CBIO-19. GENOME SHREDDING ENABLES CRISPR-MEDIATED GLIOBLASTOMA ONCOLYSIS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi31-vi31
Author(s):  
Christof Fellmann ◽  
I-Li Tan ◽  
Alexendar Perez ◽  
Rachel Lew ◽  
Karen Zhu ◽  
...  
Keyword(s):  
Residual Tumor ◽  
Therapy Resistance ◽  
Primary Brain Tumor ◽  
Therapeutic Modality ◽  
Dna Double Strand Breaks ◽  
Innovative Treatment ◽  
Treatment Regimens ◽  
Epigenetic Profile ◽  
Treatment Paradigm ◽  
Species Specific

Abstract Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults 1. Despite multimodal treatment regimens including surgical resection, radio- and chemotherapy, the growth of residual tumor often results in therapy resistance and ultimately death. GBMs are highly diffuse and exhibit extensive intratumoral heterogeneity 2,3, confounding diagnostic efforts and presenting opportunities for therapy evasion. Therefore, innovative treatment paradigms that can efficiently eliminate GBM cells irrespective of their mutational and epigenetic profile are urgently needed. CRISPR technologies have revolutionized medicine by enabling targeted genome editing through RNA-guided introduction of DNA double-strand breaks 4,5. Here, we show that CRISPR-Cas9 mediated genome fragmentation through targeting of highly repetitive loci, termed “genome shredding”, enables rapid and robust elimination of GBM cells. We characterized genome shredding across mammalian and vertebrate cells, and identified optimal repetitive pan-vertebrate and species-specific loci. Genome shredding is equally effective in temozolomide (TMZ)-sensitive and -resistant GBM cells, and multi-cycle treatment regimens are feasible. Importantly, when deployed in intracerebral GBM xenografts through local delivery, CRISPR-Cas9 genome shredding efficiently eliminated all targeted cells. Together, genome shredding enables the rapid and efficient fragmentation of a target cell’s genome and subsequent DNA damage-induced cell death. This provides an innovative treatment paradigm that is independent of a tumor’s mutational and epigenetic profile and leverages CRISPR-Cas9 as a breakthrough therapeutic modality for GBM.

scholarly journals Gene Expression Indicates Altered Immune Modulation and Signaling Pathway Activation in Ovarian Cancer Patients Resistant to Topotecan

2019 ◽  
Vol 20 (11) ◽  
pp. 2750 ◽  
Author(s):  
Otília Menyhárt ◽  
János Tibor Fekete ◽  
Balázs Győrffy
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
Disease Progression ◽  
Immune Modulation ◽  
Statistical Significance ◽  
Progression Free Survival ◽  
Therapy Resistance ◽  
Treatment Regimens ◽  
Pathway Activation ◽  
Short Period

Epithelial ovarian cancer (EOC) is one of the deadliest gynecological malignancies. Topotecan remains an essential tool in second-line therapy; even so, most patients develop resistance within a short period of time. We aimed to identify biomarkers of topotecan resistance by using gene expression signatures derived from patient specimens at surgery and available subsequent responses to therapy. Gene expression was collected for 1436 patients and 10,103 genes. Based on disease progression, patients were categorized as responders/nonresponders depending on their progression free survival (PFS) state at 9, 12, 15 and 18 months after surgery. For each gene, the median expression was compared between responders and nonresponders for two treatment regimens (chemotherapy including/excluding topotecan) with Mann–Whitney U test at each of the four different PFS cutoffs. Statistical significance was accepted in the case of p < 0.05 with a fold change (FC) ≥ 1.44. Four genes (EPB41L2, HLA-DQB1, LTF and SFRP1) were consistently overexpressed across multiple PFS cutoff times in initial tumor samples of patients with disease progression following topotecan treatment. A common theme linked to topotecan resistance was altered immune modulation. Genes associated with disease progression after systemic chemotherapy emphasize the role of the initial organization of the tumor microenvironment in therapy resistance. Our results uncover biomarkers with potential utility for patient stratification.

Intended Near-Total Removal of Koos Grade IV Vestibular Schwannomas: Reconsidering the Treatment Paradigm

Neurosurgery ◽  
2017 ◽  
Vol 82 (2) ◽  
pp. 202-210 ◽  
Author(s):  
Daniel Walter Zumofen ◽  
Tommaso Guffi ◽  
Christian Epple ◽  
Birgit Westermann ◽  
Anna-Katharina Krähenbühl ◽  
...  
Keyword(s):  
Facial Nerve ◽  
Tumor Volume ◽  
Residual Tumor ◽  
Extent Of Resection ◽  
Vestibular Schwannomas ◽  
Facial Nerve Function ◽  
Total Removal ◽  
Treatment Paradigm ◽  
The Mean

Abstract BACKGROUND The goals of treating Koos grade IV vestibular schwannomas are to relieve brainstem compression, preserve or restore neurological function, and achieve long-term tumor control while minimizing tumor- and treatment-related morbidity. OBJECTIVE To propose a treatment paradigm involving the intentional near-total removal of Koos grade IV vestibular schwannomas, in which a small amount of residual tumor is not dissected off the cisternal portion of the facial nerve. Patients are then followed by a wait-and-scan approach. Any subsequent volumetric progression of the residual tumor is treated with radiosurgery. METHODS This is a case series of 44 consecutive unselected patients who underwent intended near-total resection of a Koos grade IV vestibular schwannoma through a retrosigmoid approach from January 2009 to December 2015. Pre- and postoperative volumetric analyses were performed on routine magnetic resonance imaging sequences (constructive interference in steady state and gadolinium-enhanced T1-weighted sequence). RESULTS The mean preoperative tumor volume was 10.9 cm3. The mean extent of resection was 89%. At the last clinical follow-up, facial nerve function was good [House and Brackmann (HB) I-II] in 89%, fair (HB III) in 9%, and poor (HB IV-VI) in 2% of the patients. At the last radiological follow-up, the residual tumor had become smaller or remained the same size in 84% of patients. Volumetric progression was negatively correlated with the original extent of resection and positively correlated with postoperative residual tumor volume (P = .01, P &lt; .001, respectively). CONCLUSION Intended near-total removal results in excellent preservation of facial nerve function and has a low recurrence rate. Any progressive residual tumor may be treated by radiosurgery.

The role of stereotactic conformal radiation boost in the temozolomide-based chemoradiation for glioblastoma multiforme: Preliminary analysis

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 12513-12513
Author(s):  
M. Balducci ◽  
S. Manfrida ◽  
G. R. D’Agostino ◽  
C. Anile ◽  
L. Azario ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Preliminary Analysis ◽  
Late Toxicity ◽  
Conformal Radiotherapy ◽  
Residual Tumor ◽  
Primary Brain Tumor ◽  
Tumor Bed ◽  
Radiation Boost ◽  
Comparison Results ◽  
Grade 3

12513 Background: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. Aim of this analysis was to evaluate tolerance and outcome of the dose intensification by stereotactic conformal radiotherapy (SCRT) and concomitant chemotherapy with temozolomide Methods: From October 2003 to April 2006, 58 patients (34 males, 58.6%, 24 females, 41.4%) with histological diagnosis of glioblastoma multiforme received postoperative radiochemotherapy with SCRT boost. Median age was 58 yrs. ( range 25–80 yrs.). Twenty-nine out of 58 patients (50%) received a total dose of 70 Gy by conformal radiotherapy and SCRT boost delivered as concomitant and sequential, or sequential alone. The remainig 29 patients (50%) received a standard of 5940 cGy (180 cGy/day; CTV3: tumor bed + residual tumor if present + oedema; CTV2: tumor bed + residual tumor if present + 1.5 cm margins. CTV1: tumor bed + residual tumor if present + 0.5 cm margins only for the SCRT group). All patients received concomitant Temozolomide, 75 mg/m2 for a median duration of 28 days (range 14–45, depending on the chemoradiation schedule), and adjuvant chemotherapy with temozolomide for 6 cycles or until disease progression. Toxicity was recorded according to RTOG criteria; Survival analysis was calculated by the Kaplan-Mayer method and log-rank testing was used for groups comparison. Results: A 100% compliance was observed in both the groups of patients. A grade 3–4 acute neurological toxicity was registered in two patients treated with SCRT compared to one patient in the group which did not receive SCRT. One case of radionecrosis was observed in the SCRT group; in no case of either group neurological worsening nor corticosteroidal dependence were registered. At a median follow-up of 19 months (range 4–39), a trend towards a better outcome was observed in patients treated with SCRT, since the 1-year OS was 85.9% for SCRT patients (median not achieved) compared to 68.7% for the remaining patients (p=0.07). Conclusion: Our preliminary analysis suggests that a higher dose of RT delivered by conformal stereotactic boost did not increase acute or late toxicity and could achieve a better outcome in patients affected by GBM No significant financial relationships to disclose.

scholarly journals Wilms tumor 1 gene, CD97, and the emerging biogenetic profile of glioblastoma

2014 ◽  
Vol 37 (6) ◽  
pp. E14 ◽  
Author(s):  
Aravind Somasundaram ◽  
Nathan Ardanowski ◽  
Charles F. Opalak ◽  
Helen L. Fillmore ◽  
Archana Chidambaram ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Wilms Tumor ◽  
Growth Factor Receptor ◽  
Primary Brain Tumor ◽  
Current Treatment ◽  
Tumor Invasiveness ◽  
Treatment Regimens ◽  
Wilms Tumor 1 ◽  
And Migration ◽  
Relationship Of

Glioblastoma multiforme (GBM) is the most common type of primary brain tumor, and current treatment regimens are only marginally effective. One of the most vexing and malignant aspects of GBM is its pervasive infiltration into surrounding brain tissue. This review describes the role of the Wilms tumor 1 gene (WT1) and its relationship to GBM. WT1 has several alternative splicing products, one of which, the KTS+ variant, has been demonstrated to be involved in the transcriptional activation of a variety of oncogenes as well as the inhibition of tumor suppressor genes. Further, this paper will examine the relationship of WT1 with CD97, a gene that codes for an epidermal growth factor receptor family member, an adhesion G-protein–coupled receptor, thought to promote tumor invasiveness and migration. The authors suggest that further research into WT1 and CD97 will allow clinicians to begin to deal more effectively with the infiltrative behavior displayed by GBM and design new therapies that target this deadly disease.

scholarly journals Reviewing the potential use of scaffold-mediated localized chemotherapy in oncology

2020 ◽  
Vol 11 (3) ◽  
pp. 23-27
Author(s):  
Archana A Gupta ◽  
Supriya Kheur ◽  
A. Thirumal Raj ◽  
Ravindra V. Badhe ◽  
Ramesh. R. Bhonde
Keyword(s):  
Targeted Delivery ◽  
Residual Tumor ◽  
Systemic Toxicity ◽  
Therapeutic Modality ◽  
Residual Cancer ◽  
Conventional Radiotherapy ◽  
Surgical Recurrence ◽  
Potential Use ◽  
Interim Period

Abstract Post-surgical recurrence and metastasis remain to be the major concern in oncology. The absence of any therapeutic modality during the interim period between the surgical intervention and initiation of conventional radiotherapy and chemotherapy allows the residual cancer cells to proliferate, culminating in recurrence and/or metastasis. Introducing a therapeutic modality during this interim period could suppress the proliferation of the residual tumor cells. Further, as the detrimental effects of conventional chemotherapy and radiotherapy drastically reduce the patient’s quality of life, use of therapeutic modality with localized effect can reduce the risk of systemic toxicity. Thus, the present manuscript reviews the potential use of scaffold-mediated local chemotherapy in oncology. Its localized effect would prevent systemic toxicity, while the scaffold serves as an ideal vehicle for the sustained targeted delivery of therapeutic agents.

scholarly journals A Preclinical Pipeline for Translational Precision Medicine—Experiences from a Transdisciplinary Brain Tumor Stem Cell Project

2021 ◽  
Vol 11 (9) ◽  
pp. 892
Author(s):  
Andres Vargas-Toscano ◽  
Christoph Janiak ◽  
Michael Sabel ◽  
Ulf Dietrich Kahlert
Keyword(s):  
Brain Tumor ◽  
Precision Medicine ◽  
Clinical Application ◽  
New Technologies ◽  
Basic Research ◽  
Therapy Resistance ◽  
Primary Brain Tumor ◽  
Point Of View ◽  
Tumor Stem Cell ◽  
Tumoral Cell

Efficient transdisciplinary cooperation promotes the rapid discovery and clinical application of new technologies, especially in the competitive sector of oncology. In this review, written from a clinical-scientist point of view, we used glioblastoma—the most common and most aggressive primary brain tumor as a model disease with a largely unmet clinical need, despite decades of intensive research—to promote transdisciplinary medicine. Glioblastoma stem-like cells (GSCs), a special tumoral cell population analogue to healthy stem cells, are considered largely responsible for the progression of the disease and the mediation of therapy resistance. The presented work followed the concept of translational science, which generates the theoretical backbones of translational research projects, and aimed to close the preclinical gap between basic research and clinical application. Thus, this generated an integrated translational precision medicine pipeline model based on recent theoretical and experimental publications, which supports the accelerated discovery and development of new paths in the treatment of GSCs. The work may be of interest to the general field of precision medicine beyond the field of neuro-oncology such as in Cancer Neuroscience.

scholarly journals Tumor-Specific Catalysis-Mediated Enhanced Chemodynamic Therapy in Synergy with Mitophagy Inhibition Improves Therapeutic Efficacy in Endometrial Cancer

2021 ◽  
Author(s):  
Xiaodi Gong ◽  
Jing Wang ◽  
Linlin Yang ◽  
Lijuan Li ◽  
Xiao Sun ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Therapeutic Modality ◽  
Therapeutic Window ◽  
Tumor Growth Inhibition ◽  
Target Cells ◽  
Type I ◽  
Dna Double Strand Breaks ◽  
Quinone Oxidoreductase ◽  
Positive Target ◽  
Arginine Glycine Aspartic Acid

Abstract BackgroundChemodynamic therapy (CDT) relies on tumor microenvironment (e.g. high H2O2 level) responsive Fenton-like reactions to produce hydroxyl radicals (·OH) against tumors. However, endogenous H2O2 is insufficient for effective chemodynamic reactions.ResultsAn NAD(P)H: quinone oxidoreductase 1 (NQO1)highCatalase (CAT)low therapeutic window for the use of NQO1 bioactive drug β-lapachone (β-Lap) was firstly identified in endometrial cancer (EC). Accompanied by NADH depletion, β-Lap was catalyzed by NQO1 to produce excess H2O2 initiating oxidative stress, which selectively suppressed NQO1high EC cell proliferation, induced DNA double-strand breaks and promoted apoptosis. SiRNA-mediated NQO1 knockdown or dicoumarol rescued NQO1high EC cells from β-Lap-induced cytotoxicity. Arginine-glycine-aspartic acid (RGD)-functionalized iron-based metal organic frameworks-MOF(Fe) further promoted the conversion of accumulated H2O2 into highly oxidative ·OH, and in turn exacerbated the oxidative damage to RGD-positive target cells. Mitophagy inhibition by Mdivi-1 blocked a powerful antioxidant defense approach, ultimately ensuring the antitumor efficacy of stepwise amplified ROS signals. The tumor growth inhibition rate was about 85.92%.ConclusionsTumor specific chemotherapy in combination with CDT-triggered therapeutic modality presented unprecedented therapeutic advantages for the treatment of NQO1+ advanced type I or type II EC.

scholarly journals Inhibition of miR-1193 leads to synthetic lethality in glioblastoma multiforme cells deficient of DNA-PKcs

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Jing Zhang ◽  
Li Jing ◽  
Subee Tan ◽  
Er-Ming Zeng ◽  
Yingbo Lin ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
High Throughput Screening ◽  
Synthetic Lethality ◽  
Gene Mutations ◽  
Primary Brain Tumor ◽  
Dna Double Strand Breaks ◽  
Synthetic Lethal ◽  
Oncogenic Mutation ◽  
Damage Repair ◽  
Genome Wide

Abstract Glioblastoma multiforme (GBM) is the most malignant primary brain tumor and has the highest mortality rate among cancers and high resistance to radiation and cytotoxic chemotherapy. Although some targeted therapies can partially inhibit oncogenic mutation-driven proliferation of GBM cells, therapies harnessing synthetic lethality are ‘coincidental’ treatments with high effectiveness in cancers with gene mutations, such as GBM, which frequently exhibits DNA-PKcs mutation. By implementing a highly efficient high-throughput screening (HTS) platform using an in-house-constructed genome-wide human microRNA inhibitor library, we demonstrated that miR-1193 inhibition sensitized GBM tumor cells with DNA-PKcs deficiency. Furthermore, we found that miR-1193 directly targets YY1AP1, leading to subsequent inhibition of FEN1, an important factor in DNA damage repair. Inhibition of miR-1193 resulted in accumulation of DNA double-strand breaks and thus increased genomic instability. RPA-coated ssDNA structures enhanced ATR checkpoint kinase activity, subsequently activating the CHK1/p53/apoptosis axis. These data provide a preclinical theory for the application of miR-1193 inhibition as a potential synthetic lethal approach targeting GBM cancer cells with DNA-PKcs deficiency.

Post-therapeutic changes in the molecular profile of glioblastomas

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2026-2026
Author(s):  
C. Horbinski ◽  
A. Mintz ◽  
J. Engh ◽  
F. Lieberman ◽  
R. L. Hamilton ◽  
...  
Keyword(s):  
Therapy Resistance ◽  
Primary Brain Tumor ◽  
External Beam Radiation ◽  
Molecular Profile ◽  
Genetic Profile ◽  
Low Grade ◽  
Beam Radiation ◽  
Molecular Alterations ◽  
Development Of Resistance ◽  
Formalin Fixed Paraffin Embedded

2026 Background: Glioblastoma multiforme is the most common and malignant primary brain tumor in adults. Despite aggressive surgery, radiation, and chemotherapy, average survival time after diagnosis is about 1 year. This may be partly due to development of resistance to adjuvant therapies. While the molecular alterations in pretreated glioblastomas have been the subject of much research in recent years, changes in their genetic profile after adjuvant therapy are largely unknown. Methods: Herein we describe a cohort of over 40 glioblastomas with characterization of key genetic loci (EGFR, p53, 1p, 19q, 9p, 10q, 17p) using fluorescence in situ hybridization, PCR-based loss of heterozygosity (LOH) analysis, and immunohistochemistry on formalin-fixed, paraffin-embedded tissues. Analyses were performed on tumor tissue obtained at initial diagnosis and at first recurrence. Treatment regimen during the interval consisted of external beam radiation therapy and temozolomide, an alkylating chemotherapeutic agent. Results: About 50% showed large increases or decreases in hyperploidy of chromosomes 1, 7, 9, and/or 19 after therapy. Over 70% showed changes in LOH patterns on 1p, 19q, 9p, 10q, and/or 17p. 24% of previously non-EGFR-amplified tumors acquired low-grade amplification (less than 10 copies/chromosome 7 CEP signal) after treatment, and 16% of EGFR-amplified tumors lost amplification after treatment. Conclusions: Our results suggest that the molecular profile of these tumors is dynamic and that certain key alterations, including acquisition of low-level EGFR amplification in previously EGFR-negative tumors, occurs in a subset of cases. Such alterations may contribute to therapy resistance as the glioma evolves in a changing microenvironment. No significant financial relationships to disclose.

From sequential to combination and personalised therapy in lupus nephritis: moving towards a paradigm shift?

2021 ◽  
pp. annrheumdis-2021-221270
Author(s):  
Ioannis Parodis ◽  
Frederic A Houssiau
Keyword(s):  
Lupus Nephritis ◽  
Maintenance Phase ◽  
Tissue Level ◽  
Current Treatment ◽  
Phase Iii ◽  
Treat To Target ◽  
Treatment Regimens ◽  
Treatment Paradigm ◽  
Therapeutic Decision Making ◽  
The Right

The current treatment paradigm in lupus nephritis consists of an initial phase aimed at inducing remission and a subsequent remission maintenance phase. With this so-called sequential treatment approach, complete renal response is achieved in a disappointing proportion of 20–30% of the patients within 6–12 months, and 5–20% develop end-stage kidney disease within 10 years. Treat-to-target approaches are detained owing to uncertainty as to whether the target should be determined based on clinical, histopathological, or immunopathological features. Until reliable non-invasive biomarkers exist, tissue-based evaluation remains the gold standard, necessitating repeat kidney biopsies for treatment evaluation and therapeutic decision-making. In this viewpoint, we discuss the pros and cons of voclosporin and belimumab as add-on agents to standard therapy, the first drugs to be licenced for lupus nephritis after recent successful randomised phase III clinical trials. We also discuss the prospect of obinutuzumab and anifrolumab, also on top of standard immunosuppression, currently tested in phase III trials after initial auspicious signals. Undoubtably, the treatment landscape in lupus nephritis is changing, with combination treatment regimens challenging the sequential concept. Meanwhile, the enrichment of the treatment armamentarium shifts the need from lack of therapies to the challenge of how to select the right treatment for the right patient. This has to be addressed in biomarker surveys along with tissue-level mapping of inflammatory phenotypes, which will ultimately lead to person-centred therapeutic approaches. After many years of trial failures, we may now anticipate a heartening future for patients with lupus nephritis.

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