bims-netuvo 2025-01-12 papers

bims-netuvo

Biomed News

on Nerves in tumours of visceral organs

Issue of 2025–01–12
ten papers selected by
Maksym V. Kopanitsa, Charles River Laboratories

Targeting Perineural Invasion in Pancreatic Cancer.
Triple Combination of MEK, BET, and CDK Inhibitors Significantly Reduces Human Malignant Peripheral Nerve Sheath Tumors in Mouse Models.
Hydroxychloroquine prevents resistance and potentiates the antitumor effect of SHP2 inhibition in NF1-associated malignant peripheral nerve sheath tumors.
Clinical Features and Ultrasonographic Manifestations of Retroperitoneal Nerve Sheath Tumors.
The Emerging Role of Schwann Cells in the Tumor Immune Microenvironment and Its Potential Clinical Application.
Influence of the ERK/CHGB pathway in breast cancer progression under chronic stress.
Central Nervous System Metastases in Breast Cancer.
Current Evidence in the Systemic Treatment of Brain Metastases from Breast Cancer and Future Perspectives on New Drugs, Combinations and Administration Routes: A Narrative Review.
[Clinical Practice Guidelines for the Management of Brain Metastases from  Non-small Cell Lung Cancer with Actionable Gene Alterations in China (2025 Edition)].
A Prospective Comparison of Subjective Symptoms and Neurophysiological Findings in the Assessment of Neuropathy in Cancer Patients.

Cancers (Basel). 2024 Dec 21. pii: 4260. [Epub ahead of print]16(24):

Targeting Perineural Invasion in Pancreatic Cancer.

Ingrid Garajová, Elisa Giovannetti.

  Pancreatic cancer is an aggressive tumor with dismal prognosis. Neural invasion is one of the pathological hallmarks of pancreatic cancer. Peripheral nerves can modulate the phenotype and behavior of the malignant cells, as well as of different components of the tumor microenvironment, and thus affect tumor growth and metastasis. From a clinical point of view, neural invasion is translated into intractable pain and represents a predictor of tumor recurrence and poor prognosis. Several molecules are implicated in neural invasion and pain onset in PDAC, including neutrophins (e.g., NGF), chemokines, adhesion factors, axon-guidance molecules, different proteins, and neurotransmitters. In this review, we discuss the role of nerves within the pancreatic cancer microenvironment, highlighting how infiltrating nerve fibers promote tumor progression and metastasis, while tumor cells, in turn, drive nerve outgrowth in a reciprocal interaction that fuels tumor advancement. We outline key molecules involved in neural invasion in pancreatic cancer and, finally, explore potential therapeutic strategies to target neural invasion, aiming to both inhibit cancer progression and alleviate cancer-associated pain.

Keywords:  cancer pain; neural invasion; pancreatic ductal adenocarcinoma; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers16244260
Clin Cancer Res. 2024 Dec 30.

Triple Combination of MEK, BET, and CDK Inhibitors Significantly Reduces Human Malignant Peripheral Nerve Sheath Tumors in Mouse Models.

Sara Ortega-Bertran, Juana Fernández-Rodríguez, Miriam Magallón-Lorenz, Xiaohu Zhang, Edgar Creus-Bachiller, Adriana Paola Diazgranados, Itziar Uriarte-Arrazola, Helena Mazuelas, Ignacio Blanco, Claudia Valverde, Meritxell Carrió, Alberto Villanueva, Thomas De Raedt, Cleofé Romagosa, Bernat Gel, Héctor Salvador, Marc Ferrer, Conxi Lázaro, Eduard Serra.

PURPOSE: Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft tissue sarcoma that develops sporadically or in Neurofibromatosis type 1 patients. Its development is marked by the inactivation of specific tumor suppressor genes (TSGs): NF1, CDKN2A and SUZ12EED (Polycomb Repressor Complex 2). Each TSG loss can be targeted by particular drug inhibitors and we aimed to systematically combine these inhibitors, guided by TSG inactivation status, to test their precision medicine potential for MPNSTs.
EXPERIMENTAL DESIGN: We performed a high-throughput screening in three MPNST cell lines testing 14 MEK (MEKi), 11 CDK4/6 (CDKi) and 3 bromodomain (BETi) inhibitors as single agents and 147 pair-wise co-treatments. Best combinations were validated in 9 MPNST cell lines and three were tested in one sporadic and one NF1-associated patient-derived orthotopic xenograft (PDOX) MPNST mouse models. A final combination of the three inhibitor classes was tested in the same PDOX models.
RESULTS: A high degree of redundancy was observed in the effect of compounds of the same inhibitory class, individually or in combination, and responses matched with TSG inactivation status. The MEKi-BETi (Arry-162+I-BET151) co-treatment triggered reduction of half of the NF1-related MPNST-PDOXs, and all the sporadic tumors, reaching 65% reduction in tumor volume in the latter. Remarkably, this reduction was further increased in both models combining the three inhibitor classes, reaching 85% shrinkage on average in the sporadic MPNST.
CONCLUSIONS: Our results strongly support precision therapies for MPNSTs guided by TSG inactivation status. MEKi-BETi-CDKi triple treatment elicits a significant reduction of human MPNST PDOX.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-2807
Proc Natl Acad Sci U S A. 2025 Jan 07. 122(1): e2407745121

Hydroxychloroquine prevents resistance and potentiates the antitumor effect of SHP2 inhibition in NF1-associated malignant peripheral nerve sheath tumors.

Sameer Farouk Sait, Kwan Ho Tang, Steven P Angus, Rebecca Brown, Daochun Sun, Xuanhua Xie, Charlene Iltis, Michelle Lien, Nicholas D Socci, Tejus A Bale, Christopher Davis, Shelley A H Dixon, Chi Zhang, D Wade Clapp, Benjamin G Neel, Luis F Parada.

  Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas and the primary cause of mortality in patients with neurofibromatosis type 1 (NF1). These malignancies develop within preexisting benign lesions called plexiform neurofibromas (PNs). PNs are solely driven by biallelic NF1 loss eliciting RAS pathway activation, and they respond favorably to MEK inhibitor therapy. MPNSTs harbor additional mutations and respond poorly to MEK inhibition. Our analysis of genetically engineered and orthotopic patient-derived xenograft MPNST models indicates that MEK inhibition has poor antitumor efficacy. By contrast, upstream inhibition of RAS through the protein-tyrosine phosphatase SHP2 reduced downstream signaling and suppressed NF1 MPNST growth, although resistance eventually emerged. To investigate possible mechanisms of acquired resistance, kinomic analyses of resistant tumors were performed, and data analysis identified enrichment of activated autophagy pathway protein kinases. Combining SHP2 inhibition with hydroxychloroquine (HQ) resulted in durable responses in NF1 MPNSTs in both genetic and orthotopic xenograft mouse models. Our studies could be rapidly translated into a clinical trial to evaluate SHP2 inhibition in conjunction with HQ as a unique treatment approach for NF1 MPNSTs.

Keywords:  MPNST; NF1; SHP2 inhibition; autophagy; hydroxychloroquine

DOI:  https://doi.org/10.1073/pnas.2407745121
Curr Med Imaging. 2025 Jan 02.

Clinical Features and Ultrasonographic Manifestations of Retroperitoneal Nerve Sheath Tumors.

Xiaoqing Wang, Xiaoying Zhang, Rui Zhao, Yan Liu, Chaoyang Wen, Haining Zheng.

   OBJECTIVES: Retroperitoneal nerve sheath tumors are uncommon, representing a small fraction of all primary retroperitoneal neoplasms. Accurate differentiation between benign and malignant forms is essential for optimal clinical management. This study assessed the clinical profiles and sonographic traits of retroperitoneal nerve sheath tumors with the goal of enhancing diagnostic precision and developing therapeutic strategies.
METHODS: A retrospective analysis of patients diagnosed with benign retroperitoneal nerve sheath tumors who completed surgical treatment and underwent ultrasound imaging was carried out. Tumors were classified based on sonographic features and blood flow characteristics as per Adler's grading system. Statistical analysis was performed using SPSS 25.0. ROC curve analysis was carried out to determine the optimal diagnostic cutoff values.
RESULTS: A total of 49 patients were included in the study. There were no significant variances in age, gender, or tumor localization among the groups. However, pronounced disparities were observed in tumor number, size, shape, definition of borders, internal echo pattern, structural composition, presence of calcification, and blood flow signals between the classic and malignant groups. Notably, malignant tumors tended to manifest as larger masses with indistinct margins and irregular shapes. The maximum tumor diameter emerged as a discriminating factor for malignancy, with a diagnostic cutoff of 9.9 cm, yielding an AUC of 0.754 from the ROC curve analysis.
CONCLUSION: This study outlines the distinctive clinical and sonographic features of retroperitoneal nerve sheath tumors, with a particular focus on malignant subtypes. Ultrasonography emerges as a valuable diagnostic tool, contributing to the differentiation of tumor categories and potentially to the development of targeted treatment strategies. The identification of specific sonographic markers may facilitate the early detection and detailed characterization of these tumors, which could contribute to improved patient outcomes.

Keywords:  Diagnosis; Malignant potential.; Retroperitoneal nerve sheath tumors; Tumor characterization; Ultrasonography

DOI:  https://doi.org/10.2174/0115734056348636241213120140
Int J Mol Sci. 2024 Dec 23. pii: 13722. [Epub ahead of print]25(24):

The Emerging Role of Schwann Cells in the Tumor Immune Microenvironment and Its Potential Clinical Application.

Shan Zhang, Jing Chen, Fanjun Cheng, Fang Zheng.

  As the primary glial cells in the peripheral nervous system (PNS), Schwann cells (SCs) have been proven to influence the behavior of cancer cells profoundly and are involved in cancer progression through extensive interactions with cancer cells and other stromal cells. Indeed, the tumor microenvironment (TME) is a critical factor that can significantly limit the efficacy of immunotherapeutic approaches. The TME promotes tumor progression in part by reshaping an immunosuppressive state. The immunosuppressive TME is the result of the crosstalk between the tumor cells and the different immune cell subsets, including macrophages, natural killer (NK) cells, dendritic cells (DCs), lymphocytes, myeloid-derived suppressor cells (MDSCs), etc. They are closely related to the anti-tumor immune status and the clinical prognosis of cancer patients. Increasing research demonstrates that SCs influence these immune cells and reshape the formation of the immunosuppressive TME via the secretion of various cytokines, chemokines, and other effector molecules, eventually facilitating immune evasion and tumor progression. In this review, we summarize the SC reprogramming in TME, the emerging role of SCs in tumor immune microenvironment, and the underlying mechanisms involved. We also discuss the possible therapeutic strategies to selectively target SCs, providing insights and perspectives for future research and clinical studies involving SC-targeted treatment.

Keywords:  Schwann cells; immunocytes; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms252413722
Int J Biochem Cell Biol. 2025 Jan 03. pii: S1357-2725(24)00227-9. [Epub ahead of print]179 106733

Influence of the ERK/CHGB pathway in breast cancer progression under chronic stress.

Yue Wang, Xi Hou, Zijing Wu, Junyu Ren, Yanfang Zhao.

   BACKGROUND: Breast cancer is one of the most common malignancies among women, and its development involves a variety of complex molecular mechanisms. Extracellular signal-regulated kinase (ERK) and Chromogranin B (CHGB) are known to play key roles in various cancers. This study aims to explore the impact of the ERK/CHGB pathway in a chronic stress environment simulated by salbutamol on the development of breast cancer.
METHODS: This study utilized female BALB/c mice to establish a breast cancer model, dividing them into control, salbutamol-treated, and salbutamol-inhibitor-treated groups. Cell culture, immunohistochemistry, Western Blot, real-time fluorescent quantitative PCR, and Transwell migration assays were employed to assess the effects of salbutamol and the ERK/CHGB pathway.
RESULTS: Salbutamol treatment significantly enhanced the proliferation, migration, and invasiveness of breast cancer cells, associated with the activation of the ERK pathway and the inhibition of CHGB. The salbutamol-inhibitor-treated group exhibited a marked suppression of these effects. Additionally, the interaction of the ERK/CHGB pathway in an extracellular stress environment provided advantages for the survival and proliferation of breast cancer cells.
CONCLUSION: This study demonstrates that a chronic stress environment simulated by salbutamol can promote malignant behaviors in breast cancer cells through the ERK/CHGB pathway. These findings offer new molecular targets for breast cancer treatment and highlight the potential importance of managing chronic stress and blocking specific molecular pathways in cancer therapy.

Keywords:  Breast Cancer; Chronic Stress; ERK/CHGB; Treatments

DOI:  https://doi.org/10.1016/j.biocel.2024.106733
Curr Treat Options Oncol. 2025 Jan 09.

Central Nervous System Metastases in Breast Cancer.

Thomas Grinda, Ayal A Aizer, Nancy U Lin, Sarah L Sammons.

   OPINION STATEMENT: Breast cancer metastasizing to the central nervous system (CNS) encompasses two distinct entities: brain metastases involving the cerebral parenchyma and infiltration of the leptomeningeal space, i.e., leptomeningeal disease. CNS metastases affect 10-15% of patients with hormone receptor-positive-status and nearly one-half of those with HER2-positive and triple-negative breast cancer with distant metastatic disease. Significant clinical morbidity and heterogeneous penetration of the blood-brain barrier by systemic therapies contribute to the poor prognosis associated with brain metastases. Recent advances in radiotherapy, including stereotactic approaches and morbidity-reducing strategies such as the use of memantine and hippocampal avoidance in whole brain radiation, coupled with the development of more effective CNS-penetrant systemic therapies, including small molecules and antibody-drug conjugates, have significantly improved patient outcomes. Consequently, patients with breast cancer CNS metastases have improved survival compared to prior decades, and longitudinal care has become increasingly complex, necessitating a multidisciplinary approach to achieve optimal outcomes for patients.

Keywords:  Brain metastases; Breast cancer; Central nervous system; Leptomeningeal disease

DOI:  https://doi.org/10.1007/s11864-024-01286-1
Cancers (Basel). 2024 Dec 13. pii: 4164. [Epub ahead of print]16(24):

Current Evidence in the Systemic Treatment of Brain Metastases from Breast Cancer and Future Perspectives on New Drugs, Combinations and Administration Routes: A Narrative Review.

Ornella Garrone, Fiorella Ruatta, Carmen Giusy Rea, Nerina Denaro, Michele Ghidini, Carolina Cauchi, Claudia Bareggi, Barbara Galassi, Marco C Merlano, Roberto Rosenfeld.

  Breast cancer is the most frequently diagnosed neoplasm all over the world and the second leading cause of cancer death in women. Breast cancer prognosis has significantly improved in the last years due to the advent of novel therapeutic options, both in the early and in advanced stages. However, the spread of the disease to the brain, accounting for 15-30% of the metastatic diagnoses, is challenging, and its poor prognosis represents an unmet medical need, leading to deterioration of quality of life and causing morbidity and mortality. Generally, triple-negative and HER2-positive breast cancer subtypes more frequently spread to the brain or in the leptomeningeal space. Consequently, according to international guidelines, several systemic treatments can be offered as a first option in some subsets of patients. However, a multidisciplinary approach is recommended to offer the most appropriate strategy to patients. Antibody-drug conjugates such as trastuzumab deruxtecan or sacituzumab govitecan along with small molecules have led to important achievements in the treatment of brain metastases from HER2-positive and triple-negative breast cancer. In this narrative review, we will focus on the molecular features leading to the development of brain metastases and explore the risk and the prognostic factors involved in the development of brain metastases. Finally, we will review the major achievements in the treatment landscape of brain metastases from breast cancer and novel medical approaches.

Keywords:  brain metastases; breast cancer; systemic treatment

DOI:  https://doi.org/10.3390/cancers16244164
Zhongguo Fei Ai Za Zhi. 2025 Jan 07.

[Clinical Practice Guidelines for the Management of Brain Metastases from  Non-small Cell Lung Cancer with Actionable Gene Alterations in China (2025 Edition)].

Lung Cancer Medical Education Committee of Chinese Medical Education Association

  Brain metastasis has emerged as a significant challenge in the comprehensive management of patients with non-small cell lung cancer (NSCLC), particularly in those harboring driver gene mutations. Traditional treatments such as radiotherapy and surgery offer limited clinical benefits and are often accompanied by cognitive dysfunction and a decline in quality of life. In recent years, novel small molecule tyrosine kinase inhibitors targeting epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and other pathways have been developed, effectively penetrating the blood-brain barrier while enhancing intracranial drug concentrations and improving patient outcomes. This advancement has transformed the treatment landscape for brain metastases in NSCLC. Consequently, the Lung Cancer Medical Education Committee of the Chinese Medical Education Association and the Brain Metastasis Collaboration Group of the Lung Cancer Youth Expert Committee of the Beijing Medical Reward Foundation have jointly initiated and formulated the Clinical Practice Guidelines for the Management of Brain Metastases from Non-small Cell Lung Cancer with Actionable Gene Alterations in China (2025 Edition). This guideline integrates the latest research findings with clinical experience, adhering to multidisciplinary treatment principles, and encompasses aspects such as diagnosis, timing of intervention, and systemic and local treatment options for driver gene positive NSCLC brain metastases. Additionally, it proposes individualized treatment strategies tailored to different driver gene types, aiming to provide clinicians with a reference to enhance the overall diagnostic and therapeutic standards for NSCLC brain metastases in China. .

Keywords:  Actionable gene alterations; Brain metastasis; Clinical practice guidelines; Lung neoplasms; Targeted therapy

DOI:  https://doi.org/10.3779/j.issn.1009-3419.2024.102.42
Diagnostics (Basel). 2024 Dec 19. pii: 2861. [Epub ahead of print]14(24):

A Prospective Comparison of Subjective Symptoms and Neurophysiological Findings in the Assessment of Neuropathy in Cancer Patients.

Vera Elisabeth Adreana Kleinveld, Miriam Emmelheinz, Daniel Egle, Magdalena Ritter, Wolfgang N Löscher, Christian Marth, Corinne Gosewina Cornelia Horlings, Julia Wanschitz, Christine Brunner.

  Objectives: Neurotoxic effects causing peripheral nerve damage have been reported for several chemotherapy agents. There is no established and standardized method to assess the presence of chemotherapy-induced peripheral neuropathy (CIPN). We compared patient-reported CIPN symptoms to neurophysiological findings and neurological assessments in patients receiving taxane-based chemotherapy. Methods: Patients scheduled to receive taxane-based chemotherapy for the treatment of gynecologic cancer were included and prospectively followed for up to 9 months after chemotherapy discontinuation, between May 2020 and January 2023. Patient-reported symptoms, using the EORTC-QLQ-CIPN20 questionnaire, and nerve conduction studies (NCSs) were performed at baseline, halfway through the treatment cycle, at the end of the treatment, 3 months after treatment, and 6-9 months after treatment. Results: A total of 149 patients were included. Overall, 47.0% of patients reported symptoms compatible with CIPN at any of the follow-ups. Subjective symptoms did not correlate with nerve conduction studies. SNAP amplitudes at baseline were lower in patients who developed CIPN compared to the group without CIPN. Conclusions: The overall diagnostic accuracy of electrophysiological parameters as a marker for CIPN was low.

Keywords:  adverse events; nerve conduction studies; taxane-based chemotherapy-induced polyneuropathy; toxicity

DOI:  https://doi.org/10.3390/diagnostics14242861