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19 pages, 2946 KiB

Open AccessArticle

The Analysis of Trends in Survival for Patients with Melanoma Brain Metastases with Introduction of Novel Therapeutic Options before the Era of Combined Immunotherapy—Multicenter Italian–Polish Report

by Joanna Placzke, Paweł Teterycz, Pietro Quaglino, Bozena Cybulska-Stopa, Marco Tucci, Marco Rubatto, Tomasz Skora, Valeria Interno, Magdalena Rosinska, Aneta Borkowska, Anna Szumera-Cieckiewicz, Mario Mandala and Piotr Rutkowski

Cancers 2022, 14(23), 5763; https://doi.org/10.3390/cancers14235763 - 23 Nov 2022

Cited by 4 | Viewed by 1707

Abstract

Stage IV melanoma patients develop melanoma brain metastases (MBM) in 50% of cases. Their prognosis is improving, and its understanding outside the context of clinical trials is relevant. We have retrospectively analyzed the clinical data, course of treatment, and outcomes of 531 subsequent [...] Read more.

Stage IV melanoma patients develop melanoma brain metastases (MBM) in 50% of cases. Their prognosis is improving, and its understanding outside the context of clinical trials is relevant. We have retrospectively analyzed the clinical data, course of treatment, and outcomes of 531 subsequent stage IV melanoma patients with BM treated in five reference Italian and Polish melanoma centers between 2014 and 2021. Patients with MBM after 2017 had a better prognosis, with a significantly improved median of overall survival (OS) after 2017 in the worst mol-GPA prognostic groups (mol-GPA ≤ 2): a median OS >6 months and HR 0.76 vs. those treated before 2017 (CI: 0.60–0.97, p = 0.027). In our prognostic model, mol-GPA was highly predictive for survival, and symptoms without steroid use did not have prognostic significance. Local therapy significantly improved survival regardless of the year of diagnosis (treated before or after 2017), with median survival >12 months. Systemic therapy improved outcomes when it was combined with local therapy. Local surgery was associated with improved OS regardless of the timing related to treatment start (i.e., before or after 30 days from MBM diagnosis). Local and systemic treatment significantly prolong survival for the poorest mol-GPA prognosis. Use of modern treatment modalities is justified in all mol-GPA prognostic groups. Full article

(This article belongs to the Special Issue New Approaches with Precision Medicine in Brain Tumors)

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14 pages, 3137 KiB

Open AccessArticle

The Effect of Atm Loss on Radiosensitivity of a Primary Mouse Model of Pten-Deleted Brainstem Glioma

by Connor E. Stewart, María E. Guerra-García, Lixia Luo, Nerissa T. Williams, Yan Ma, Joshua A. Regal, Debosir Ghosh, Patrick Sansone, Mark Oldham, Katherine Deland, Oren J. Becher, David G. Kirsch and Zachary J. Reitman

Cancers 2022, 14(18), 4506; https://doi.org/10.3390/cancers14184506 - 17 Sep 2022

Cited by 2 | Viewed by 2217

Abstract

Diffuse midline gliomas arise in the brainstem and other midline brain structures and cause a large proportion of childhood brain tumor deaths. Radiation therapy is the most effective treatment option, but these tumors ultimately progress. Inhibition of the phosphoinositide-3-kinase (PI3K)-like kinase, ataxia–telangiectasia mutated [...] Read more.

Diffuse midline gliomas arise in the brainstem and other midline brain structures and cause a large proportion of childhood brain tumor deaths. Radiation therapy is the most effective treatment option, but these tumors ultimately progress. Inhibition of the phosphoinositide-3-kinase (PI3K)-like kinase, ataxia–telangiectasia mutated (ATM), which orchestrates the cellular response to radiation-induced DNA damage, may enhance the efficacy of radiation therapy. Diffuse midline gliomas in the brainstem contain loss-of-function mutations in the tumor suppressor PTEN, or functionally similar alterations in the phosphoinositide-3-kinase (PI3K) pathway, at moderate frequency. Here, we sought to determine if ATM inactivation could radiosensitize a primary mouse model of brainstem glioma driven by Pten loss. Using Cre/loxP recombinase technology and the RCAS/TVA retroviral gene delivery system, we established a mouse model of brainstem glioma driven by Pten deletion. We find that Pten-null brainstem gliomas are relatively radiosensitive at baseline. In addition, we show that deletion of Atm in the tumor cells does not extend survival of mice bearing Pten-null brainstem gliomas after focal brain irradiation. These results characterize a novel primary mouse model of PTEN-mutated brainstem glioma and provide insights into the mechanism of radiosensitization by ATM deletion, which may guide the design of future clinical trials. Full article

(This article belongs to the Special Issue New Approaches with Precision Medicine in Brain Tumors)

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17 pages, 16683 KiB

Open AccessArticle

A Tumor-Homing Peptide Platform Enhances Drug Solubility, Improves Blood–Brain Barrier Permeability and Targets Glioblastoma

by Choi-Fong Cho, Charlotte E. Farquhar, Colin M. Fadzen, Benjamin Scott, Pei Zhuang, Niklas von Spreckelsen, Andrei Loas, Nina Hartrampf, Bradley L. Pentelute and Sean E. Lawler

Cancers 2022, 14(9), 2207; https://doi.org/10.3390/cancers14092207 - 28 Apr 2022

Cited by 9 | Viewed by 3697

Abstract

Background: Glioblastoma (GBM) is the most common and deadliest malignant primary brain tumor, contributing significant morbidity and mortality among patients. As current standard-of-care demonstrates limited success, the development of new efficacious GBM therapeutics is urgently needed. Major challenges in advancing GBM chemotherapy include [...] Read more.

Background: Glioblastoma (GBM) is the most common and deadliest malignant primary brain tumor, contributing significant morbidity and mortality among patients. As current standard-of-care demonstrates limited success, the development of new efficacious GBM therapeutics is urgently needed. Major challenges in advancing GBM chemotherapy include poor bioavailability, lack of tumor selectivity leading to undesired side effects, poor permeability across the blood–brain barrier (BBB), and extensive intratumoral heterogeneity. Methods: We have previously identified a small, soluble peptide (BTP-7) that is able to cross the BBB and target the human GBM extracellular matrix (ECM). Here, we covalently attached BTP-7 to an insoluble anti-cancer drug, camptothecin (CPT). Results: We demonstrate that conjugation of BTP-7 to CPT improves drug solubility in aqueous solution, retains drug efficacy against patient-derived GBM stem cells (GSC), enhances BBB permeability, and enables therapeutic targeting to intracranial GBM, leading to higher toxicity in GBM cells compared to normal brain tissues, and ultimately prolongs survival in mice bearing intracranial patient-derived GBM xenograft. Conclusion: BTP-7 is a new modality that opens the door to possibilities for GBM-targeted therapeutic approaches. Full article

(This article belongs to the Special Issue New Approaches with Precision Medicine in Brain Tumors)

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20 pages, 5207 KiB

Open AccessArticle

7T HR FID-MRSI Compared to Amino Acid PET: Glutamine and Glycine as Promising Biomarkers in Brain Tumors

by Gilbert Hangel, Philipp Lazen, Sukrit Sharma, Barbara Hristoska, Cornelius Cadrien, Julia Furtner, Ivo Rausch, Alexandra Lipka, Eva Niess, Lukas Hingerl, Stanislav Motyka, Stephan Gruber, Bernhard Strasser, Barbara Kiesel, Matthias Preusser, Thomas Roetzer-Pejrimovsky, Adelheid Wöhrer, Wolfgang Bogner, Georg Widhalm, Karl Rössler, Tatjana Traub-Weidinger and Siegfried Trattnig Show full author list Hide full author list

Cancers 2022, 14(9), 2163; https://doi.org/10.3390/cancers14092163 - 26 Apr 2022

Cited by 6 | Viewed by 2177

Abstract

(1) Background: Recent developments in 7T magnetic resonance spectroscopic imaging (MRSI) made the acquisition of high-resolution metabolic images in clinically feasible measurement times possible. The amino acids glutamine (Gln) and glycine (Gly) were identified as potential neuro-oncological markers of importance. For the first [...] Read more.

(1) Background: Recent developments in 7T magnetic resonance spectroscopic imaging (MRSI) made the acquisition of high-resolution metabolic images in clinically feasible measurement times possible. The amino acids glutamine (Gln) and glycine (Gly) were identified as potential neuro-oncological markers of importance. For the first time, we compared 7T MRSI to amino acid PET in a cohort of glioma patients. (2) Methods: In 24 patients, we co-registered 7T MRSI and routine PET and compared hotspot volumes of interest (VOI). We evaluated dice similarity coefficients (DSC), volume, center of intensity distance (CoI), median and threshold values for VOIs of PET and ratios of total choline (tCho), Gln, Gly, myo-inositol (Ins) to total N-acetylaspartate (tNAA) or total creatine (tCr). (3) Results: We found that Gln and Gly ratios generally resulted in a higher correspondence to PET than tCho. Using cutoffs of 1.6-times median values of a control region, DSCs to PET were 0.53 ± 0.36 for tCho/tNAA, 0.66 ± 0.40 for Gln/tNAA, 0.57 ± 0.36 for Gly/tNAA, and 0.38 ± 0.31 for Ins/tNAA. (4) Conclusions: Our 7T MRSI data corresponded better to PET than previous studies at lower fields. Our results for Gln and Gly highlight the importance of future research (e.g., using Gln PET tracers) into the role of both amino acids. Full article

(This article belongs to the Special Issue New Approaches with Precision Medicine in Brain Tumors)

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20 pages, 2778 KiB

Open AccessArticle

MR Fingerprinting—A Radiogenomic Marker for Diffuse Gliomas

by Elisabeth Springer, Pedro Lima Cardoso, Bernhard Strasser, Wolfgang Bogner, Matthias Preusser, Georg Widhalm, Mathias Nittka, Gregor Koerzdoerfer, Pavol Szomolanyi, Gilbert Hangel, Johannes A. Hainfellner, Wolfgang Marik and Siegfried Trattnig

Cancers 2022, 14(3), 723; https://doi.org/10.3390/cancers14030723 - 30 Jan 2022

Cited by 11 | Viewed by 2988

Abstract

(1) Background: Advanced MR imaging (MRI) of brain tumors is mainly based on qualitative contrast images. MR Fingerprinting (MRF) offers a novel approach. The purpose of this study was to use MRF-derived T1 and T2 relaxation maps to differentiate diffuse gliomas according to [...] Read more.

(1) Background: Advanced MR imaging (MRI) of brain tumors is mainly based on qualitative contrast images. MR Fingerprinting (MRF) offers a novel approach. The purpose of this study was to use MRF-derived T1 and T2 relaxation maps to differentiate diffuse gliomas according to isocitrate dehydrogenase (IDH) mutation. (2) Methods: Twenty-four patients with histologically verified diffuse gliomas (14 IDH-mutant, four 1p/19q-codeleted, 10 IDH-wildtype) were enrolled. MRF T1 and T2 relaxation times were compared to apparent diffusion coefficient (ADC), relative cerebral blood volume (rCBV) within solid tumor, peritumoral edema, and normal-appearing white matter (NAWM), using contrast-enhanced MRI, diffusion-, perfusion-, and susceptibility-weighted imaging. For perfusion imaging, a T2* weighted perfusion sequence with leakage correction was used. Correlations of MRF T1 and T2 times with two established conventional sequences for T1 and T2 mapping were assessed (a fast double inversion recovery-based MR sequence (‘MP2RAGE’) for T1 quantification and a multi-contrast spin echo-based sequence for T2 quantification). (3) Results: MRF T1 and T2 relaxation times were significantly higher in the IDH-mutant than in IDH-wildtype gliomas within the solid part of the tumor (p = 0.024 for MRF T1, p = 0.041 for MRF T2). MRF T1 and T2 relaxation times were significantly higher in the IDH-wildtype than in IDH-mutant gliomas within peritumoral edema less than or equal to 1cm adjacent to the tumor (p = 0.038 for MRF T1 mean, p = 0.010 for MRF T2 mean). In the solid part of the tumor, there was a high correlation between MRF and conventionally measured T1 and T2 values (r = 0.913, p < 0.001 for T1, r = 0.775, p < 0.001 for T2), as well as between MRF and ADC values (r = 0.813, p < 0.001 for T2, r = 0.697, p < 0.001 for T1). The correlation was weak between the MRF and rCBV values (r = −0.374, p = 0.005 for T2, r = −0.181, p = 0.181 for T1). (4) Conclusions: MRF enables fast, single-sequence based, multi-parametric, quantitative tissue characterization of diffuse gliomas and may have the potential to differentiate IDH-mutant from IDH-wildtype gliomas. Full article

(This article belongs to the Special Issue New Approaches with Precision Medicine in Brain Tumors)

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17 pages, 2659 KiB

Open AccessArticle

Frequent Epigenetic Inactivation of DIRAS-1 and DIRAS-2 Contributes to Chemo-Resistance in Gliomas

by Tanja Rothhammer-Hampl, Franziska Liesenberg, Natalie Hansen, Sabine Hoja, Sabit Delic, Guido Reifenberger and Markus J. Riemenschneider

Cancers 2021, 13(20), 5113; https://doi.org/10.3390/cancers13205113 - 12 Oct 2021

Cited by 6 | Viewed by 2208

Abstract

We previously reported that DIRAS-3 is frequently inactivated in oligodendrogliomas due to promoter hypermethylation and loss of the chromosomal arm 1p. DIRAS-3 inactivation was associated with better overall survival. Consequently, we now investigated regulation and function of its family members DIRAS-1 and DIRAS-2. [...] Read more.

We previously reported that DIRAS-3 is frequently inactivated in oligodendrogliomas due to promoter hypermethylation and loss of the chromosomal arm 1p. DIRAS-3 inactivation was associated with better overall survival. Consequently, we now investigated regulation and function of its family members DIRAS-1 and DIRAS-2. We found that DIRAS-1 was strongly downregulated in 65% and DIRAS-2 in 100% of analyzed glioma samples compared to non-neoplastic brain tissue (NNB). Moreover, a significant down-regulation of DIRAS-1 and -2 was detected in glioma data obtained from the TCGA database. Mutational analyses did not reveal any inactivating mutations in the DIRAS-1 and -2 coding regions. Analysis of the DIRAS-1 and -2 promoter methylation status showed significantly higher methylation in IDH-mutant astrocytic and IDH-mutant and 1p/19q-codeleted oligodendroglial tumors compared to NNB. Treatment of U251MG and Hs683 glioblastoma cells lines with 5-azacytidine led to significant re-expression of DIRAS-1 and -2. For IDH-wild-type primary gliomas, however, we did not observe significantly elevated DIRAS-1 and -2 promoter methylation levels, but still detected strong downregulation of both DIRAS family members. Additional analyses revealed that DIRAS-1 and -2 expression was also regulated by histone modifications. We observed a shift towards promoter heterochromatinization for DIRAS-1 and less promoter euchromatinization for DIRAS-2 in IDH-wild-type glioblastomas compared to controls. Treatment of the two glioblastoma cell lines with a histone deacetylase inhibitor led to significant re-expression of DIRAS-1 and -2. Functionally, overexpression of DIRAS-1 and -2 in glioblastoma cells translated into significantly higher sensitivity to lomustine treatment. Analyses of DNA damage markers revealed that DIRAS-1 and -2 may play a role in p53-dependent response to alkylating chemotherapy. Full article

(This article belongs to the Special Issue New Approaches with Precision Medicine in Brain Tumors)

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Review

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18 pages, 1276 KiB

Open AccessReview

Three-Dimensional Cell Culture Systems in Pediatric and Adult Brain Tumor Precision Medicine

by Nicole C. Riedel, Flavia W. de Faria, Amelie Alfert, Jan M. Bruder and Kornelius Kerl

Cancers 2022, 14(23), 5972; https://doi.org/10.3390/cancers14235972 - 2 Dec 2022

Cited by 3 | Viewed by 2268

Abstract

Primary brain tumors often possess a high intra- and intertumoral heterogeneity, which fosters insufficient treatment response for high-grade neoplasms, leading to a dismal prognosis. Recent years have seen the emergence of patient-specific three-dimensional in vitro models, including organoids. They can mimic primary parenteral [...] Read more.

Primary brain tumors often possess a high intra- and intertumoral heterogeneity, which fosters insufficient treatment response for high-grade neoplasms, leading to a dismal prognosis. Recent years have seen the emergence of patient-specific three-dimensional in vitro models, including organoids. They can mimic primary parenteral tumors more closely in their histological, transcriptional, and mutational characteristics, thus approximating their intratumoral heterogeneity better. These models have been established for entities including glioblastoma and medulloblastoma. They have proven themselves to be reliable platforms for studying tumor generation, tumor–TME interactions, and prediction of patient-specific responses to establish treatment regimens and new personalized therapeutics. In this review, we outline current 3D cell culture models for adult and pediatric brain tumors, explore their current limitations, and summarize their applications in precision oncology. Full article

(This article belongs to the Special Issue New Approaches with Precision Medicine in Brain Tumors)

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29 pages, 2541 KiB

Open AccessReview

Pleiotropy of PP2A Phosphatases in Cancer with a Focus on Glioblastoma IDH Wildtype

by Elham Kashani and Erik Vassella

Cancers 2022, 14(21), 5227; https://doi.org/10.3390/cancers14215227 - 25 Oct 2022

Cited by 7 | Viewed by 2786

Abstract

Serine/Threonine protein phosphatase 2A (PP2A) is a heterotrimeric (or occasionally, heterodimeric) phosphatase with pleiotropic functions and ubiquitous expression. Despite the fact that they all contribute to protein dephosphorylation, multiple PP2A complexes exist which differ considerably by their subcellular localization and their substrate specificity, [...] Read more.

Serine/Threonine protein phosphatase 2A (PP2A) is a heterotrimeric (or occasionally, heterodimeric) phosphatase with pleiotropic functions and ubiquitous expression. Despite the fact that they all contribute to protein dephosphorylation, multiple PP2A complexes exist which differ considerably by their subcellular localization and their substrate specificity, suggesting diverse PP2A functions. PP2A complex formation is tightly regulated by means of gene expression regulation by transcription factors, microRNAs, and post-translational modifications. Furthermore, a constant competition between PP2A regulatory subunits is taking place dynamically and depending on the spatiotemporal circumstance; many of the integral subunits can outcompete the rest, subjecting them to proteolysis. PP2A modulation is especially important in the context of brain tumors due to its ability to modulate distinct glioma-promoting signal transduction pathways, such as PI3K/Akt, Wnt, Ras, NF-κb, etc. Furthermore, PP2A is also implicated in DNA repair and survival pathways that are activated upon treatment of glioma cells with chemo-radiation. Depending on the cancer cell type, preclinical studies have shown some promise in utilising PP2A activator or PP2A inhibitors to overcome therapy resistance. This review has a special focus on “glioblastoma, IDH wild-type” (GBM) tumors, for which the therapy options have limited efficacy, and tumor relapse is inevitable. Full article

(This article belongs to the Special Issue New Approaches with Precision Medicine in Brain Tumors)

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17 pages, 922 KiB

Open AccessReview

New Approaches with Precision Medicine in Adult Brain Tumors

by Annette Leibetseder, Matthias Preusser and Anna Sophie Berghoff

Cancers 2022, 14(3), 712; https://doi.org/10.3390/cancers14030712 - 29 Jan 2022

Cited by 2 | Viewed by 2306

Abstract

Primary central nervous system (CNS) tumors represent a heterogenous group of tumors. The 2021 fifth edition of the WHO Classification of Tumors of the CNS emphasizes the advanced role of molecular diagnostics with routine implementation of molecular biomarkers in addition to histologic features [...] Read more.

Primary central nervous system (CNS) tumors represent a heterogenous group of tumors. The 2021 fifth edition of the WHO Classification of Tumors of the CNS emphasizes the advanced role of molecular diagnostics with routine implementation of molecular biomarkers in addition to histologic features in the classification of CNS tumors. Thus, novel diagnostic methods such as DNA methylome profiling are increasingly used to provide a more precise diagnostic work-up of CNS tumors. In addition to these diagnostic precision medicine advantages, molecular alterations are also addressed therapeutically with targeted therapies. Like in other tumor entities, precision medicine has therefore also arrived in the treatment of CNS malignancies as the application of targeted therapies has shown promising response rates. Nevertheless, large prospective studies are currently missing as most targeted therapies were evaluated in single arm, basket, or platform trials. In this review, we focus on the current evidence of precision medicine in the treatment of primary CNS tumors in adults. We outline the pathogenic background and prevalence of the most frequent targetable genetic alterations and summarize the existing evidence of precision medicine approaches for the treatment of primary CNS tumors. Full article

(This article belongs to the Special Issue New Approaches with Precision Medicine in Brain Tumors)

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