bims-netuvo 2023-07-09 papers

Issue of 2023‒07‒09
five papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute

Neuropharmacology. 2023 Jun 29. pii: S0028-3908(23)00231-9. [Epub ahead of print]237 109641

Understanding the initiation, delivery and processing of bone cancer pain from the peripheral to the central nervous system.

Lei Yang, Beibei Liu, Shang Zheng, Longsheng Xu, Ming Yao.

Bone cancer pain is a complex condition characterized by persistent, sudden, spontaneous pain accompanied by hyperalgesia that typically arises from bone metastases or primary bone tumors, causing severe discomfort and significantly diminishing cancer patients' quality of life and confidence in their ability to overcome the disease. It is widely known that peripheral nerves are responsible for detecting harmful stimuli, which are then transmitted to the brain via the spinal cord, resulting in the perception of pain. In the case of bone cancer, tumors and stromal cells within the bone marrow release various chemical signals, including inflammatory factors, colony-stimulating factors, chemokines, and hydrogen ions. Consequently, the nociceptors located at the nerve endings within the bone marrow sense these chemical signals, generating electrical signals that are then transmitted to the brain through the spinal cord. Subsequently, the brain processes these electrical signals in a complex manner to create the sensation of bone cancer pain. Numerous studies have investigated the transmission of bone cancer pain from the periphery to the spinal cord. However, the processing of pain information induced by bone cancer within the brain remains unclear. With the continuous advancements in brain science and technology, the brain mechanism of bone cancer pain would become more clearly understood. Herein, we focus on summarizing the peripheral nerve perception of the spinal cord transmission of bone cancer pain and provide a brief overview of the ongoing research regarding the brain mechanisms involved in bone cancer pain.

Keywords: Bone cancer pain; Brain; Dorsal root ganglia; Spinal cord

DOI: https://doi.org/10.1016/j.neuropharm.2023.109641

Front Oncol. 2023 ;13 1166373

Bioinformatic-based genetic characterizations of neural regulation in skin cutaneous melanoma.

Fengdi Wang, Fanjun Cheng, Fang Zheng.

Background: Recent discoveries uncovered the complex cancer-nerve interactions in several cancer types including skin cutaneous melanoma (SKCM). However, the genetic characterization of neural regulation in SKCM is unclear.Methods: Transcriptomic expression data were collected from the TCGA and GTEx portal, and the differences in cancer-nerve crosstalk-associated gene expressions between normal skin and SKCM tissues were analyzed. The cBioPortal dataset was utilized to implement the gene mutation analysis. PPI analysis was performed using the STRING database. Functional enrichment analysis was analyzed by the R package clusterProfiler. K-M plotter, univariate, multivariate, and LASSO regression were used for prognostic analysis and verification. The GEPIA dataset was performed to analyze the association of gene expression with SKCM clinical stage. ssGSEA and GSCA datasets were used for immune cell infiltration analysis. GSEA was used to elucidate the significant function and pathway differences.
Results: A total of 66 cancer-nerve crosstalk-associated genes were identified, 60 of which were up- or downregulated in SKCM and KEGG analysis suggested that they are mainly enriched in the calcium signaling pathway, Ras signaling pathway, PI3K-Akt signaling pathway, and so on. A gene prognostic model including eight genes (GRIN3A, CCR2, CHRNA4, CSF1, NTN1, ADRB1, CHRNB4, and CHRNG) was built and verified by independent cohorts GSE59455 and GSE19234. A nomogram was constructed containing clinical characteristics and the above eight genes, and the AUCs of the 1-, 3-, and 5-year ROC were 0.850, 0.811, and 0.792, respectively. Expression of CCR2, GRIN3A, and CSF1 was associated with SKCM clinical stages. There existed broad and strong correlations of the prognostic gene set with immune infiltration and immune checkpoint genes. CHRNA4 and CHRNG were independent poor prognostic genes, and multiple metabolic pathways were enriched in high CHRNA4 expression cells.
Conclusion: Comprehensive bioinformatics analysis of cancer-nerve crosstalk-associated genes in SKCM was performed, and an effective prognostic model was constructed based on clinical characteristics and eight genes (GRIN3A, CCR2, CHRNA4, CSF1, NTN1, ADRB1, CHRNB4, and CHRNG), which were widely related to clinical stages and immunological features. Our work may be helpful for further investigation in the molecular mechanisms correlated with neural regulation in SKCM, and in searching new therapeutic targets.

Keywords: bioinformatics; cancer immunotherapies; cancer–nerve crosstalk; neural regulation; skin cutaneous melanoma

DOI: https://doi.org/10.3389/fonc.2023.1166373

Mol Biol Rep. 2023 Jul 07.

The evidence for repurposing anti-epileptic drugs to target cancer.

Mir Aroosa, Jonaid Ahmad Malik, Sakeel Ahmed, Onur Bender, Nafees Ahemad, Sirajudheen Anwar.

Antiepileptic drugs are versatile drugs with the potential to be used in functional drug formulations with drug repurposing approaches. In the present review, we investigated the anticancer properties of antiepileptic drugs and interlinked cancer and epileptic pathways. Our focus was primarily on those drugs that have entered clinical trials with positive results and those that provided good results in preclinical studies. Many contributing factors make cancer therapy fail, like drug resistance, tumor heterogeneity, and cost; exploring all alternatives for efficient treatment is important. It is crucial to find new drug targets to find out new antitumor molecules from the already clinically validated and approved drugs utilizing drug repurposing methods. The advancements in genomics, proteomics, and other computational approaches speed up drug repurposing. This review summarizes the potential of antiepileptic drugs in different cancers and tumor progression in the brain. Valproic acid, oxcarbazepine, lacosamide, lamotrigine, and levetiracetam are the drugs that showed potential beneficial outcomes against different cancers. Antiepileptic drugs might be a good option for adjuvant cancer therapy, but there is a need to investigate further their efficacy in cancer therapy clinical trials.

Keywords: Antiepileptic drugs; Antiepileptic drugs for cancer; Breast cancer; Cancer treatment; Drug repurposing

DOI: https://doi.org/10.1007/s11033-023-08568-1

Clin Cancer Res. 2023 Jul 05. pii: CCR-22-2854. [Epub ahead of print]

Combined CDK4/6 and ERK1/2 inhibition enhances anti-tumor activity in NF1-associated plexiform neurofibroma.

PURPOSE: Plexiform neurofibromas (PNF) are peripheral nerve sheath tumors that cause significant morbidity in persons with neurofibromatosis type 1 (NF1), yet treatment options remain limited. To identify novel therapeutic targets for PNF, we applied an integrated multi-omic approach to quantitatively profile kinome enrichment in a mouse model that has predicted therapeutic responses in clinical trials for NF1-associated PNF with high fidelity.EXPERIMENTAL DESIGN: Utilizing RNA sequencing combined with chemical proteomic profiling of the functionally enriched kinome using multiplexed inhibitor beads coupled with mass spectrometry, we identified molecular signatures predictive of response to CDK4/6 and RAS/MAPK pathway inhibition in PNF. Informed by these results, we evaluated the efficacy of the CDK4/6 inhibitor, abemaciclib, and the ERK1/2 inhibitor, LY3214996, alone and in combination in reducing PNF tumor burden in Nf1flox/flox;PostnCre mice.
RESULTS: Converging signatures of CDK4/6 and RAS/MAPK pathway activation were identified within the transcriptome and kinome that were conserved in both murine and human PNF. We observed robust additivity of the CDK4/6 inhibitor, abemaciclib, in combination with the ERK1/2 inhibitor, LY3214996, in murine and human NF1(Nf1) mutant Schwann cells. Consistent with these findings, the combination of abemaciclib (CDK4/6i) and LY3214996 (ERK1/2i) synergized to suppress molecular signatures of MAPK activation and exhibited enhanced anti-tumor activity in Nf1flox/flox;PostnCre mice in vivo.
CONCLUSION: These findings provide rationale for the clinical translation of CDK4/6 inhibitors alone and in combination with therapies targeting the RAS/MAPK pathway for the treatment of PNF and other peripheral nerve sheath tumors in persons with NF1.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-2854

Urol Case Rep. 2023 Sep;50 102458

Excision of recurrent penile schwannoma with neurovascular bundle sparing: A novel surgical approach.

Sandeep Sai Voleti, Christopher J Warren, Nicholas R Parker, Melissa Stanton, Aqsa A Khan, Shelley S Noland, Nahid Punjani.

Penile schwannomas are rare, often painless lesions usually growing on the dorsum of the penis. A young and otherwise healthy male with recurrent painful penile schwannomas and decreased libido was successfully treated with surgical excision. Through fine dissection of the nerve fascicles leading to the primary schwannoma, the lesion was successfully removed without compromising erectile or ejaculatory function. This novel approach allowed for significant symptomatic relief and improved quality of life.

DOI: https://doi.org/10.1016/j.eucr.2023.102458