Evaluation of the EMulate Therapeutics Voyager’s ultra-low radiofrequency energy in murine model of glioblastoma (original) (raw)
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CNS Oncology
Aim: The EMulate Therapeutics Voyager™ is a simple, wearable, home-use device that uses an alternating electromagnetic field to alter biologic signaling within cells. Objective: To assess the safety/feasibility of the Voyager in the treatment of recurrent glioblastoma (rGBM). Methods: In this study, patients with rGBM were treated with Voyager as monotherapy or in combination with standard chemotherapy at the Investigator's discretion. Safety was assessed by incidence of adverse events associated with the Voyager. Patients were followed until death. Results: A total of 75 patients were enrolled and treated for at least one day with the Voyager (safety population). Device-related adverse events were uncommon and generally did not result in interruption or withdrawal from treatment. There were no serious adverse events associated with Voyager. A total of 60 patients were treated for at least one month (clinical utility population). The median progression-free survival (PFS) was 17...
Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma
Proceedings of the National Academy of Sciences, 2013
Current therapy for glioblastoma multiforme is insufficient, with nearly universal recurrence. Available drug therapies are unsuccessful because they fail to penetrate through the region of the brain containing tumor cells and they fail to kill the cells most responsible for tumor development and therapy resistance, brain cancer stem cells (BCSCs). To address these challenges, we combined two major advances in technology: (i) brain-penetrating polymeric nanoparticles that can be loaded with drugs and are optimized for intracranial convection-enhanced delivery and (ii) repurposed compounds, previously used in Food and Drug Administration-approved products, which were identified through library screening to target BCSCs. Using fluorescence imaging and positron emission tomography, we demonstrate that brain-penetrating nanoparticles can be delivered to large intracranial volumes in both rats and pigs. We identified several agents (from Food and Drug Administration-approved products) that potently inhibit proliferation and self-renewal of BCSCs. When loaded into brain-penetrating nanoparticles and administered by convection-enhanced delivery, one of these agents, dithiazanine iodide, significantly increased survival in rats bearing BCSC-derived xenografts. This unique approach to controlled delivery in the brain should have a significant impact on treatment of glioblastoma multiforme and suggests previously undescribed routes for drug and gene delivery to treat other diseases of the central nervous system.
Preclinical Models of Glioblastoma in Radiobiology: Evolving Protocols and Research Methods
2016
Gliomas are the most common form of primary brain tumors with glioblastoma (GBM) being the most malignant. The standard therapy for newly diagnosed malignant gliomas involves maximal surgical resection, radiotherapy, and chemotherapy with a median survival of 9–14 months. The combination of RT with chemotherapeutic agents that sensitize tumor cells to the cytotoxic effects of RT has been studied in an attempt to enhance tumor control and minimize the radiation toxicity. Although such combination chemoradiation protocols have improved treatment outcomes in several human malignancies, they are still less than optimal, as the existing agents can cause undesirable toxicity. Therefore, a continuing endeavor in experimental and translational oncology research has been to identify more effective agents to augment the radiosensitivity of tumor cells. Recent efforts toward this goal have focused on molecularly targeted agents directed against certain components of intracellular signaling pat...
Biomedgrid LLC - A Review: Targeted Cancer Therapy as a Fight Against Brain Tumor
American Journal of Biomedical Science & Research , 2019
The brain tumor is the second most deadly disease for causing death among cancer patients. It can be treated by conventional treatment techniques i.e. chemotherapy, neurosurgery, and radiotherapy but with some improvement, it mostly results in the increase of medical problems by non-specific targeting of normal cells in addition to the cancerous cells. Different CNS diseases include cerebrovascular disease, Parkinson’s disease, epilepsy, Alzheimer disease, and other neurogenerative disorders. Despite advance ongoing research, a number of patients are dying every year by these diseases. Different techniques are used including invasive and non- invasive to treat these diseases. Molecular targeting agents are being used which have the advantages of easily crossing multiple barriers i.e. Brain blood barrier (BBB), cerebrospinal fluid (CSF) and brain bloodtumor barrier to reach the malignant site, low toxicity and better efficacy than conventional treatment techniques. Antibodies, nanoparticles and proton therapy can be used for specific targeting of tumor antigens which spare normal cells from the diseased ones. Although there are some issues i.e. difficulty in crossing multiple barriers, toxicity profiles, sometimes non-specific delivery, degradation of therapeutic agents by the enzymes. Research work is in progress to solve these issues.
Clinically Relevant Brain Tumor Model and Device Development for Experimental Therapeutics
Journal of Analytical Oncology, 2015
This paper assesses the subcutaneous, orthotopic, and transgenic mouse models used to study glioblastomas (GBMs) as well as delineates our model to overcome the limitations of these currently used models. Subcutaneous model involves the injection of GBM cells into hind leg or back of a mouse, whereas in orthotopic model, the injection of GBM cells into the cranium of mice is required. Neither subcutaneous nor orthotopic models accurately display the infiltrative growth pattern of the tumor into the brain parenchyma characteristic of GBMs in humans. Transgenic models are achieved by pronuclear microinjection (into the male pronucleus, immediately after fertilization) or the injection of DNA into embryonic stem cells. Transgenic models are similar to human GBMs in every way, except they are not as genetically complex. To overcome the limitations in these models, we have developed a brain tumor model that exhibits all the histologic hallmarks of human GBM. We used a flank model initia...
Translational Cancer Research, 2016
Tumor-treating fields (TTFields) is a novel treatment modality that has been recently approved for the treatment of patients with both newly diagnosed and recurrent glioblastoma multiforme (GBM). This approach comprises of a portable device delivering low intensity and intermediate frequency alternating electric fields aiming at selectively inhibiting cellular proliferation of neoplastic cells. Promising findings of recent large scale multinational clinical trials have indicated that TTFields have a favorable safety profile without causing significant adverse effects on patients. One of these trials reported that GBM patients treated with TTFields had significantly prolonged overall and progression free survival (PFS) compared to patients receiving standard chemotherapy. Moreover, improved quality of life with better cognitive and emotional functions was observed in TTFields treated cohorts of patients. Conventional MR imaging using modified RANO criteria is currently considered as the standard protocol for assessing disease progression and treatment response in patients with GBM. Using physiological and metabolic MR imaging, we recently reported our experience with evaluating treatment response to TTFields in newly diagnosed GBM. We believe that additional studies evaluating the treatment response of TTFields will have a profound impact on the clinical use of this novel and effective treatment modality for GBM patients.
Clinical development of experimental therapies for malignant glioma
Sultan Qaboos University Medical Journal, 2011
Advances in medical and surgical treatments in the last two to three decades have resulted in quantum leaps in the overall survival of patients with many types of non-central nervous system (CNS) malignant disease, while survival of patients with malignant gliomas (WHO grades 3 and 4) has only moderately improved. Surgical resection, external fractionated radiotherapy and oral chemotherapy, during and after irradiation, remain the pillars of malignant glioma therapy and have shown significant benefits. However, numerous clinical trials with adjuvant agents, most of them administered systemically and causing serious complications and side effects, have not achieved a noteworthy extension of survival, or only with considerable deterioration in patients’ quality of life. Significant attention was focussed in the last decades on the cell biology and molecular genetics of gliomas. Improved understanding of the fundamental features of tumour cells has resulted in the introduction and increasing clinical use of local therapies, which employ spatially defined delivery methods and tumour-selective agents specifically designed to be used in the environment of a glioma-invaded brain. This review summarises the key findings of some of the most recent and important clinical studies of locally administered novel treatments for malignant glioma. Several such therapies have shown considerable anti-tumour activity and a favourable profile of local and systemic side effects. These include biodegradable polymers for interstitial chemotherapy, targeted toxins administered by convection enhanced delivery, and intra- and peritumourally injected genetically modified viruses conferring glioma-selective toxicity. Areas of possible improvement of these therapies and essential future developments are also outlined.
Tumor protease-activated theranostic nanoparticles for MRI-guided glioblastoma therapy
Theranostics
Rationale: As a cancer, Glioblastoma (GBM) is a highly lethal and difficult-to-treat. With the aim of improving therapies to GBM, we developed novel and target-specific theranostic nanoparticles (TNPs) that can be selectively cleaved by cathepsin B (Cat B) to release the potent toxin monomethyl auristatin E (MMAE). Methods: We synthesized TNPs composed of a ferumoxytol-based nanoparticle carrier and a peptide prodrug with a Cat-B-responsive linker and the tubulin inhibitor MMAE. We hypothesized that intratumoral Cat B can cleave our TNPs and release MMAE to kill GBM cells. The ferumoxytol core enables in vivo drug tracking with magnetic resonance imaging (MRI). We incubated U87-MG GBM cells with TNPs or ferumoxytol and evaluated the TNP content in the cells with transmission electron microscopy and Prussian blue staining. In addition, we stereotaxically implanted 6-to 8-week-old nude mice with U87-MG with U87-MG GBM cells that express a fusion protein of Green Fluorescence Protein and firefly Luciferase (U87-MG/GFP-fLuc). We then treated the animals with an intravenous dose of TNPs (25 mg/kg of ferumoxytol, 0.3 mg/kg of MMAE) or control. We also evaluated the combination of TNP treatment with radiation therapy. We performed MRI before and after TNP injection. We compared the results for tumor and normal brain tissue between the TNP and control groups. We also monitored tumor growth for a period of 21 days. Results: We successfully synthesized TNPs with a hydrodynamic size of 41 ± 5 nm and a zeta potential of 6 ± 3 mV. TNP-treated cells demonstrated a significantly higher iron content than ferumoxytol-treated cells (98 ± 1% vs. 3 ± 1% of cells were iron-positive, respectively). We also found significantly fewer live attached cells in the TNP-treated group (3.8 ± 2.0 px 2) than in the ferumoxytol-treated group (80.0 ± 14.5 px 2 , p < 0001). In vivo MRI studies demonstrated a decline in the tumor signal after TNP (T2= 28 ms) but not control (T2= 32 ms) injections. When TNP injection was combined with radiation therapy, the tumor signals dropped further (T2 = 24 ms). The combination therapy of radiation therapy and TNPs extended the median survival from 14.5 days for the control group to 45 days for the combination therapy group. Conclusion: The new cleavable TNPs reported in this work accumulate in GBM, cause tumor cell death, and have synergistic effects with radiation therapy.
Targetable Multi-Drug Nanoparticles for Treatment of Glioblastoma with Neuroimaging Assessment
2020
Glioblastoma (GBM) is a deadly, malignant brain tumor with a poor long-term prognosis. The current median survival is approximately fifteen to seventeen months with the standard of care therapy which includes surgery, radiation, and chemotherapy. An important factor contributing to recurrence of GBM is high resistance of GBM cancer stem cells (CSCs), for which a systematically delivered single drug approach will be unlikely to produce a viable cure. Therefore, multi-drug therapies are needed. Currently, only temozolomide (TMZ), which is a DNA alkylator, affects overall survival in GBM patients. CSCs regenerate rapidly and over-express a methyl transferase which overrides the DNA-alkylating mechanism of TMZ, leading to drug resistance. Idasanutlin (RG7388, R05503781) is a potent, selective MDM2 antagonist that additively kills GBM CSCs when combined with diagnostics in a truly theranostic manner for enhancing personalized medicine against GBM. The goal of this thesis was to develop a...