Impact of KRASG12D subtype and concurrent pathogenic mutations on advanced non-small cell lung cancer outcomes

Propósito: Las mutaciones en el oncogén viral del sarcoma de rata de Kirsten (KRAS) constituyen un importante impulsor del adenocarcinoma de pulmón, presente en el 10-40% de los pacientes, que exhiben resultados clínicos heterogéneos, principalmente impulsados por alteraciones genéticas concurrentes. Sin embargo, la caracterización de los subtipos mutacionales de KRAS y su impacto en los resultados clínicos en Latinoamérica es limitada. Métodos: Se realizó un estudio de cohorte en el Instituto Nacional de Cancerología (INCan) de México. Se incluyeron para el análisis individuos con estadios avanzados de adenocarcinoma y mutaciones de KRAS, detectadas por secuenciación de próxima generación, que habían sido sometidos al menos a una línea de terapia. Las características clínicas y patológicas se recuperaron de la base de datos institucional de junio de 2014 a marzo de 2023. Resultados: KRAS fue identificado en cincuenta y cuatro (15,6%) de 346 pacientes, entre los cuales 50 casos fueron incluidos para el análisis. KRASG12D (n = 16, 32%) y KRASG12C (n = 16, 32%) representaron los subtipos más prevalentes. Las mutaciones en KRASG12D se asociaron con el sexo femenino (p = 0,018), con no haber fumado nunca (p = 0,108) y con concurrencias con EGFR (25,0% frente a 17,6%, p = 0,124) y CDKN2A (18,8% frente a 14,7%, p = 0,157). Los pacientes con KRASG12D mostraron una mejor ORR (66,6% vs. 30,0%; OR 4,66; IC 95% 1,23-17,60; p = 0,023) y en el análisis multivariante se asoció significativamente con una mejor SLP (HR 0,36; IC 95% 0,16-0,80; p = 0,012) y SG (HR 0,24; IC 95% 0,08-0,70; p = 0,009). Conclusiones: Hasta donde sabemos, este estudio representa el primer esfuerzo por caracterizar exhaustivamente la heterogeneidad molecular del CPCNP con mutación de KRAS en pacientes latinoamericanos. Nuestros datos refuerzan la opinión actual de que el CPNM con mutación de KRAS no es una enfermedad impulsada por un único oncogén y enfatiza el impacto pronóstico de los diversos perfiles moleculares en este subconjunto genómicamente definido de CPNM. Se justifica una mayor validación en cohortes latinoamericanas multicéntricas más grandes para confirmar nuestros hallazgos. 2023, El Autor (es).Purpose: Mutations in the Kirsten rat sarcoma viral (KRAS) oncogene constitute a significant driver of lung adenocarcinoma, present in 10–40% of patients, which exhibit heterogeneous clinical outcomes, mainly driven by concurrent genetic alterations. However, characterization of KRAS mutational subtypes and their impact on clinical outcomes in Latin America is limited. Methods: A cohort study was conducted at the National Cancer Institute (INCan) of Mexico. Individuals with advance-staged of adenocarcinoma and KRAS mutations, detected by next-generation sequencing, having undergone at least one line of therapy were included for analysis. Clinical and pathological characteristics were retrieved from institutional database from June 2014 to March 2023. Results: KRAS was identified in fifty-four (15.6%) of 346 patients, among which 50 cases were included for analysis. KRASG12D (n = 16, 32%) and KRASG12C (n = 16, 32%) represented the most prevalent subtypes. KRASG12D mutations were associated with female (p = 0.018), never smokers (p = 0.108), and concurrences with EGFR (25.0% vs. 17.6%, p = 0.124) and CDKN2A (18.8% vs. 14.7%, p = 0.157). KRASG12D patients showed a better ORR (66.6% vs. 30.0%; OR 4.66, 95% CI 1.23–17.60, p = 0.023) and on multivariate analysis was significantly associated with better PFS (HR 0.36, 95% CI 0.16–0.80; p = 0.012) and OS (HR 0.24, 95% CI 0.08–0.70; p = 0.009). Conclusions: To our knowledge, this study represents the first effort to comprehensively characterize the molecular heterogeneity of KRAS-mutant NSCLC in Latin American patients. Our data reinforce the current view that KRAS-mutated NSCLC is not a single oncogene-driven disease and emphasizes the prognostic impact of diverse molecular profiles in this genomically defined subset of NSCLC. Further validation is warranted in larger multicenter Latin American cohorts to confirm our findings. © 2023, The Author(s)

An Update in the Use of Antibodies to Treat Glioblastoma Multiforme

Glioblastoma is a deadly brain disease and modest improvement in survival has been made. At initial diagnosis, treatment consists of maximum safe surgical resection, followed by temozolomide and chemoirradiation or adjuvant temozolomide alone. However, these treatments do not improve the prognosis and survival of patients. New treatment strategies are being sought according to the biology of tumors. The epidermal growth factor receptor has been considered as the hallmark in glioma tumors; thereby, some antibodies have been designed to bind to this receptor and block the downstream signaling pathways. Also, it is known that vascularization plays an important role in supplying new vessels to the tumor; therefore, new therapy has been guided to inhibit angiogenic growth factors in order to limit tumor growth. An innovative strategy in the treatment of glial tumors is the use of toxins produced by bacteria, which may be coupled to specific carrier-ligands and used for tumoral targeting. These carrier-ligands provide tumor-selective properties by the recognition of a cell-surface receptor on the tumor cells and promote their binding of the toxin-carrier complex prior to entry into the cell. Here, we reviewed some strategies to improve the management and treatment of glioblastoma and focused on the use of antibodies

RB mutation and RAS overexpression induce resistance to NK cell-mediated cytotoxicity in glioma cells

Several theories aim to explain the malignant transformation of cells, including the mutation of tumor suppressors and proto-oncogenes. Deletion of Rb (a tumor suppressor), overexpression of mutated Ras (a proto-oncogene), or both, are sufficient for in vitro gliomagenesis, and these genetic traits are associated with their proliferative capacity. An emerging hallmark of cancer is the ability of tumor cells to evade the immune system. Whether specific mutations are related with this, remains to be analyzed. To address this issue, three transformed glioma cell lines were obtained (Rb(-/-), Ras(V12), and Rb(-/-)/Ras(V12)) by in vitro retroviral transformation of astrocytes, as previously reported. In addition, Ras(V12) and Rb(-/-)/Ras(V12) transformed cells were injected into SCID mice and after tumor growth two stable glioma cell lines were derived. All these cells were characterized in terms of Rb and Ras gene expression, morphology, proliferative capacity, expression of MHC I, Rae1delta, and Rae1alphabetagammadeltaepsilon, mult1, H60a, H60b, H60c, as ligands for NK cell receptors, and their susceptibility to NK cell-mediated cytotoxicity. Our results show that transformation of astrocytes (Rb loss, Ras overexpression, or both) induced phenotypical and functional changes associated with resistance to NK cell-mediated cytotoxicity. Moreover, the transfer of cell lines of transformed astrocytes into SCID mice increased resistance to NK cell-mediated cytotoxicity, thus suggesting that specific changes in a tumor suppressor (Rb) and a proto-oncogene (Ras) are enough to confer resistance to NK cell-mediated cytotoxicity in glioma cells and therefore provide some insight into the ability of tumor cells to evade immune responses.Xunta de GaliciaComisión EuropeaInstituto de Salud Carlos IIIConsejo Nacional de Ciencia y Tecnologia (CONACyT)Consejo Nacional de Ciencia y Tecnologia (CONACyT)FOSSISXunta de Galicia/PXIB208091PRISCIII/CB158340ISCIII/CB180851FOSSIS/18236

Cytotoxicity induced by carbon nanotubes in experimental malignant glioma

"Despite multiple advances in the diagnosis of brain tumors, there is no effective treatment for glioblastoma. Multiwalled carbon nanotubes (MWCNTs), which were previously used as a diagnostic and drug delivery tool, have now been explored as a possible therapy against neoplasms. However, although the toxicity profile of nanotubes is dependent on the physicochemical characteristics of specific particles, there are no studies exploring how the effectivity of the carbon nanotubes (CNTs) is affected by different methods of production. In this study, we characterize the structure and biocompatibility of four different types of MWCNTs in rat astrocytes and in RG2 glioma cells as well as the induction of cell lysis and possible additive effect of the combination of MWCNTs with temozolomide. We used undoped MWCNTs (labeled simply as MWCNTs) and nitrogen-doped MWCNTs (labeled as N-MWCNTs). The average diameter of both pristine MWCNTs and pristine N-MWCNTs was ~22 and ~35 nm, respectively. In vitro and in vivo results suggested that these CNTs can be used as adjuvant therapy along with the standard treatment to increase the survival of rats implanted with malignant glioma.

Protein Translation Inhibition is Involved in the Activity of the Pan-PIM Kinase Inhibitor PIM447 in Combination with Pomalidomide-Dexamethasone in Multiple Myeloma

Background: Proviral Insertion site for Moloney murine leukemia virus (PIM) kinases are overexpressed in hematologic malignancies, including multiple myeloma. Previous preclinical data from our group demonstrated the anti-myeloma effect of the pan-PIM kinase inhibitor PIM447. Methods: Based on those data, we evaluate here, by in vitro and in vivo studies, the activity of the triple combination of PIM447 + pomalidomide + dexamethasone (PIM-Pd) in multiple myeloma. Results: Our results show that the PIM-Pd combination exerts a potent anti-myeloma effect in vitro and in vivo, where it markedly delays tumor growth and prolongs survival of treated mice. Mechanism of action studies performed in vitro and on mice tumor samples suggest that the combination PIM-Pd inhibits protein translation processes through the convergent inhibition of c-Myc and mTORC1, which subsequently disrupts the function of eIF4E. Interestingly the MM pro-survival factor IRF4 is also downregulated after PIM-Pd treatment. As a whole, all these molecular changes would promote cell cycle arrest and deregulation of metabolic pathways, including glycolysis and lipid biosynthesis, leading to inhibition of myeloma cell proliferation. Conclusions: Altogether, our data support the clinical evaluation of the triple combination PIM-Pd for the treatment of patients with multiple myeloma.This work was supported by funding from Spanish FIS (PI15/00067, PI15/02156 and PI18/01600) and FEDER, AECC (GCB120981SAN), Junta de Castilla y León, Consejería de Sanidad (GRS 862/A/13 and BIO/SA05/14), Fundación Memoria de D. Samuel Solórzano Barruso of the University of Salamanca (FS/22-2015), Fundación Ramón Areces (FRA16/003), Sociedad Española de Hematología y Hemoterapia and Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León. E.M.O. was supported by an Inplant grant from IDIVAL. T.P. is supported by a grant from AECC (INVES18043PAÍN)

Preclinical evaluation of the simultaneous inhibition of MCL-1 and BCL-2 with the combination of S63845 and venetoclax in multiple myeloma

This work was supported by the Spanish ISCIII-FIS and FEDER Funds (PI 15/00067 and PI 15/02156) and the Regional Health Council of Castilla y León (GRS 1604/A/17). EMA was supported by a grant from the Regional Education Council of Castilla y León co-financed by the European Social Fund

The kinesin spindle protein inhibitor filanesib enhances the activity of pomalidomide and dexamethasone in multiple myeloma

[EN]Kinesin spindle protein inhibition is known to be an effective therapeutic approach in several malignancies. Filanesib (ARRY-520), an inhibitor of this protein, has demonstrated activity in heavily pre-treated multiple myeloma patients. The aim of the work herein was to investigate the activity of filanesib in combination with pomalidomide plus dexamethasone backbone, and the mechanisms underlying the potential synergistic effect. The ability of filanesib to enhance the activity of pomalidomide plus dexamethasone was studied in several in vitro and in vivo models. Mechanisms of this synergistic combination were dissected by gene expression profiling, immunostaining, cell cycle and short interfering ribonucleic acid studies. Filanesib showed in vitro, ex vivo, and in vivo synergy with pomalidomide plus dexamethasone treatment. Importantly, the in vivo synergy observed in this combination was more evident in large, highly proliferative tumors, and was shown to be mediated by the impairment of mitosis transcriptional control, an increase in monopolar spindles, cell cycle arrest and the induction of apoptosis in cells in proliferative phases. In addition, the triple combination increased the activation of the proapoptotic protein BAX, which has previously been associated with sensitivity to filanesib, and could potentially be used as a predictive biomarker of response to this combination. Our results provide preclinical evidence for the potential benefit of the combination of filanesib with pomalidomide and dexamethasone, and supported the initiation of a recently activated trial being conducted by the Spanish Myeloma group which is investigating this combination in relapsed myeloma patients.Array BioPharma, the Spanish ISCIII-FIS and FEDER, the Spanish RTICC, Spanish Association Against Cancer (AECC) and the Regional Council of Castilla y León (Consejería de Medicina y Educación)

Manejo actual de la otitis externa maligna. Una revisión sistemática.

INTRODUCTION: Malignant external otitis (OEM), or also called necrotizing external otitis, is a life-threatening infection, mainly affecting the external auditory canal, producing osteomyelitis of the temporal bone; extends to the base of the skull and surrounding tissue, causing sepsis; eventually compromising the cranial nerves and generating multisystemic. Objectives: To describe the current management of malignant external otitis. Specific objectives: 1) To determine the etiology of malignant external otitis. 2) To determine the complications of malignant external otitis. METHODS: A systematic review was performed according to the PRISMA 2020 guidelines with a search for scientific articles, with the term malignant external otitis. We recovered 40 articles corresponding to the last 5 years, obtained from databases such as Cochrane, academic Google, Medline, Mendeley, ScientDirect, IntechOpen. The risks of bias in the studies showed systematic differences due to the heterogeneity of the patients and the treatments between the groups. RESULTS: the management of malignant external otitis includes treatment with anti-pseudomonas antibiotics such as fluoroquinolones in combination with a beta-lactam and an antifungal such as amphotericin B, voriconazole, fluconazole, or echinocandin; in addition to treatment with surgical debridement of the ear canal and radical mastoidectomy, to avoid the risk of neurocranial sepsis, obtaining good results. DISCUSSION: Malignant external otitis is a pathology of rare occurrence that affects immune immunocompromised patients, whose morbidity and mortality is high, if not treated properly. Its main causal agents are: pseudomona aeruginosa, staphylococcus aureus, Candida spp, Aspergillus spp and Geotrichum. The importance of this research lies in optimizing care in the patient with OEM, making a timely clinical and imaging diagnosis, to provide an effective therapeutic alternative, based on broad-spectrum antibiotic therapy, antifungal treatment, and surgical treatment, to avoid complications.INTRODUCCIÓN: La otitis externa maligna (OEM), o también llamada otitis externa necrotizante, es una infección potencialmente mortal, que afecta principalmente al canal auditivo externo, produciendo osteomielitis del hueso temporal; se extiende hasta la base del cráneo y tejido circundante, provocando sepsis; llegando a comprometer los nervios craneales y generar afección multisistémica. Objetivos General: Describir el manejo actual de la otitis externa maligna. Objetivos específicos: 1) Determinar la etiología de la otitis externa maligna.  2) Determinar las complicaciones de la de la otitis externa maligna. MÉTODOS: se realizó una revisión sistemática según las guías PRISMA 2020 con búsqueda de artículos científicos, con el termino otitis externa maligna. Se recuperaron 40 artículos correspondientes a los últimos 5 años, obtenidos de bases de datos como Cochrane, Google académico, Medline, Mendeley, ScientDirect, IntechOpen. Los riesgos de sesgo en los estudios observaron diferencias sistemáticas por la heterogeneidad de los pacientes y los tratamientos entre los grupos.  RESULTADOS: el manejo de la otitis externa maligna incluye tratamiento con antibióticos anti pseudomona como las fluoroquinolonas en combinación con un betalactámico y un antifúngico como la anfotericina B, voriconazol, fluconazol o equinocandinas; además del tratamiento con desbridamiento quirúrgico del canal auditivo y mastoidectomía radical, para evitar el riesgo de sepsis neurocraneal, obteniéndose buenos resultados.  DISCUSIÓN: La otitis externa maligna, es una patología de rara ocurrencia que afecta a pacientes inmunocomprometidos, cuya morbimortalidad es alta, si no se trata adecuadamente. Sus principales agentes causales son: pseudomona aeruginosa, estafilococo aureus, Cándida spp, Aspergillus spp y Geotrichum. La importancia de esta investigación radica en optimizar la atención en el paciente con OEM, realizando un diagnóstico clínico e imagenológico oportuno, para brindar una alternativa terapéutica eficaz, basada en antibioticoterapia de amplio espectro, el tratamiento antifúngico, complementario al tratamiento quirúrgico, para evitar complicaciones