RESUMEN
Despite major advances in health care including improved diagnostic tools, robust chemotherapeutic regimens, advent of precision, adjuvant and multimodal therapies, there is a major proportion of patients that still go on to experience tumor progression and recurrence. Cancer stem cells (CSCs) are shown to be responsible for tumor persistence and relapse. This subpopulation of cancer cells possess normal stem cell like traits of self-renewal, proliferation, and multilineage differentiation. Currently, they are isolated and enriched based on the cell surface markers that can be detected and sorted through fluorescence and magnetic-based cell sorting. In this chapter, we review the current challenges and limitations often encountered in CSC research, including the identification of universal markers, therapy resistance, and new drug development. Current and future perspectives are discussed to address these challenges including utilization of cutting-edge technologies such as next-generation sequencing to elucidate the genome, epigenome, and transcriptome on a single-cell level and genome-wide CRISPR-Cas9 screens to identify novel pathway-based targeted therapies. Further, we discuss the future of precision medicine and the need for the improvement of clinical trial designs.
Asunto(s)
Neoplasias , Humanos , Neoplasias/genética , Neoplasias/terapia , Neoplasias/metabolismo , Células Madre Neoplásicas/metabolismo , TranscriptomaRESUMEN
Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. In this study, we investigated functional drivers of post-treatment recurrent GBM through integrative genomic analyses, genome-wide genetic perturbation screens in patient-derived GBM models and independent lines of validation. Specific genetic dependencies were found consistent across recurrent tumor models, accompanied by increased mutational burden and differential transcript and protein expression compared to its primary GBM predecessor. Our observations suggest a multi-layered genetic response to drive tumor recurrence and implicate PTP4A2 (protein tyrosine phosphatase 4A2) as a modulator of self-renewal, proliferation and tumorigenicity in recurrent GBM. Genetic perturbation or small-molecule inhibition of PTP4A2 acts through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1) and its downstream molecular players, exploiting a functional dependency on ROBO signaling. Because a pan-PTP4A inhibitor was limited by poor penetrance across the blood-brain barrier in vivo, we engineered a second-generation chimeric antigen receptor (CAR) T cell therapy against ROBO1, a cell surface receptor enriched across recurrent GBM specimens. A single dose of ROBO1-targeted CAR T cells doubled median survival in cell-line-derived xenograft (CDX) models of recurrent GBM. Moreover, in CDX models of adult lung-to-brain metastases and pediatric relapsed medulloblastoma, ROBO1 CAR T cells eradicated tumors in 50-100% of mice. Our study identifies a promising multi-targetable PTP4A-ROBO1 signaling axis that drives tumorigenicity in recurrent GBM, with potential in other malignant brain tumors.
RESUMEN
Pediatric medulloblastoma (MB) is the most common solid malignant brain neoplasm, with Group 3 (G3) MB representing the most aggressive subgroup. MYC amplification is an independent poor prognostic factor in G3 MB, however, therapeutic targeting of the MYC pathway remains limited and alternative therapies for G3 MB are urgently needed. Here we show that the RNA-binding protein, Musashi-1 (MSI1) is an essential mediator of G3 MB in both MYC-overexpressing mouse models and patient-derived xenografts. MSI1 inhibition abrogates tumor initiation and significantly prolongs survival in both models. We identify binding targets of MSI1 in normal neural and G3 MB stem cells and then cross referenced these data with unbiased large-scale screens at the transcriptomic, translatomic and proteomic levels to systematically dissect its functional role. Comparative integrative multi-omic analyses of these large datasets reveal cancer-selective MSI1-bound targets sharing multiple MYC associated pathways, providing a valuable resource for context-specific therapeutic targeting of G3 MB.