RESUMEN
The blood brain barrier (BBB) plays a critically important role in the regulation of central nervous system (CNS) homeostasis, but also represents a major limitation to treatments of brain pathologies. In recent years, focused ultrasound (FUS) in conjunction with gas-filled microbubble contrast agents has emerged as a powerful tool for transiently and non-invasively disrupting the BBB in a targeted and image-guided manner, allowing for localized delivery of drugs, genes, or other therapeutic agents. Beyond the delivery of known therapeutics, FUS-mediated BBB opening also demonstrates the potential for use in neuromodulation and the stimulation of a range of cell- and tissue-level physiological responses that may prove beneficial in disease contexts. Clinical trials investigating the safety and efficacy of FUS-mediated BBB opening are well underway, and offer promising non-surgical approaches to treatment of devastating pathologies. This article reviews a range of pre-clinical and clinical studies demonstrating the tremendous potential of FUS to fundamentally change the paradigm of treatment for CNS diseases.
Asunto(s)
Barrera Hematoencefálica , Microburbujas , Humanos , Transporte Biológico , Medios de Contraste , Sistemas de Liberación de Medicamentos , Imagen por Resonancia MagnéticaRESUMEN
Solid tumor treatment relies heavily upon chemotherapies, radiation, surgical resection, and/or immunotherapies. Although many alternative non-invasive solid tumor therapies have been proposed through the years and continue to be tested in various contexts, tumor cell eradication remains a daunting task for the current cancer armamentarium. Indeed, solid tumors exhibit physically and biochemically heterogenous microenvironments, allowing them to easily acquire resistance mechanisms. Progress in sonodynamic therapy (SDT), a treatment modality capable of controlling tumor growth while limiting off-target effects and toxicities, has accelerated in recent years. SDT combines "sonosensitizing" agents with the non-invasive application of focused acoustic energy [i.e. focused ultrasound (FUS)] to drive highly localized formation of tumor cell-killing reactive oxygen species (ROS). Sonosensitizers selectively accumulate in tumor cells, after which FUS radiation eliminates the tumor by forcing the tumor cells to undergo cell death. In this article, we comprehensively review recent studies wherein SDT has been applied to treat primary and metastatic tumors. We discuss sonosensitizers, combination therapies with SDT, developments in defining the mechanism of SDT-induced cell cytotoxicity, and the promise SDT offers as a modulator of anti-tumor immunity.
Asunto(s)
Neoplasias , Terapia por Ultrasonido , Muerte Celular , Línea Celular Tumoral , Terapia Combinada , Humanos , Neoplasias/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Microambiente TumoralRESUMEN
To identify therapeutic targets for KRAS mutant pancreatic cancer, we conduct a druggable genome small interfering RNA (siRNA) screen and determine that suppression of BCAR1 sensitizes pancreatic cancer cells to ERK inhibition. Integrative analysis of genome-scale CRISPR-Cas9 screens also identify BCAR1 as a top synthetic lethal interactor with mutant KRAS. BCAR1 encodes the SRC substrate p130Cas. We determine that SRC-inhibitor-mediated suppression of p130Cas phosphorylation impairs MYC transcription through a DOCK1-RAC1-ß-catenin-dependent mechanism. Additionally, genetic suppression of TUBB3, encoding the ßIII-tubulin subunit of microtubules, or pharmacological inhibition of microtubule function decreases levels of MYC protein in a calpain-dependent manner and potently sensitizes pancreatic cancer cells to ERK inhibition. Accordingly, the combination of a dual SRC/tubulin inhibitor with an ERK inhibitor cooperates to reduce MYC protein and synergistically suppress the growth of KRAS mutant pancreatic cancer. Thus, we demonstrate that mechanistically diverse combinations with ERK inhibition suppress MYC to impair pancreatic cancer proliferation.