bims-netuvo 2023-02-19 papers

Theranostics. 2023 ;13(3): 1109-1129

Exploring neurotransmitters and their receptors for breast cancer prevention and treatment.

Ruo Qi Li, Xiao Hong Zhao, Qin Zhu, Tao Liu, Hubert Hondermarck, Rick F Thorne, Xu Dong Zhang, Jin Nan Gao.

While psychological factors have long been linked to breast cancer pathogenesis and outcomes, accumulating evidence is revealing how the nervous system contributes to breast cancer development, progression, and treatment resistance. Central to the psychological-neurological nexus are interactions between neurotransmitters and their receptors expressed on breast cancer cells and other types of cells in the tumor microenvironment, which activate various intracellular signaling pathways. Importantly, the manipulation of these interactions is emerging as a potential avenue for breast cancer prevention and treatment. However, an important caveat is that the same neurotransmitter can exert multiple and sometimes opposing effects. In addition, certain neurotransmitters can be produced and secreted by non-neuronal cells including breast cancer cells that similarly activate intracellular signaling upon binding to their receptors. In this review we dissect the evidence for the emerging paradigm linking neurotransmitters and their receptors with breast cancer. Foremost, we explore the intricacies of such neurotransmitter-receptor interactions, including those that impinge on other cellular components of the tumor microenvironment, such as endothelial cells and immune cells. Moreover, we discuss findings where clinical agents used to treat neurological and/or psychological disorders have exhibited preventive/therapeutic effects against breast cancer in either associative or pre-clinical studies. Further, we elaborate on the current progress to identify druggable components of the psychological-neurological nexus that can be exploited for the prevention and treatment of breast cancer as well as other tumor types. We also provide our perspectives regarding future challenges in this field where multidisciplinary cooperation is a paramount requirement.

Keywords: Breast cancer; Nerves; Neurotransmitter receptors; Neurotransmitters; Tumor microenvironments

DOI: https://doi.org/10.7150/thno.81403

bioRxiv. 2023 Feb 06. pii: 2023.02.06.527377. [Epub ahead of print]

Co-Targeting IL-6 and EGFR signaling for the treatment of schwannomatosis and associated pain.

Patients with Schwannomatosis (SWN) overwhelmingly present with intractable, debilitating chronic pain. There are no effective therapies to treat SWN. The drivers of pain response and tumor progression in SWN are not clear. The pain is not proportionally linked to tumor size and is not always relieved by tumor resection, suggesting that mechanisms other than mechanical nerve compression exist to cause pain. SWN research is limited by the lack of clinically-relevant models. Here, we established novel patient-derived xenograft (PDX) models, dorsal root ganglia (DRG) imaging model, and combined with single-cell resolution intravital imaging and RNASeq, we discovered: i) schwannomas on the peripheral nerve cause macrophage influx into the DRG, via secreting HMGB1 to directly stimulate DRG neurons to express CCL2, the key macrophage chemokine, ii) once recruited, macrophages cause pain response via overproduction of IL-6, iii) IL-6 blockade in a therapeutic setting significantly reduces pain but has modest efficacy on tumor growth, iv) EGF signaling is a potential driver of schwannoma growth and escape mechanism from anti-IL6 treatment, and v) combined IL-6 and EGFR blockade simultaneously controlled pain and tumor growth in SWN models. Our findings prompted the initiation of phase II clinical trial ( NCT05684692 ) for pain relief in patients with SWN.

DOI: https://doi.org/10.1101/2023.02.06.527377

Front Neurol. 2023 ;14 1103604

Case report: A rare case of massive peripheral nerve melanotic schwannoma and review of the literature.

Han Wang, Lin Shi, Tong Tian, Hang Xian, Zhao Song, Rui Cong, Rui Zhao.

Melanotic schwannoma is a rare tumor with indeterminate biologic behavior and varying treatment recommendations. Just about 200 cases have been reported worldwide, in which occurred in peripheral nerves has even less reported. Due to the lack of cognition of melanotic schwannoma, it is easy to be misdiagnosed and mistreatment in primary hospitals. Herein, we presented a case of massive melanotic schwannoma growing in the brachial plexus of an elderly male patient. First, the patient underwent a left forearm tumor resection in the local primary hospital because a painless lump was found there in 2017, of which details remain unclear. After this operation, the patient developed the symptoms of left median nerve injury. Thus, he came to our hospital and underwent a second operation. During this operation, we found that a part of the median nerve was absent at the left forearm, and the remanent median nerve, from the broken end to the elbow, was totally turned black, which was accompanied by petroleum-like exudate. Losing the opportunity for nerve repair, the black nerve was removed extensively and thoroughly. Postoperative pathological diagnosis revealed that the tumor was melanotic schwannoma. Then 4 years later, the tumor recurrence again, which led to the paralysis of the whole left arm and severe nerve pain, and the pulmonary metastasis of the tumor was detected at the same time. The black nerve was resected again in our hospital, and the nerve pain was partially relieved after the operation. To the best of our knowledge, it is the first time to report a melanotic schwannoma case that happened in the peripheral nerve trunk and then spread to the whole brachial plexus. There were many questions that worthy of discussion could be invited from this case, and we analyzed and discussed them based on the relevant literature. In conclusion, we reported a rare case of melanotic schwannoma that happened in the brachial plexus and illustrated the problems of the diagnosis and treatment of it based on the analysis of the relevant literature, which is helpful for the cognition of this rare nerve tumor.

Keywords: brachial plexus; melanotic schwannoma; neuropathic pain; pathological diagnosis; peripheral nerves

DOI: https://doi.org/10.3389/fneur.2023.1103604

Clin Cancer Res. 2023 Feb 17. pii: CCR-22-3722. [Epub ahead of print]

MEK inhibition synergizes with TYK2 inhibitors in NF1-associated Malignant Peripheral Nerve Sheath Tumors.

Dana C Borcherding, Neha V Amin, Kevin He, Xiaochun Zhang, Yang Lyu, Carina Dehner, Himanshi Bhatia, Angad Gothra, Layla Daud, Peter Ruminski, Christine A Pratilas, Kai Pollard, Taylor Sundby, Brigitte C Widemann, Angela C Hirbe.

PURPOSE: Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas with limited treatment options and poor survival rates. About half of MPNST cases are associated with the Neurofibromatosis Type 1 (NF1) cancer predisposition syndrome. Overexpression of TYK2 occurs in the majority of MPNST implicating TYK2 as a therapeutic target.
EXPERIMENTAL DESIGN: The effects of pharmacologic TYK2 inhibition on MPNST cell proliferation and survival were examined using IncuCyte live cell assays in vitro, and downstream actions were analyzed using RNAseq, qPCR arrays, and validation of protein changes with the WES automated western system. Inhibition of TYK2 alone and in combination with MEK inhibition was evaluated in vivo using both murine and human MPNST cell lines, as well as MPNST PDX.
RESULTS: Pharmacologic inhibition of TYK2 dose-dependently decreased proliferation and induced apoptosis over time. RNAseq pathway analysis on TYK2 inhibitor treated MPNST demonstrated decreased expression of cell cycle, mitotic, and glycolysis pathways. TYK2 inhibition resulted in upregulation of the MEK/ERK pathway gene expression, by both RNA-seq and qPCR array as well as increased pERK1/2 levels by WES Western system. The compensatory response was tested with dual treatment with TYK2 and MEK inhibitors, which synergistically decreased proliferation and increased apoptosis in vitro. Finally, combination therapy was shown to inhibit growth of MPNST in multiple in vivo models.
CONCLUSIONS: These data provide the preclinical rationale for the development of a phase 1 clinical trial of deucravacitinib and mirdametinib in NF1-assosciated MPNST.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-3722

Clin Nucl Med. 2023 Feb 17.

Solitary Malignant Peripheral Nerve Sheath Tumor of Lumbar Vertebra Mimicking Metastatic Malignancy.

Ziyu Guo, Wei Liu, Ziqian Dong, Lan Yang, Peng Xie.

ABSTRACT: Malignant peripheral nerve sheath tumor involving solitary lumbar vertebra is extremely rare. A 72-year-old man had a chief complaint of growing lumbocrural pain for 2 months. The CT scan detected a solitary vertebral lesion, which highly supported the diagnosis of metastatic malignancy. 18F-FDG PET/CT demonstrated that the vertebral lesion had heterogeneous intense FDG accumulation with an SUVmax of 16.4. The pathological examination confirmed the diagnosis of malignant peripheral nerve sheath tumor. This case highlights that MPNST should be considered when there is solitary vertebra invasion with increased FDG uptake.

DOI: https://doi.org/10.1097/RLU.0000000000004606

Cureus. 2023 Jan;15(1): e33710

A Rare Case of an Adrenal Schwannoma.

Madiha Ahmed, Taaha Mendha, Laura J Cui, Steve Carlan, Raymond J Leveille.

Schwannomas are tumors of neoplastic Schwann cells generally found in peripheral nerves in the head, neck, and extremities. They do not demonstrate hormonal abnormalities, and initial symptoms are typically secondary to adjacent organ compression. These tumors are rarely found in the retroperitoneum. We present a rare finding of an adrenal schwannoma in a 75-year-old female who presented to the emergency department with right flank pain. Imaging incidentally demonstrated a 4.8 cm left adrenal mass. Ultimately, she underwent a left robotic adrenalectomy, and immunohistochemical testing confirmed the presence of an adrenal schwannoma. It is imperative to undergo adrenalectomy and immunohistochemical testing to confirm the diagnosis and rule out malignancy.

Keywords: adrenal disease; adrenal schwannoma; distal ureteral stone; retroperitoneal laparoscopy; retroperitoneal tumor

DOI: https://doi.org/10.7759/cureus.33710