Jaione Auzmendi-Iriarte

Bio: Jaione Auzmendi-Iriarte is an academic researcher. The author has contributed to research in topics: Glioma & Stem cell. The author has an hindex of 6, co-authored 10 publications receiving 110 citations.

Liquid Biopsy in Glioblastoma: Opportunities, Applications and Challenges

Abstract: Liquid biopsy represents a minimally invasive procedure that can provide similar information from body fluids to what is usually obtained from a tissue biopsy sample. Its implementation in the clinical setting might significantly renew the field of medical oncology, facilitating the introduction of the concepts of precision medicine and patient-tailored therapies. These advances may be useful in the diagnosis of brain tumors that currently require surgery for tissue collection, or to perform genetic tumor profiling for disease classification and guidance of therapy. In this review, we will summarize the most recent advances and putative applications of liquid biopsy in glioblastoma, the most common and malignant adult brain tumor. Moreover, we will discuss the remaining challenges and hurdles in terms of technology and biology for its clinical application.

Characterization of a new small-molecule inhibitor of HDAC6 in glioblastoma.

Abstract: Histone deacetylase 6 (HDAC6) is an epigenetic modifier that is an attractive pharmacological target in cancer. In this work, we show that HDAC6 is elevated in glioblastoma, the most malignant and common brain tumor in adults, in which its high levels correlate with poor patient survival and is more abundant in glioma stem cell subpopulation. Moreover, we identified a new small-molecule inhibitor of HDAC6, which presents strong sensitivity for HDAC6 inhibition and exerts high cytotoxic activity, alone or in combination with temozolomide. It is also able to significantly reduce tumor growth in vivo. Transcriptomic analysis of patient-derived glioma stem cells revealed an increase in cell differentiation and cell death pathways, as well as a decrease in cell-cycle activity and cell division by the treatment with the compound. Finally, the comparison with a pan-HDAC inhibitor, Vorinostat (SAHA), or HDAC6-specific inhibitor, Tubastatin A, showed higher target specificity and antitumor activity of the new HDAC6 inhibitor. In conclusion, our data reveal the efficacy of a novel HDAC6 inhibitor in glioblastoma preclinical setting.

High expression of MKP1/DUSP1 counteracts glioma stem cell activity and mediates HDAC inhibitor response

Abstract: The elucidation of mechanisms involved in resistance to therapies is essential to improve the survival of patients with malignant gliomas. A major feature possessed by glioma cells that may aid their ability to survive therapy and reconstitute tumors is the capacity for self-renewal. We show here that glioma stem cells (GSCs) express low levels of MKP1, a dual-specificity phosphatase, which acts as a negative inhibitor of JNK, ERK1/2, and p38 MAPK, while induction of high levels of MKP1 expression are associated with differentiation of GSC. Notably, we find that high levels of MKP1 correlate with a subset of glioblastoma patients with better prognosis and overall increased survival. Gain of expression studies demonstrated that elevated MKP1 impairs self-renewal and induces differentiation of GSCs while reducing tumorigenesis in vivo. Moreover, we identified that MKP1 is epigenetically regulated and that it mediates the anti-tumor activity of histone deacetylase inhibitors (HDACIs) alone or in combination with temozolomide. In summary, this study identifies MKP1 as a key modulator of the interplay between GSC self-renewal and differentiation and provides evidence that the activation of MKP1, through epigenetic regulation, might be a novel therapeutic strategy to overcome therapy resistance in glioblastoma.

Impact of Chaperone-Mediated Autophagy in Brain Aging: Neurodegenerative Diseases and Glioblastoma

Abstract: Brain aging is characterized by a time-dependent decline of tissue integrity and function, and it is a major risk for neurodegenerative diseases and brain cancer. Chaperone-mediated autophagy (CMA) is a selective form of autophagy specialized in protein degradation, which is based on the individual translocation of a cargo protein through the lysosomal membrane. Regulation of processes such as proteostasis, cellular energetics, or immune system activity has been associated with CMA, indicating its pivotal role in tissue homeostasis. Since first studies associating Parkinson's disease (PD) to CMA dysfunction, increasing evidence points out that CMA is altered in both physiological and pathological brain aging. In this review article, we summarize the current knowledge regarding the impact of CMA during aging in brain physiopathology, highlighting the role of CMA in neurodegenerative diseases and glioblastoma, the most common and aggressive brain tumor in adults.

Methylation of MGMT promoter does not predict response to temozolomide in patients with glioblastoma in Donostia Hospital.

Abstract: O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status has been considered a prognostic factor in newly diagnosed glioblastoma (GBM). In this study, we evaluated the prognostic and predictive value of MGMT promoter methylation in patients with glioblastoma in Donostia Hospital. Surprisingly, methylation of MGMT promoter did not predict response to temozolomide in patients with glioblastoma in Donostia Hospital. Specifically, overall survival (OS) and progression-free survival (PFS) did not differ significantly by MGMT methylation status in our cohort. In contrast, both were longer in patients who received treatment, received more TMZ cycles, had a better general status and perform at least a partial resection. No association was detected between methylation of MGMT promoter and molecular markers such as ATRX, IDH, p53 and Ki67. These results indicate that MGMT methylation did not influence in patient survival in our cohort.

The somatic genomic landscape of glioblastoma

Abstract: We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

Emerging blood–brain-barrier-crossing nanotechnology for brain cancer theranostics

Abstract: Brain cancer, especially the most common type of glioblastoma, is highly invasive and known as one of the most devastating and deadly neoplasms. Despite surgical and medical advances, the prognosis for most brain cancer patients remains dismal and the median survival rarely exceeds 16 months. Drug delivery to the brain is significantly hindered by the existence of the blood–brain barrier (BBB), which serves as a protective semi-permeable membrane for the central nervous system. Recent breakthroughs in nanotechnology have yielded multifunctional theranostic nanoplatforms with the ability to cross or bypass the BBB, enabling accurate diagnosis and effective treatment of brain tumours. Herein, we make our efforts to present a comprehensive review on the latest remarkable advances in BBB-crossing nanotechnology, with an emphasis on the judicious design of multifunctional nanoplatforms for effective BBB penetration, efficient tumour accumulation, precise tumour imaging, and significant tumour inhibition of brain cancer. The detailed elucidation of BBB-crossing nanotechnology in this review is anticipated to attract broad interest from researchers in diverse fields to participate in the establishment of powerful BBB-crossing nanoplatforms for highly efficient brain cancer theranostics.

Amyloid-type Protein Aggregation and Prion-like Properties of Amyloids.

Abstract: This review will focus on the process of amyloid-type protein aggregation. Amyloid fibrils are an important hallmark of protein misfolding diseases and therefore have been investigated for decades. Only recently, however, atomic or near-atomic resolution structures have been elucidated from various in vitro and ex vivo obtained fibrils. In parallel, the process of fibril formation has been studied in vitro under highly artificial but comparatively reproducible conditions. The review starts with a summary of what is known and speculated from artificial in vitro amyloid-type protein aggregation experiments. A partially hypothetic fibril selection model will be described that may be suitable to explain why amyloid fibrils look the way they do, in particular, why at least all so far reported high resolution cryo-electron microscopy obtained fibril structures are in register, parallel, cross-β-sheet fibrils that mostly consist of two protofilaments twisted around each other. An intrinsic feature of the model is the prion-like nature of all amyloid assemblies. Transferring the model from the in vitro point of view to the in vivo situation is not straightforward, highly hypothetic, and leaves many open questions that need to be addressed in the future.

Liquid Biopsy in Glioblastoma: Opportunities, Applications and Challenges

Abstract: Liquid biopsy represents a minimally invasive procedure that can provide similar information from body fluids to what is usually obtained from a tissue biopsy sample. Its implementation in the clinical setting might significantly renew the field of medical oncology, facilitating the introduction of the concepts of precision medicine and patient-tailored therapies. These advances may be useful in the diagnosis of brain tumors that currently require surgery for tissue collection, or to perform genetic tumor profiling for disease classification and guidance of therapy. In this review, we will summarize the most recent advances and putative applications of liquid biopsy in glioblastoma, the most common and malignant adult brain tumor. Moreover, we will discuss the remaining challenges and hurdles in terms of technology and biology for its clinical application.