Glycolysis-non-canonical glutamine dual-metabolism regulation nanodrug enhanced the phototherapy effect for pancreatic ductal adenocarcinoma treatment.

Clinical pancreatic ductal adenocarcinoma (PDAC) treatment is severely limited by lack of effective KRAS suppression strategies. To address this dilemma, a reactive oxygen species (ROS)-responsive and PDAC-targeted nanodrug named Z/B-PLS was constructed to confront KRAS through dual-blockade of its downstream PI3K/AKT/mTOR and RAF/MEK/ERK for enhanced PDAC treatment. Specifically, photosensitizer zinc phthalocyanine (ZnPc) and PI3K/mTOR inhibitor BEZ235 (BEZ) were co-loaded into PLS which was constructed by click chemistry conjugating MEK inhibitor selumetinib (SEL) to low molecular weight heparin with ROS-responsive oxalate bond. The BEZ and SEL blocked PI3K/AKT/mTOR and RAF/MEK/ERK respectively to remodel glycolysis and non-canonical glutamine metabolism. ZnPc mediated photodynamic therapy (PDT) could enhance drug release through ROS generation, further facilitating KRAS downstream dual-blockade to create treatment-promoting drug delivery-therapeutic positive feedback. Benefiting from this broad metabolic modulation cascade, the metabolic symbiosis between normoxic and hypoxic tumor cells was also cut off simultaneously and effective tumor vascular normalization effects could be achieved. As a result, PDT was dramatically promoted through glycolysis-non-canonical glutamine dual-metabolism regulation, achieving complete elimination of tumors in vivo. Above all, this study achieved effective multidimensional metabolic modulation based on integrated smart nanodrug delivery, helping overcome the therapeutic challenges posed by KRAS mutations of PDAC.

Clinical Outcomes of Radioactive Iodine Redifferentiation Therapy in Previously Iodine Refractory Differentiated Thyroid Cancers.

Objective: Redifferentiation therapy (RDT) can restore radioactive iodine (RAI) uptake in differentiated thyroid cancer (DTC) cells to enable salvage 131I therapy for previously RAI refractory (RAIR) disease. This study evaluated the clinical outcomes of patients who underwent RDT and identified clinicopathologic characteristics predictive of RAI restoration following RDT. Methods: This is a retrospective case series of 33 patients with response evaluation criteria in solid tumors (RECIST)-progressive metastatic RAIR-DTC who underwent RDT between 2017 and 2022 at the Mayo Clinic (Rochester, MN). All patients underwent genomic profiling and received MEK, RET or ALK inhibitors alone, or combination BRAF-MEK inhibitors for 4 weeks. At week 3, those with increased RAI avidity in metastatic foci received high-dose 131I therapy. Baseline and clinicopathologic outcomes were comprehensively reviewed. Results: Of the 33 patients, 57.6% had restored RAI uptake following RDT (Redifferentiated subgroup). 42.1% (8/19) with papillary thyroid cancers (PTC), 100% (4/4) with invasive encapsulated follicular variant PTCs (IEFV-PTCs), and 100% (7/7) with follicular thyroid cancers (FTC) redifferentiated. All (11/11) RAS mutant tumors redifferentiated compared with 38.9% (7/18) with BRAF mutant disease (6 PTC and 1 IEFV-PTC). 76.5% (13/17) of redifferentiated and 66.7% (8/12) of non-redifferentiated patients achieved a best overall RECIST response of stable disease (SD) or non-complete response/non-progressive disease. Both subgroups had a median 12% tumor shrinkage at 3 weeks on drug(s) alone. The redifferentiated subgroup, following high-dose 131I therapy, achieved an additional median 20% tumor reduction at 6 months after RDT. There were no statistically significant differences between both groups in progression free survival (PFS), time to initiation of systemic therapy, and time to any additional therapy. Of the entire cohort, 6.1% (2/33) experienced histologic transformation to anaplastic thyroid cancer, 15.1% (5/33) died, and all had redifferentiated following RDT and received 131I therapy. Conclusion: RDT has the potential to restore RAI avidity and induce RECIST responses following 131I therapy in select patients with RAIR-DTC, particularly those with RAS-driven "follicular" phenotypes. In patients with PTC, none of the evaluated clinical outcomes differed statistically between the redifferentiated and non-redifferentiated subgroups. Further studies are needed to better characterize the long-term survival and/or safety outcomes of high-dose RAI following RDT, particularly whether it could be associated with histologic anaplastic transformation.

Combination of the LARS1 Inhibitor, BC-LI-0186 with a MEK1/2 Inhibitor Enhances the Anti-Tumor Effect in Non-Small Cell Lung Cancer.

PURPOSE: The mammalian target of rapamycin complex 1 (mTORC1) regulates cell growth and proliferation by growth factor coordination and amino acid availability. Leucyl-tRNA synthetase 1 (LARS1) senses the intracellular leucine concentration and mediates amino acid-induced activation of mTORC1. Thus, LARS1 inhibition could be useful in cancer treatment. However, the fact that mTORC1 can be stimulated by various growth factors and amino acids suggests that LARS1 inhibition alone has limitations in inhibiting cell growth and proliferation. We investigated the combined effects of BC-LI-0186, a LARS1 inhibitor, and trametinib, an MEK inhibitor, on non-small cell lung cancer (NSCLC). Materials and Methods: Protein expression and phosphorylation were observed by immunoblotting, and genes differentially expressed between BC-LI-0186-sensitive and -resistant cells were identified by RNA sequencing. The combined effect of the two drugs was inferred from the combination index values and a xenograft model. RESULTS: LARS1 expression was positively correlated with mTORC1 in NSCLC cell lines. BC-LI-0186 treatment of A549 and H460 cells maintained in media supplemented with fetal bovine serum revealed paradoxical phosphorylation of S6 and activation of mitogen- activated protein kinase (MAPK) signaling. Compared with BC-LI-0186-sensitive cells, -resistant cells showed enrichment of the MAPK gene set. The combination of trametinib and BC-LI-0186 inhibited the phosphorylation of S6, MEK, and extracellular signal-regulated kinase and their synergistic effects were confirmed in a mouse xenograft model. CONCLUSION: The combination of BC-LI-0186 and trametinib inhibited the non-canonical mTORC1-activating function of LARS1. Our study demonstrated a new therapeutic approach for NSCLC without targetable driver mutations.

Valtrate, an iridoid compound in Valeriana, elicits anti-glioblastoma activity through inhibition of the PDGFRA/MEK/ERK signaling pathway.

BACKGROUND: Valtrate, a natural compound isolated from the root of Valeriana, exhibits antitumor activity in many cancers through different mechanisms. However, its efficacy for the treatment of glioblastoma (GBM), a tumor type with a poor prognosis, has not yet been rigorously investigated. METHODS: GBM cell lines were treated with valtrate and CCK-8, colony formation and EdU assays, flow cytometry, and transwell, 3D tumor spheroid invasion and GBM-brain organoid co-culture invasion assays were performed to assess properties of proliferation, viability, apoptosis and invasion/migration. RNA sequencing analysis on valtrate-treated cells was performed to identify putative target genes underlying the antitumor activity of the drug in GBM cells. Western blot analysis, immunofluorescence and immunohistochemistry were performed to evaluate protein levels in valtrate-treated cell lines and in samples obtained from orthotopic xenografts. A specific activator of extracellular signal-regulated kinase (ERK) was used to identify the pathways mediating the effect. RESULTS: Valtrate significantly inhibited the proliferation of GBM cells in vitro by inducing mitochondrial apoptosis and suppressed invasion and migration of GBM cells by inhibiting levels of proteins associated with epithelial mesenchymal transition (EMT). RNA sequencing analysis of valtrate-treated GBM cells revealed platelet-derived growth factor receptor A (PDGFRA) as a potential target downregulated by the drug. Analysis of PDGFRA protein and downstream mediators demonstrated that valtrate inhibited PDGFRA/MEK/ERK signaling. Finally, treatment of tumor-bearing nude mice with valtrate led to decreased tumor volume (fivefold difference at day 28) and enhanced survival (day 27 vs day 36, control vs valtrate-treated) relative to controls. CONCLUSIONS: Taken together, our study demonstrated that the natural product valtrate elicits antitumor activity in GBM cells through targeting PDGFRA and thus provides a candidate therapeutic compound for the treatment of GBM.

Electroacupuncture-Regulated miR-34a-3p/PDCD6 Axis Promotes Post-Spinal Cord Injury Recovery in Both In Vitro and In Vivo Settings.

Electroacupuncture (EA) could enhance neuroregeneration and posttraumatic conditions; however, the underlying regulatory mechanisms remain ambiguous. PDCD6 (programmed cell death 6) is an established proapoptotic regulator which is responsible for motoneuronal death. However, its potential regulatory role in post-spinal cord injury (SCI) regeneration has remained largely unknown. Further investigations are warranted to clarify the involvement of PDCD6 post-SCI recovery and the underlying mechanisms. In our study, based on bioinformatics prediction, we found that miR-34a-3p might be an upstream regulator miRNA for PDCD6, which was subsequently validated through combined utilization of the qRT-PCR, western blot, and dual-luciferase reporter system. Our in vitro results showed that miR-34a-3p might promote the in vitro differentiation of neural stem cell (NSC) through suppressing PDCD6 and regulating other important neural markers such as fibroblast growth factor receptor 1 (FGFR1), MAP1/2 (MAP kinase kinases 1/2), myelin basic protein (MBP), ßIII-tubulin Class III ß-tubulin (ßIII tubulin), and glial fibrillary acidic protein (GFAP). Notably, in the post-SCI rat model, exogenous miR-34a-3p agomir obviously inhibited the expression of PDCD6 at the protein level and promoted neuronal proliferation, motoneurons regeneration, and axonal myelination. The restorations at cellular level might contribute to the improved hindlimbs functions of post-SCI rats, which was manifested by the Basso-Beattie-Bresnahan (BBB) locomotor test. The impact of miR-34a-3p was further promoted by EA treatment in vivo. Conclusively, this paper argues that a miR-34a-3p/PDCD6 axis might be a candidate therapeutic target for treating SCI and that the therapeutic effect of EA is driven through this pathway.

Eficacia y seguridad de vemurafenib más cobimetinib para el tratamiento de pacientes adultos con melanoma maligno avanzado o metastásico, con mutacion BRAF V600E, inoperable y con ECOG 0-1 / Efficacy and safety of vemurafenib plus cobimetinib for the treatment of adult patients with advanced or metastatic malignant melanoma, with BRAF V600E mutation, inoperable and with ECOG 0-1

INTRODUCCIÓN: El melanoma maligno (MM), es un tipo de cáncer de piel agresivo que afecta a los melanocitos. El MM representa solo el 4 % de los tumores malignos de la piel, pero es el responsable del 80 % de las muertes por estos tumores. Actualmente, la quimioterapia se usa con menos frecuencia que la inmunoterapia o la terapia dirigida. La inmunoterapia inhibe la proteína PD-1; y la terapia dirigida inhibe la proteína mutada BRAF y las proteínas quinasas MEK. A diferencia de la inmunoterapia (que puede usarse para todos los pacientes con MM metastásico), la terapia dirigida está indicada solo para aquellos pacientes con la mutación BRAF V600. La mutación BRAF está presente en el 50 % de los casos de MM y el 70 % de las mutaciones BRAF son de tipo V600E. En EsSalud, los pacientes adultos con MM avanzado o metastásico, con mutación BRAF V600E, inoperable y con ECOG 0-1 disponen de la inmunoterapia (nivolumab) y la quimioterapia como tratamientos de primera línea. No obstante, los especialistas en oncología señalan que la terapia dirigida podría ser más eficaz, en aquellos con la mutación BRAF V600E, que las opciones disponibles en EsSalud. De esta forma, sugieren el uso de vemurafenib más cobimetinib (V+C) como tratamiento de primera línea para estos pacientes. OBJETIVO: El objetivo del presente dictamen fue evaluar la eficacia y seguridad de V+C, comparado con nivolumab o quimioterapia, para el tratamiento de pacientes adultos con MM avanzado o metastásico, con mutación BRAF V600E, inoperable y con ECOG 0-1. METODOLOGÍA: Tras la búsqueda de la evidencia, se incluyeron cinco guías de práctica clínica (GPC) elaboradas por la National Comprehensive Cancer Network (NCCN), la American Society of Clinical Oncology (ASCO), el Cancer Council Australia (CCA), la European Society for Medical Oncology (ESMO) y la Scottish Intercollegiate Guidelines Network (SIGN); tres evaluaciones de tecnologías sanitarias (ETS) realizadas por el National Institute for Health and Care Excellence (NICE), la Canadian Agency for Drugs and Technologies in Health (CADTH) y el Institute for Quality and Efficiency in Healthcare (IQWiG); y dos revisiones sistemáticas con metaanálisis en red (RSMAR) desarrolladas por Zoratti et al. 2019 y Pike et al. 2017. RESULTADOS: Se llevó a cabo una búsqueda de evidencia científica con respecto al uso de V+C como tratamiento de primera línea en pacientes adultos con MM avanzado o metastásico, con mutación BRAF V600E, inoperable y con ECOG 0-1. CONCLUSIONES: El presente dictamen preliminar tuvo por objetivo evaluar la mejor evidencia disponible sobre la eficacia y seguridad de V+C, comparado con nivolumab o quimioterapia, para el tratamiento de pacientes adultos con MM avanzado o metastásico, con mutación BRAF, inoperable y con ECOG 0-1. Los desenlaces de interés fueron SG, calidad de vida y eventos adversos. Tras la búsqueda de la literatura se identificaron cinco GPC elaboradas por NCCN, CCA, ASCO, ESMO y SIGN; tres ETS desarrolladas por NICE, CADTH e IQWiG. No se identificaron ECA o estudios observacionales comparativos que respondieran a la pregunta PICO. Por tal motivo, se optó por incluir dos estudios que evaluaron de manera indirecta (metaanálisis en red) V+C vs. nivolumab o quimioterapia (la RSMAR de Zoratti et al. 2019 y la RSMAR de Pike et al. 2017). Cuatro GPC (NCCN, ASCO, ESMO, CCA) de las cinco evaluadas recomiendan nivolumab o V+C; la guía restante (SIGN), solo nivolumab; y ninguna guia mencionó a la quimioterapia como tratamiento de primera línea. La ESMO recomienda a los inhibidores de PD-1(nivolumab) como el tratamiento estándar de primera línea para los pacientes con MM metastásico, además, la CCA y la ESMO señalaron que es preferible iniciar con anti PD-1 (nivolumab); sobre todo en pacientes con buen estado de salud y cuya enfermedad no progrese rápidamente. Las ETS fueron disimiles en sus recomendaciones. La CADTH condicionó su recomendación a la reducción en el precio del medicamento; IQWiG concluyó que existe beneficio adicional a favor de V+C; pero que la información sobre eventos adversos (EA) presenta limitaciones importantes. Por su parte NICE no recomendó el uso de V+C por no ser costo-efectivo. Es de destacar que las tres ETS no incluyen entre sus comparadores a nivolumab o quimioterapia, medicamentos que son alternativas disponibles y con las que se tienen experiencia de uso en EsSalud. Las RSMAR sugieren que V+C es similar a nivolumab en términos de SG y EA. Aunque sugieren diferencias a favor de V+C, en comparación con quimioterapia, las estimaciones indirectas no cumplieron con el criterio de transitividad y presentaron limitaciones que afectan su validez. Además, reportes más recientes muestran una alta incidencia de EA serios para V+C diferentes a los reportados por las RSMAR. Dado que la evidencia disponible no ha mostrado que la relación riesgo-beneficio sea favorable a V+C, en comparación con nivolumab o quimioterapia, la aprobación de uso de V+C en EsSalud no sería una decisión costo-oportuna; tomando en cuenta la disponibilidad del tratamiento con nivolumab, el cual fue aprobado al ser comparado con quimioterapia, eficaz y seguro, recomendado por guías internacionales, con el cual se tiene experiencia de uso y es menos costoso. Por lo expuesto, el IETSI no aprueba el uso de vemurafenib más cobimetinib para el tratamiento de pacientes adultos con melanoma maligno avanzado o metastásico, con mutación BRAF, inoperable y con ECOG 0-1.