scholarly journals ANGI-10. CHEMOTHERAPEUTIC STRESS INDUCES TRANSDIFFERENTIATION OF GLIOBLASTOMA CELLS TO PROMOTE VASCULAR MIMICRY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi32-vi32
Author(s):  
Shivani Baisiwala ◽  
Brenda Auffinger ◽  
Seamus Caragher ◽  
Jack Shireman ◽  
Riasat Ahsan ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Ex Vivo ◽  
Treatment Strategies ◽  
Standard Of Care ◽  
Current Treatment ◽  
Treatment Modalities ◽  
Current Standard ◽  
Tube Forming ◽  
Key Factor ◽  
Orthotopic Xenografts

Abstract Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor affecting adults, with a median survival of approximately 21 months after diagnosis. A key factor underlying the limited efficacy of current treatment modalities is the remarkable plasticity exhibited by GBM cells, which allows them to effectively adapt to changes induced by our current treatment strategies. In addition to their plasticity, GBM tumors are also highly vascularized with aberrant vessels that further promote its aggressiveness. Recent research has demonstrated that GBM cells have the ability to transdifferentiate into endothelial cells (ECs), which suggests that GBM cells may use their properties of plasticity and vascularity in concert, leading to the creation of tumor-derived blood vessels. The mechanism behind this transdifferentiation remains unclear. Here, we show that treatment with temozolamide (TMZ)-based chemotherapy (the current standard of care) induces time-dependent increases in expression of markers for glioma stem cells (GSCs) and immature and mature ECs over 8 days of treatment (p < .001) in multiple patient-derived xenograft (PDX) lines. In addition, GBM tumors growing as orthotopic xenografts in nude mice showed significantly increased expression of GSC markers (CD15 and CD133) and EC markers (CD105 and CD144) after 8 days of TMZ treatment (p < .01). Ex-vivo FACS analysis of these orthotopic xenografts showed the presence of immature and mature EC populations in addition to GSC populations. To assess the functionality of these increased EC populations, a tube forming assay was performed. Results showed that the tube forming capacity of PDX lines was significantly increased (p < .01) after therapy. Furthermore, immunofluorescence analysis revealed increased tumor-derived vessels in TMZ-recurrent tumors. Overall, this study identifies chemotherapeutic stress as a new driver of transdifferentiation of tumor cells to endothelial cells and highlights cellular plasticity as a key player in therapeutic resistance and tumor recurrence.

scholarly journals Chemotherapeutic Stress Induces Transdifferentiation of Glioblastoma Cells to Endothelial Cells and Promotes Vascular Mimicry

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Shivani Baisiwala ◽  
Brenda Auffinger ◽  
Seamus P. Caragher ◽  
Jack M. Shireman ◽  
Riasat Ahsan ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Antitumor Agents ◽  
Ex Vivo ◽  
Current Treatment ◽  
Treatment Modalities ◽  
Immunofluorescence Analysis ◽  
Key Factor ◽  
Orthotopic Xenografts ◽  
Vascular Mimicry ◽  
Aberrant Vessels

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor affecting adults, with a median survival of approximately 21 months. One key factor underlying the limited efficacy of current treatment modalities is the remarkable plasticity exhibited by GBM cells, which allows them to effectively adapt to changes induced by anticancer therapeutics. Moreover, GBM tumors are highly vascularized with aberrant vessels that complicate the delivery of antitumor agents. Recent research has demonstrated that GBM cells have the ability to transdifferentiate into endothelial cells (ECs), illustrating that GBM cells may use plasticity in concert with vascularization leading to the creation of tumor-derived blood vessels. The mechanism behind this transdifferentiation, however, remains unclear. Here, we show that treatment with temozolomide (TMZ) chemotherapy induces time-dependent expression of markers for glioma stem cells (GSCs) and immature and mature ECs. In addition, GBM tumors growing as orthotopic xenografts in nude mice showed increased expression of GSC and EC markers after TMZ treatment. Ex vivo FACS analysis showed the presence of immature and mature EC populations. Furthermore, immunofluorescence analysis revealed increased tumor-derived vessels in TMZ-recurrent tumors. Overall, this study identifies chemotherapeutic stress as a new driver of transdifferentiation of tumor cells to endothelial cells and highlights cellular plasticity as a key player in therapeutic resistance and tumor recurrence.

Bevacizumab as Treatment for Epistaxis in Hereditary Hemorrhagic Telangiectasia: A Literature Review

2019 ◽  
Vol 128 (5) ◽  
pp. 467-471 ◽  
Author(s):  
Sameer D. Kini ◽  
Daniel W. Yiu ◽  
Reid A. Weisberg ◽  
Juan F. Davila ◽  
Daniel C. Chelius
Keyword(s):  
Literature Review ◽  
Significant Risk ◽  
Standard Of Care ◽  
Current Treatment ◽  
Treatment Modalities ◽  
Treatment Schedule ◽  
Common Symptom ◽  
Current Standard ◽  
Vegf Inhibitor ◽  
Optimal Dosing

Background: Severe, recurring epistaxis is the most common symptom of hereditary hemorrhagic telangiectasias (HHT). Current treatment modalities range from noninvasive treatments that frequently fail to achieve even short-term control to surgeries and systemic therapies that carry significant risk of complications. Recently, bevacizumab, a VEGF inhibitor, has been proposed as an alternative option to alleviate epistaxis symptoms in HHT. Objective: To review the current literature regarding the use of bevacizumab for the treatment of epistaxis in patients with HHT and provide guidance on its usage for this indication. Methods: A narrative literature review was performed to analyze various methods and dosages of bevacizumab administration for the treatment of HHT-related epistaxis, along with a review of current treatment modalities and their drawbacks. Results: The current standard of care for HHT-related epistaxis consists of treatments that are largely ineffective or invasive with significant potential complications. Submucosal bevacizumab has demonstrated efficacy in reducing frequency, duration, and severity of epistaxis in those with HHT. Conclusion: Given the inadequacies and potential drawbacks of current treatments for epistaxis in HHT, there is a need for new therapeutic options. Submucosal bevacizumab has been effective with a limited risk profile in a number of studies and should now be considered as a treatment option for refractory epistaxis. Controlled studies are recommended to quantify optimal dosing, treatment schedule, and specific subpopulations that will respond best to this treatment.

scholarly journals Updated Insights on EGFR Signaling Pathways in Glioma

2021 ◽  
Vol 22 (2) ◽  
pp. 587
Author(s):  
Alexandru Oprita ◽  
Stefania-Carina Baloi ◽  
Georgiana-Adeline Staicu ◽  
Oana Alexandru ◽  
Daniela Elise Tache ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Egfr Signaling ◽  
Current Standard ◽  
Egfr Amplification ◽  
Epidermal Growth ◽  
New Diagnosis ◽  
Clear Clinical Benefit

Nowadays, due to recent advances in molecular biology, the pathogenesis of glioblastoma is better understood. For the newly diagnosed, the current standard of care is represented by resection followed by radiotherapy and temozolomide administration, but because median overall survival remains poor, new diagnosis and treatment strategies are needed. Due to the quick progression, even with aggressive multimodal treatment, glioblastoma remains almost incurable. It is known that epidermal growth factor receptor (EGFR) amplification is a characteristic of the classical subtype of glioma. However, targeted therapies against this type of receptor have not yet shown a clear clinical benefit. Many factors contribute to resistance, such as ineffective blood–brain barrier penetration, heterogeneity, mutations, as well as compensatory signaling pathways. A better understanding of the EGFR signaling network, and its interrelations with other pathways, are essential to clarify the mechanisms of resistance and create better therapeutic agents.

scholarly journals Towards Personalization in the Curative Treatment of Gastric Cancer

2020 ◽  
Vol 10 ◽  
Author(s):  
Astrid E. Slagter ◽  
Marieke A. Vollebergh ◽  
Edwin P. M. Jansen ◽  
Johanna W. van Sandick ◽  
Annemieke Cats ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Standard Of Care ◽  
Molecular Characteristics ◽  
Perioperative Chemotherapy ◽  
Current Standard ◽  
Common Cancer ◽  
Resectable Gastric Cancer

Gastric cancer is the fifth most common cancer worldwide and has a high mortality rate. In the last decades, treatment strategy has shifted from an exclusive surgical approach to a multidisciplinary strategy. Treatment options for patients with resectable gastric cancer as recommended by different worldwide guidelines, include perioperative chemotherapy, pre- or postoperative chemoradiotherapy and postoperative chemotherapy. Although gastric cancer is a heterogeneous disease with respect to patient-, tumor-, and molecular characteristics, the current standard of care is still according to a one-size-fits-all approach. In this review, we discuss the background of the different treatment strategies in resectable gastric cancer including the current standard, the specific role of radiotherapy, and describe the current areas of research and potential strategies for personalization of therapy.

scholarly journals Temozolomide Treatment Increases Fatty Acid Uptake in Glioblastoma Stem Cells

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3126
Author(s):  
Seamus Caragher ◽  
Jason Miska ◽  
Jack Shireman ◽  
Cheol H. Park ◽  
Megan Muroski ◽  
...  
Keyword(s):  
Stem Cells ◽  
Fatty Acid ◽  
Fatty Acid Uptake ◽  
Current Treatment ◽  
Metabolic Phenotype ◽  
Treatment Modalities ◽  
Environmental Cues ◽  
Acid Uptake ◽  
Current Standard ◽  
Cell State

Among all cancers, glioblastoma (GBM) remains one of the least treatable. One key factor in this resistance is a subpopulation of tumor cells termed glioma stem cells (GSCs). These cells are highly resistant to current treatment modalities, possess marked self-renewal capacity, and are considered key drivers of tumor recurrence. Further complicating an understanding of GBM, evidence shows that the GSC population is not a pre-ordained and static group of cells but also includes previously differentiated GBM cells that have attained a GSC state secondary to environmental cues. The metabolic behavior of GBM cells undergoing plasticity remains incompletely understood. To that end, we probed the connection between GSCs, environmental cues, and metabolism. Using patient-derived xenograft cells, mouse models, transcriptomics, and metabolic analyses, we found that cell state changes are accompanied by sharp changes in metabolic phenotype. Further, treatment with temozolomide, the current standard of care drug for GBM, altered the metabolism of GBM cells and increased fatty acid uptake both in vitro and in vivo in the plasticity driven GSC population. These results indicate that temozolomide-induced changes in cell state are accompanied by metabolic shifts—a potentially novel target for enhancing the effectiveness of current treatment modalities.

scholarly journals How I treat atypical chronic myeloid leukemia

Blood ◽  
2017 ◽  
Vol 129 (7) ◽  
pp. 838-845 ◽  
Author(s):  
Jason Gotlib
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasm ◽  
Treatment Strategies ◽  
Standard Of Care ◽  
High Rate ◽  
Current Standard ◽  
Hematopoietic Stem ◽  
Genetic Features ◽  
Atypical Chronic Myeloid Leukemia

Abstract Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML) is a rare myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) for which no current standard of care exists. The challenges of aCML relate to its heterogeneous clinical and genetic features, high rate of transformation to acute myeloid leukemia, and historically poor survival. Therefore, allogeneic hematopoietic stem cell transplantation should always be an initial consideration for eligible patients with a suitable donor. Nontransplant approaches for treating aCML have otherwise largely relied on adopting treatment strategies used for MDS and MPN. However, such therapies, including hypomethylating agents, are based on a paucity of data. With an eye toward making a more meaningful impact on response rates and modification of the natural history of the disease, progress will rely on enrollment of patients into clinical trials and molecular profiling of individuals so that opportunities for targeted therapy can be exploited.

scholarly journals 3D Mathematical modeling of glioblastoma suggests that transdifferentiated vascular endothelial cells promote resistance to current standard-of-care therapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13535-e13535
Author(s):  
Daniela Annenelie Bota ◽  
Huaming Yan ◽  
Monica Romero-López ◽  
Lesli Benitez ◽  
Kaijun Di ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Standard Of Care ◽  
Cancer Therapies ◽  
Vascular Endothelial ◽  
Current Standard ◽  
Tumor Invasiveness ◽  
Cancer Aggressiveness ◽  
Cell Niche ◽  
Experimental Findings

e13535 Background: Glioblastoma (GBM), the most aggressive brain tumor in human patients, is highly heterogeneous and intensively vascularized. Glioma stem/initiating cells (GSC) are found to play a crucial role by increasing cancer aggressiveness and by promoting resistance to therapy. Recently, crosstalk between GSCs and vascular endothelial cells that line capillaries has been shown to considerably promote GSC self-renewal and tumor progression. GSCs have been shown to also transdifferentiate into bona-fide vascular endothelial cells (GEC). GECs inherit mutations present in GSCs and are resistant to traditional anti-angiogenic therapies. Methods: We develop a multispecies mathematical model to investigate the 3D spatiotemporal dynamics of vascularized GBM progression and response to cancer therapies. Results: The model predicts GSCs drive invasive fingering and that GECs spontaneously form a network within the hypoxic core, consistent with published experimental findings. We demonstrate that standard-of-care treatments using DNA-targeted therapy (radiation/chemo) together with anti-angiogenic therapies reduce GBM tumor sizes but increase invasiveness. Anti-GEC treatments block the GEC support of GSCs and reduce tumor sizes but can lead to increased invasiveness. Anti-GSC therapies that promote differentiation or disturb the stem cell niche effectively reduce tumor invasiveness and sizes, but are ultimately limited in reducing tumor sizes because GECs can maintain GSCs. Anti-GEC therapies are required to remove the tumor completely. Conclusions: Our results suggest that a combinatorial regimen targeting the vasculature, GSCs and GECs, using drugs already approved by the FDA, can reduce both tumor sizes and invasiveness and could lead to tumor eradication without recurrence when the treatment is stopped.

scholarly journals Rapamycin microparticles induce autophagy, prevent senescence and are effective in treatment of Osteoarthritis

2021 ◽  
Author(s):  
Kaamini M Dhanabalan ◽  
Ameya A Dravid ◽  
Smriti Agarwal ◽  
Ramanath K Sharath ◽  
Ashok K Padmanabhan ◽  
...  
Keyword(s):  
Articular Chondrocytes ◽  
Symptomatic Relief ◽  
Cartilage Damage ◽  
Treatment Strategies ◽  
Standard Of Care ◽  
Cartilage Degeneration ◽  
Current Standard ◽  
Disease Modifying Drugs ◽  
Post Traumatic ◽  
Sulphated Glycosaminoglycans

Trauma to the knee joint is associated with significant cartilage degeneration and erosion of subchondral bone, which eventually leads to osteoarthritis (OA), resulting in substantial morbidity and healthcare burden. With no disease-modifying drugs in clinics, the current standard of care focuses on symptomatic relief and viscosupplementation. Modulation of autophagy and targeting senescence pathways are emerging as potential treatment strategies. Rapamycin has shown promise in OA disease amelioration by autophagy upregulation, yet its clinical use is hindered by difficulties in achieving therapeutic concentrations, necessitating multiple weekly injections. Here, we have synthesized rapamycin - loaded poly (lactic-co-glycolic acid) microparticles (RMPs) that induced autophagy, prevented senescence and sustained sulphated glycosaminoglycans(sGAG) production in primary human articular chondrocytes from OA patients. RMPs were potent, nontoxic, and exhibited high retention time (up to 35 days) in mice joints. Intra-articular delivery of RMPs effectively mitigated cartilage damage and inflammation in surgery-induced OA when administered as a prophylactic or therapeutic regimen. Together, our studies demonstrate the feasibility of using RMPs as a potential clinically translatable therapy to prevent and treat post-traumatic osteoarthritis.

scholarly journals GCT-23. MULTI-INSTITUTIONAL ANALYSIS OF TREATMENT MODALITIES IN BASAL GANGLIA AND THALAMIC GERMINOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii332-iii332
Author(s):  
Richard T Graham ◽  
Mohammad H Abu-Arja ◽  
Joseph Stanek ◽  
Ute Bartels ◽  
Andrea Cappellano ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Institutional Analysis ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Treatment Modalities ◽  
Event Free Survival ◽  
Free Survival ◽  
Combine Chemotherapy ◽  
Imaging Characteristics ◽  
Significant Difference

Abstract BACKGROUND Central nervous system (CNS) germinomas are radiotherapy (RT)-sensitive tumors with excellent survival. Current treatment strategies combine chemotherapy with RT to reduce the field and dose of RT. There is no standard treatment for germinomas originating in the basal ganglia/thalami (BGTG) given their rarity and poorly-defined imaging characteristics. Craniospinal (CSI), whole brain (WBI), whole ventricle (WVI), and focal RT have been previously utilized; however, the optimal strategy remains unclear. METHODS Retrospective multi-institutional analysis was conducted across 18 institutions in four countries. RESULTS For 46 cases with non-metastatic BGTG, the event-free survival (EFS) was 86.9% at both 5 and 10 years, while overall survival (OS) was 100%, and 95.7% respectively at 5 and 10 years. Median RT dose and range for the various treatment volumes were as follows: CSI (n=10): 2340 cGy (1980–3060 cGy), WBI (n=8): 2340 (1800–3000 cGy), WVI (n=14): 2340 cGy (1800–2550 cGy), focal (n=9): 3600 cGy (3060–5400 cGy). There was no statistically significant difference in the EFS based on RT modality (p=0.57), but EFS for subjects with CSI and WBI were both 100%. The three subjects who received chemotherapy alone had significantly lower EFS than those who received chemotherapy and RT (p=0.001), but were salvageable with RT. CONCLUSION In the largest study to date for BGTG, there were no significant differences in outcomes between patients who received CSI, WBI, WVI or focal RT. This group of patients should be included in future prospective clinical trials, and a more limited RT field may be considered.

scholarly journals Novel Treatment Strategies for Glioblastoma

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2883
Author(s):  
Stanley S. Stylli
Keyword(s):  
Median Survival ◽  
Treatment Strategies ◽  
Drug Repurposing ◽  
Standard Of Care ◽  
Invasive Disease ◽  
Central Nervous System Tumor ◽  
Current Standard ◽  
Novel Treatment ◽  
Novel Treatment Strategies ◽  
Molecular Landscape

Glioblastoma (GBM) is the most common primary central nervous system tumor in adults. It is a highly invasive disease, making it difficult to achieve a complete surgical resection, resulting in poor prognosis with a median survival of 12–15 months after diagnosis, and less than 5% of patients survive more than 5 years. Surgical, instrument technology, diagnostic and radio/chemotherapeutic strategies have slowly evolved over time, but this has not translated into significant increases in patient survival. The current standard of care for GBM patients involving surgery, radiotherapy, and concomitant chemotherapy temozolomide (known as the Stupp protocol), has only provided a modest increase of 2.5 months in median survival, since the landmark publication in 2005. There has been considerable effort in recent years to increase our knowledge of the molecular landscape of GBM through advances in technology such as next-generation sequencing, which has led to the stratification of the disease into several genetic subtypes. Current treatments are far from satisfactory, and studies investigating acquired/inherent resistance to current therapies, restricted drug delivery, inter/intra-tumoral heterogeneity, drug repurposing and a tumor immune-evasive environment have been the focus of intense research over recent years. While the clinical advancement of GBM therapeutics has seen limited progression compared to other cancers, developments in novel treatment strategies that are being investigated are displaying encouraging signs for combating this disease. This aim of this editorial is to provide a brief overview of a select number of these novel therapeutic approaches.

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