KIT/PDGFRA inhibitors for the treatment of gastrointestinal stromal tumors: getting to the gist of the problem.

INTRODUCTION: Approximately 90% of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in receptor tyrosine-kinases KIT or PDGFRA. Despite the outstanding results of first-line imatinib in advanced GIST, resistance ultimately occurs mainly through secondary mutations in KIT/PDGFRA. Other tyrosine-kinase inhibitors (TKIs) with a broader spectrum of activity against these mutations are approved after imatinib failure. However, response rates and progression-free survival are drastically lower compared to imatinib. Notably, imatinib also triggers early tolerance adaptation mechanisms, which precede the occurrence of secondary mutations. AREAS COVERED: In this review, we outline the current landscape of KIT inhibitors, discuss the novel agents, and present additional biological pathways that may be therapeutically exploitable. EXPERT OPINION: The development of broad-spectrum and highly selective TKIs able to induce a sustained KIT/PDGFRA inhibition is the pillar of preclinical and clinical investigation in GIST. However, it is now recognized that the situation is more intricate, with various factors interacting with KIT and PDGFRA, playing a crucial role in the response and resistance to treatments. Future strategies in the management of advanced GIST should integrate driver inhibition with the blockade of other molecules to enhance cell death and establish enduring responses in patients.

E3 ubiquitin ligase Atrogin-1 mediates adaptive resistance to KIT-targeted inhibition in gastrointestinal stromal tumor.

KIT/PDGFRA oncogenic tyrosine kinase signaling is the central oncogenic event in most gastrointestinal stromal tumors (GIST), which are human malignant mesenchymal neoplasms that often feature myogenic differentiation. Although targeted inhibition of KIT/PDGFRA provides substantial clinical benefit, GIST cells adapt to KIT/PDGFRA driver suppression and eventually develop resistance. The specific molecular events leading to adaptive resistance in GIST remain unclear. By using clinically representative in vitro and in vivo GIST models and GIST patients' samples, we found that the E3 ubiquitin ligase Atrogin-1 (FBXO32)-the main effector of muscular atrophy in cachexia-resulted in the most critical gene derepressed in response to KIT inhibition, regardless the type of KIT primary or secondary mutation. Atrogin-1 in GISTs is transcriptionally controlled by the KIT-FOXO3a axis, thus indicating overlap with Atrogin-1 regulation mechanisms in nonneoplastic muscle cells. Further, Atrogin-1 overexpression was a GIST-cell-specific pro-survival mechanism that enabled the adaptation to KIT-targeted inhibition by apoptosis evasion through cell quiescence. Buttressed on these findings, we established in vitro and in vivo the preclinical proof-of-concept for co-targeting KIT and the ubiquitin pathway to maximize the therapeutic response to first-line imatinib treatment.

Commensal Clostridiales strains mediate effective anti-cancer immune response against solid tumors.

Despite overall success, T cell checkpoint inhibitors for cancer treatment are still only efficient in a minority of patients. Recently, intestinal microbiota was found to critically modulate anti-cancer immunity and therapy response. Here, we identify Clostridiales members of the gut microbiota associated with a lower tumor burden in mouse models of colorectal cancer (CRC). Interestingly, these commensal species are also significantly reduced in CRC patients compared with healthy controls. Oral application of a mix of four Clostridiales strains (CC4) in mice prevented and even successfully treated CRC as stand-alone therapy. This effect depended on intratumoral infiltration and activation of CD8+ T cells. Single application of Roseburia intestinalis or Anaerostipes caccae was even more effective than CC4. In a direct comparison, the CC4 mix supplementation outperformed anti-PD-1 therapy in mouse models of CRC and melanoma. Our findings provide a strong preclinical foundation for exploring gut bacteria as novel stand-alone therapy against solid tumors.

A comprehensive overview of FCGR3A gene variability by full-length gene sequencing including the identification of V158F polymorphism.

The FCGR3A gene encodes for the receptor important for antibody-dependent natural killer cell-mediated cytotoxicity. FCGR3A gene polymorphisms could affect the success of monoclonal antibody therapy. Although polymorphisms, such as the FcγRIIIA-V158F and -48L/R/H, have been studied extensively, an overview of other polymorphisms within this gene is lacking. To provide an overview of FCGR3A polymorphisms, we analysed the 1000 Genomes project database and found a total of 234 polymorphisms within the FCGR3A gene, of which 69%, 16%, and 15% occur in the intron, UTR, and exon regions respectively. Additionally, only 16% of all polymorphisms had a minor allele frequency (MAF) > 0.01. To facilitate (full-length) analysis of FCGR3A gene polymorphism, we developed a FCGR3A gene-specific amplification and sequencing protocol for Sanger sequencing and MinION (Nanopore Technologies). First, we used the Sanger sequencing protocol to study the presence of the V158F polymorphism in 76 individuals resulting in frequencies of 38% homozygous T/T, 7% homozygous G/G and 55% heterozygous. Next, we performed a pilot with both Sanger sequencing and MinION based sequencing of 14 DNA samples which showed a good concordance between Sanger- and MinION sequencing. Additionally, we detected 13 SNPs listed in the 1000 Genome Project, from which 11 had MAF > 0.01, and 10 SNPs were not listed in 1000 Genome Project. In summary, we demonstrated that FCGR3A gene is more polymorphic than previously described. As most novel polymorphisms are located in non-coding regions, their functional relevance needs to be studied in future functional studies.

Esquema Móvil de insulina: El principio del fin

Existe una alta prevalencia de diabetes mellitus tipo 2 (DM) a nivel mundial, y se espera que ésta se duplique en los próximos veinte años. Los pacientes con DM corresponden a un cuarto de los pacientes hospitalizados, debiendo ser manejados con insulina durante su hospitalización. El esquema móvil de insulina es el modo de administración de insulina más utilizado en el paciente con DM hospitalizado, y actualmente existe gran controversia alrededor de su uso, con escasa evidencia científica que sustente su beneficio, estableciéndose una tendencia actual a su eliminación. Se hace una revisión al respecto.

There is a high prevalence of type 2 diabetes mellitus (DM) worldwide and it is expected to double over the next twenty years. Patients with DM correspond to one quarter of hospitalized patients and should be managed with insulin during their hospitalization. The sliding scale regular insulin is the way most used of insulin therapy in hospitalized patients with DM, and there is now controversy about its use, with little scientific evidence to support its benefit, establishing a trend for disposal. A review on the matter is done.

Síndrome metabólico como factor de riesgo para enfermedad cardiovascular / Cardiovascular disease and the metabolic syndrome

Investigar la asociación entre enfermedad cardiovascular y síndrome metabólico, definido este por los criterios del NCEP/ATP III en pacientes del Servicio de Medicina Interna del Hospital Universitario de Los Andes, en el período comprendido entre el 15 de marzo al 30 de junio de 2004. Se incluyeron 82 pacientes hospitalizados por enfermedad cardiovascular (caso) y 82 pacientes ambulatorios sin enfermedad cardiovascular (controles). Se recopiló y analizó la información relacionada con los datos demográficos, criterios para identificar síndrome metabólico, y variables relacionadas. El promedio de edad fue de 54,76 años. Un 59,8 por ciento correspondió al sexo femenino y 40,2 por ciento masculino. La frecuencia de síndrome metabólico fue de 72(43,9 por ciento), 56,09 por ciento en el grupo de casos y 31,7 por ciento en el grupo control. Se encontró asociación estadística y epidemiológica entre la presencia de enfermedad cardiovascular y síndrome metabólico con (P=0,003) y OR=2,75 (IC 95 por ciento = 1,39-5,49). No se encontró asociación con género, diabetes y obesidad. Hubo diferencia significativa en los valores de C-HDL(P<0,001), glicemia basal (P<0,001), y tensión arterial diastólica (p=0,02) en relación con la presencia de enfermedad cardiovascular.

Inmunodiagnóstico de la neurocisticercosis: estudio comparativo de extractos antigénicos de Cysticercus cellulosae y Taenia crassiceps / Immunodiagnosis of neurocysticercosis: comparative study of antigenic extracts from Cysticercus cellulosae and Taenia crassiceps

Different antigenic extracts of Taenia solium and Taenia crassiceps were evaluated in connection with the detection of antibodies in patients with neurocysticercosis aimed at selecting immunorelevant antigens for the diagnosis of neurocysticercosis by means of the immunoenzymatic assay and immunoblotting. The vesicular fluid of T. crassiceps proved to be more sensitive (100) and specific (86). On using the immunoblotting technique it was also observed that this extract was the most sensitive and specific. Within the protein profile of the antigen the band of 18 kDa was mostly recognized by the serum and cerebrospinal fluid of patients with neurocysticercosis. The vesicular fluid of T. crassiceps represents an alternative in the optimization of the diagnosis of neurocysticercosis in the serum and cerebrospinal fluid and in the substitution of T. solium antigens due to its high sensitivity and specificity and to its easy obtention under controlled laboratory conditions.