9](https://doi.org/10.1007/s10637-025-01540-9) Unraveling BOLD‑100 synergistic potential in pleural mesothelioma treatment: an in vitro study Gregorio Bonsignore1,2 · Elia Ranzato1,2 · Simona Martinotti1,2 Received: 8 January 2025 / Accepted: 21 April 2025 / Published online: 8 May 2025 © The Author(s) 2025 Summary Pleural mesothelioma (PM) is a rare cancer affecting the pleural layer on the body’s serosal surfaces. Exposure to asbestos fibers, a naturally occurring fibrous material with insulating characteristics, contributes to PM’s prevalence. PM has a long latency period, making major surgery ineffective and necessitating systemic treatment. Despite the progress of mesothelioma treatment, the median survival is very poor; so, there is a strong need to explore new therapeutic approaches. This study explores the use of BOLD-100, a novel therapeutic drug that targets GRP78, a protein overexpressed in PM cells. BOLD- 100, a ruthenium-based small molecule therapeutic drug, is being investigated for the treatment of advanced gastrointestinal malignancies in conjunction with chemotherapy. Our aim is to investigate cellular responses of several PM cell lines to a regimen that includes BOLD-100 in addition to other commonly used treatments. BOLD-100 is a ruthenium-based anticancer therapeutic. Keywords Chemotherapy · GRP78 · Mesothelioma · Synergy Introduction Pleural mesothelioma (PM) is an uncommon type of cancer that mostly affects the pleural layer on the body’s serosal surfaces. A group of naturally occurring fibrous materials with outstanding physical and electrochemical insulating characteristics and a long history of industrial usage, asbestos fibers, are the major cause of PM when exposed to them in the workplace or in the environment [1]. The long incubation period (20 to 50 years) between asbestos exposure and Elia Ranzato and Simona Martinotti have equal contribution. * Elia Ranzato[elia.ranzato@uniupo.it](elia.ranzato@uniupo.it) Gregorio Bonsignore [gregorio.bonsignore@uniupo.it](gregorio.bonsignore@uniupo.it) Simona Martinotti [simona.martinotti@uniupo.it](simona.martinotti@uniupo.it) 1 DiSIT-Dipartimento di Scienze e Innovazione Tecnologica, University of Piemonte Orientale, Viale Teresa Michel 11, 15121 Alessandria, Italy 2 Laboratorio Integrato di Ricerca Preclinica, AOU “SS Antonio E Biagio e Cesare Arrigo”, Via Venezia 16, 15121 Alessandria, Italy the development of the tumor contributes to the prevalence of PM, even though the material has been gradually banned from manufacturing and use in over 50 nations worldwide since the 1980 s [2] . PM is usually discovered at a locally advanced stage because of its lengthy latency period (20 to 50 years), which renders major surgery useless and calls for systemic treatment. For around 20 years, chemotherapy (such as gemcitabine) in combination with either carboplatin or cisplatin plus pemetrexed has been the only approved first-line treatment, despite its poor response outcomes and median overall survival that is just slightly more than 12 months [3] . No meaningful treatment advance had happened until the emergence of immunotherapy, specifically immune checkpoint inhibitors (ICIs) . The recent phase III trial Checkmate-743 found that the combination of two ICIs, ipilimumab and nivolumab, improved overall survival statistically significantly when compared to pemetrexed and platinum treatment (median overall survival (OS) of 18.1 versus 14.1 months, p = 0.002), especially for non-epithelioid subtypes [4] . So, chemotherapy with platinum compounds and pemetrexed remains the backbone of PM treatment. Immunotherapy with double immune checkpoint blockade is a major advance in PM treatment but it is not available in every country for every patient. And there is no standard option in PM patients in further line. Gemcitabine, vinorelbine and immunotherap

FAQs

Why is pleural mesothelioma difficult to treat effectively?

PM has a long latency period, so it is often discovered at locally advanced stages where major surgery is ineffective, requiring systemic therapy. Even with standard chemotherapy, median survival remains very poor.

What is BOLD-100 and what target does it engage?

BOLD-100 is a ruthenium-based anticancer small molecule designed to target GRP78, a protein overexpressed in PM cells. The study examines how this targeting affects PM cell responses and treatment synergy.

How is the study designed to evaluate treatment effects?

The study tests cellular responses of several PM cell lines to treatment regimens that include BOLD-100 alongside other commonly used therapies. It emphasizes GRP78-related mechanisms, including apoptosis through caspase activation and mitochondrial membrane instability.

Sep 24, 2026

Uploaded by Aran