Censoring in trials testing immunotherapy in advanced cancers. A systematic review and a meta-research study.

Background: Informative censoring affects interpretation of trials results. We investigated censoring rates in randomized controlled trials (RCTs) of immune checkpoint inhibitors (ICIs).

Methods: We searched articles of RCTs testing ICIs in advanced cancers, published up to 12/2023.

A bedside-to-bench translational analysis of NF1 alterations and CDK4/6 inhibitor resistance in hormone receptor-positive metastatic breast cancer.

Background: CDK4/6 inhibitors (CDK4/6i) are used for management of hormone receptor-positive (HR+) metastatic breast cancer (MBC), and activation of the RAS/MAPK and PI3K/AKT signalling pathways has been implicated in resistance to these agents. Pathogenic NF1 mutations (pNF1m) dysregulate RAS signalling, but NF1 has not been linked to CDK4/6i resistance. We analysed multi-institutional data, real-world evidence, and preclinical models to characterise the impact of pNF1m on CDK4/6i sensitivity.

Nutritional bioactive compounds with beneficial effects for multiple sclerosis: Potential implication of G-Quadruplexes?

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease resulting in myelin destruction and consequent physical disability. Several nutritional molecules modulate genes of reported relevance in MS eliciting beneficial effects. Intriguingly, some of these molecules are able to bind G-Quadruplexes (G4), specific DNA secondary structures involved in the regulation of gene expression and function.

Plasmonic optical fiber biosensors for ultra-low detection of respiratory syncytial virus via point-of-care tests.

Respiratory syncytial virus (RSV) is a major cause of bronchiolitis and pneumonia, particularly in children, the elderly, and immunocompromised individuals. Despite significant health impacts, annual RSV-related hospitalizations may be underreported due to undertesting and limited diagnostic sensitivity. Point-of-care tests (POCTs) could enhance the rapid and accurate detection of RSV, enabling timely treatment and reducing hospitalizations.

AP1-mediated reprogramming of EGFR expression triggers resistance to BLU-667 and LOXO-292 in RET-rearranged tumors.

Background: Non-small cell lung cancer (NSCLC) is a significant global health challenge, with 2% of cases fuelled by RET rearrangements. RET inhibitors (RETi) have revolutionized treatment for these patients, but resistance remains an important clinical challenge limiting therapy effectiveness. This study investigated the mechanisms underlying resistance to RETi.

Selective degradation of FGFR1/2 overcomes antiestrogen resistance in ER+ breast cancer with FGFR1/2 alterations.

FGFR1 amplification and FGFR1/2 activating mutations have been associated with antiestrogen resistance in estrogen receptor-positive (ER+) breast cancer. However, there are no approved FGFR1-targeted therapies for breast cancers harboring these alterations. In this study, we investigated the selective degradation of FGFR1/2 using the proteolysis-targeting chimera (PROTAC) DGY-09-192 as a novel therapeutic strategy in ER + breast cancers harboring FGFR1/2 somatic alterations.

ESR1 Y537S and D538G Mutations Drive Resistance to CDK4/6 Inhibitors in Estrogen Receptor-Positive Breast Cancer.

Purpose: Breast cancers with ESR1 mutations are resistant to antiestrogen therapy. In this study, we aimed to investigate the association of ESR1 mutations with resistance to CDK4/6 inhibitors (CDK4/6i) using real-world data analysis and experimental validation.

Experimental Design: A total of 3,958 patients with estrogen receptor-positive metastatic breast cancer with DNA sequencing data were analyzed.

Early assessment of IL8 and PD1+ Treg predicts response and guides treatment monitoring in cemiplimab-treated cutaneous squamous cell carcinoma.

Purpose: Anti-programmed cell death 1 (PD1) is the first-choice treatment in patients with advanced cutaneous squamous cell carcinoma (cSCC), when curative options are unavailable. However, reliable biomarkers for patient selection are still lacking.

Experimental Design: In this translational study, clinical annotations, tissue and liquid biopsies were acquired to investigate the association between sustained objective responses and transcriptional profiles, immune cell dynamics in tumor tissue and peripheral blood samples, as well as circulating cytokine levels.

Repurposing FDA-approved drugs to target G-quadruplexes in breast cancer.

Breast cancer, a leading cause of cancer-related mortality in women, is characterized by genomic instability and aberrant gene expression, often influenced by noncanonical nucleic acid structures such as G-quadruplexes (G4s). These structures, commonly found in the promoter regions and 5'-untranslated RNA sequences of several oncogenes, play crucial roles in regulating transcription and translation. Stabilizing these G4 structures offers a promising therapeutic strategy for targeting key oncogenic pathways.

Blinded independent central review versus local investigator assessment of PFS in RCTs of immunotherapy in advanced cancers: A systematic review and meta-analysis.

Background: Assessment of Progression-free survival (PFS) events by investigators might be inaccurate in randomized controlled trials (RCTs) with open-label design. We explored differences in PFS evaluated by blinded independent central review (BICR) or local investigator assessment (IA) in trials testing immunotherapy (IO) in advanced cancers.

Methods: We systematically reviewed articles of RCTs investigating IO in advanced tumors, published in PubMed-indexed journals up to December 2023.

Mapping cellular interactions from spatially resolved transcriptomics data.

Cell-cell communication (CCC) is essential to how life forms and functions. However, accurate, high-throughput mapping of how expression of all genes in one cell affects expression of all genes in another cell is made possible only recently through the introduction of spatially resolved transcriptomics (SRT) technologies, especially those that achieve single-cell resolution. Nevertheless, substantial challenges remain to analyze such highly complex data properly.

Mesothelioma-Associated Fibroblasts Modulate the Response of Mesothelioma Patient-Derived Organoids to Chemotherapy via Interleukin-6.

Malignant pleural mesothelioma (MPM) remains an incurable disease. This is partly due to the lack of experimental models that fully recapitulate the complexity and heterogeneity of MPM, a major challenge for therapeutic management of the disease. In addition, the contribution of the MPM microenvironment is relevant for the adaptive response to therapy.

EGFR and HER2 hyper-activation mediates resistance to endocrine therapy and CDK4/6 inhibitors in ER+ breast cancer.

In patients with ER + metastatic breast cancer (mBC), the first-line treatment involves the combination of endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i). However, a significant group of patients experiences disease progression, emphasizing the urgent clinical need to identify novel anti-tumor therapies. We previously generated breast cancer cells resistant to the combination of fulvestrant (ER downregulator) and abemaciclib (CDK4/6 inhibitor) from MCF7 and T47D (MCF7-FAR and T47D-FAR).

PRMT5 is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancer.

CDK4/6 inhibitors (CDK4/6i) have improved survival of patients with estrogen receptor-positive (ER+) breast cancer. However, patients treated with CDK4/6i eventually develop drug resistance and progress. RB1 loss-of-function alterations confer resistance to CDK4/6i, but the optimal therapy for these patients is unclear.

Analysis of Health-Related Quality of Life Reporting in Phase III RCTs of Advanced Genitourinary Tumors.

Background: As recommended in the European Society for Medical Oncology (ESMO) guidelines, assessment of health-related quality of life (HRQoL) should be a relevant endpoint in randomized controlled trials (RCTs) testing new anticancer therapies. However, previous publications by our group and others revealed a frequent underestimation and underreporting of HRQoL results in publication of RCTs in oncology. Herein, we systematically reviewed HRQoL reporting in RCTs testing new treatments in advanced prostate, kidney and urothelial cancers and published between 2010 and 2022.

Combined blockade of mTOR and p21-activated kinases pathways prevents tumour growth in KRAS-mutated colorectal cancer.

Background: The identification of novel therapeutic strategies for metastatic colorectal cancer (mCRC) patients harbouring KRAS mutations represents an unmet clinical need. In this study, we aimed to clarify the role of p21-activated kinases (Paks) as therapeutic target for KRAS-mutated CRC.

Methods: Paks expression and activation levels were evaluated in a cohort of KRAS-WT or -mutated CRC patients by immunohistochemistry.

Toxicity profile of antibody-drug conjugates in breast cancer: practical considerations.

Antibody-drug conjugates (ADCs) represent a novel and evolving class of antineoplastic agents, constituted by monoclonal antibody linked to biologically active drugs, delivering cytotoxic compounds at the tumor site, reducing the likelihood of systemic exposure and toxicity. They are generally well tolerated, nevertheless some predictable adverse reactions need careful monitoring and timely approach. These include neutropenia, nausea and vomiting, alopecia, diarrhea, left ventricular dysfunction, ILD/pneumonitis.

Protein arginine methyltransferase 5 (PRMT5) is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancer.

CDK4/6 inhibitors (CDK4/6i) have improved survival of patients with estrogen receptor-positive (ER+) breast cancer. However, patients treated with CDK4/6i eventually develop drug resistance and progress. loss-of-function alterations confer acquired resistance to CDK4/6i, but the optimal therapy for these patients is unclear.

Pak1 pathway hyper-activation mediates resistance to endocrine therapy and CDK4/6 inhibitors in ER+ breast cancer.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have been approved in combination with endocrine therapy (ET) to treat estrogen receptor-positive (ER+) metastatic breast cancer (BC). However, drug resistance represents the leading cause of breast cancer patients mortality. This study aimed to identify novel resistance mechanisms to ER antagonists in combination with CDK4/6 inhibitors.