SapC–DOPS as a Novel Therapeutic and Diagnostic Agent for Glioblastoma Therapy and Detection: Alternative to Old Drugs and Agents

Glioblastoma multiforme (GBM), the most common type of brain cancer, is extremely aggressive and has a dreadful prognosis. GBM comprises 60% of adult brain tumors and the 5 year survival rate of GBM patients is only 4.3%. Standard-of-care treatment includes maximal surgical removal of the tumor in combination with radiation and temozolomide (TMZ) chemotherapy. TMZ is the “gold-standard” chemotherapy for patients suffering from GBM. However, the median survival is only about 12 to 18 months with this protocol. Consequently, there is a critical need to develop new therapeutic options for treatment of GBM. Nanomaterials have unique properties as multifunctional platforms for brain tumor therapy and diagnosis. As one of the nanomaterials, lipid-based nanocarriers are capable of delivering chemotherapeutics and imaging agents to tumor sites by enhancing the permeability of the compound through the blood–brain barrier, which makes them ideal for GBM therapy and imaging. Nanocarriers also can be used for delivery of radiosensitizers to the tumor to enhance the efficacy of the radiation therapy. Previously, high-atomic-number element-containing particles such as gold nanoparticles and liposomes have been used as radiosensitizers. SapC–DOPS, a protein-based liposomal drug comprising the lipid, dioleoylphosphatidylserine (DOPS), and the protein, saposin C (SapC), has been shown to be effective for treatment of a variety of cancers in small animals, including GBM. SapC–DOPS also has the unique ability to be used as a carrier for delivery of radiotheranostic agents for nuclear imaging and radiotherapeutic purposes. These unique properties make tumor-targeting proteo-liposome nanocarriers novel therapeutic and diagnostic alternatives to traditional chemotherapeutics and imaging agents. This article reviews various treatment modalities including nanolipid-based delivery and therapeutic systems used in preclinical and clinical trial settings for GBM treatment and detection.

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EXTH-52. CO-TARGETING ONCOSTATIN M RECEPTOR USING MONOCLONAL ANTIBODIES IN COMBINATION WITH PRESENT STANDARDS OF CARE FOR GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.383 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi93-vi93

Author(s):

Audrey Burban ◽

Ahmad Sharanek ◽

Arezu Jahani-Asl

Keyword(s):

Stem Cells ◽

Monoclonal Antibodies ◽

Tumor Growth ◽

Standard Of Care ◽

Adult Brain ◽

Oncostatin M ◽

Standards Of Care ◽

Surgical Removal ◽

Current Standard ◽

Therapeutic Monoclonal Antibodies

Abstract Glioblastoma Multiform (GBM) is the most aggressive primary tumor in the adult brain. The present standard of care includes surgical removal of the tumors followed by treatment with Temozolomide (TMZ) and radiation therapy. Despite intense efforts and advances in surgery and combination therapy, the median survival rate for GB patients remain 16 months following diagnosis. EGFRvIII/STAT3 signaling plays critical roles in GBM pathogenesis. We have recently discovered that the tumorigenic capacity of EGFRvIll/STAT3 pathway crucially depends on the cytokine receptor for Oncostatin M (OSMR). OSMR is a required co-receptor of EGFRvIII and a direct transcriptional target of STAT3. Strikingly, OSMR is highly expressed in brain tumor stem cells (BTSCs), a population of self-renewing malignant stem cells within GBM that contribute to tumor growth, recurrence and therapeutic resistance. We have generated therapeutic monoclonal antibodies against OSMR (OSMR mAb) that function as powerful inhibitors of OSMR. Treatment of BTSCs with OSMR mAb resulted in inhibition of OSMR-mediated signaling pathways and significantly impaired the phosphorylation of STAT3. Strikingly, treatment of BTSCs with OSMR mAb significantly attenuated BTSC self-renewal in limiting dilution assay and sensitized their response to tyrosine kinase inhibitors (TKI), ionizing radiation and TMZ. Using patient derived stem cell tumor xenografts, we have shown that OSMR mAb significantly reduced tumor growth compared to IgG control. Together, our findings suggest that targeting OSMR using therapeutic monoclonal antibodies in combination with EGFR inhibitors and/ or the current standard of care may provide a promising therapeutic strategy for glioblastoma.

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MON-LB59 Radiofrequency Ablation as a Primary Therapy for Benign Functioning Insulinoma

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.2105 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Ebtihal Y Alyusuf ◽

Aishah Ali Ekhzaimy ◽

Basil Alomair

Keyword(s):

Radiofrequency Ablation ◽

Treatment Option ◽

Standard Of Care ◽

Uncinate Process ◽

Therapeutic Modality ◽

Treatment Modalities ◽

Surgical Removal ◽

Primary Therapy ◽

Alternative Treatment Option

Abstract Background Insulinomas are rare life-threatening pancreatic neuroendocrine tumors. Surgical removal continues to be the treatment of choice for such benign cases with a high cure rate. However, surgery is associated with a considerable risk of morbidity and mortality.Here we describe a case of benign solitary insulinoma successfully treated with RFA in a patient who strongly refused surgery. Case Description A 56-year- old non- diabetic, male is known to have hypertension and lymphoma diagnosed at age of 20 years, in remission. He presented with recurrent episodes of transient ischemic attack and stroke over the last three years. A change in his cognitive function, behavior, and memory was noticed. During his hospital stay for the second episode of stroke, he was found to have hypoglycemia which was asymptomatic. Insulinoma was confirmed based on the followings: low plasma glucose level of 2.04 mmol/l (4.0- 5.6), inappropriately elevated plasma f insulin and C-peptide 68.9 mU/l (3-13) and 4.08 ug/l (1.0-3.1); respectively. Sulfonylurea screening test was negative. MRI of the abdomen showed a 3.2x2.5 cm, well-circumscribed hypervascular lesion at the uncinate process of the pancreas, which is compatible with neuroendocrine tumor. Treatment modalities have been explained to the patient who was fully informed about the risk and benefit of each treatment option. However, he strongly refused surgery. Meanwhile, he was admitted with a third attack of stroke with concurrent hypoglycemia. In view of his refusal of the surgical treatment and due to his recent stroke and high-risk status for surgery, the option of radiofrequency ablation was decided. RFA of the pancreatic tumor using 40.75 GY fractions was carried out with a favorable outcome. The patient achieved biochemical normalization and remains euglycemic during his follow up. Reversal of his cognitive, behavioral, and memory changes was recognized. CT abdomen during a follow-up of 2 months after radiation showed a mild regression of the size of the tumor with no evidence of new lesions or distance metastasis. He remained under close follow up at the neuroendocrine clinic. Conclusion This case shows a treatment challenge which required the use of an alternative treatment option other than the standard of care in managing a case of benign insulinoma. Successful treatment was achieved in our case with the use of RFA rather than surgery. This report highlights the evolving evidence of nonsurgical RFA being a potential safe, feasible therapeutic modality option or even an alternative to surgery in selected cases of benign insulinoma. Because of the rarity of this tumor and low rate of therapeutic application of RFA in similar cases, the role of RFA had not been extensively studied. Large studies are needed to evaluate the long-term outcomes of RFA in this setting.

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Novel treatment opportunities in Graves’ orbitopathy

Orvosi Hetilap ◽

10.1556/oh.2014.29963 ◽

2014 ◽

Vol 155 (33) ◽

pp. 1295-1300

Author(s):

Annamária Erdei ◽

Annamária Gazdag ◽

Miklós Bodor ◽

Eszter Berta ◽

Mónika Katkó ◽

...

Keyword(s):

Clinical Experience ◽

Clinical Course ◽

Treatment Protocol ◽

Treatment Modalities ◽

Graves Disease ◽

Novel Treatment ◽

Graves Orbitopathy ◽

Cd20 Antibody ◽

Anti Cd20 ◽

Novel Therapeutic

Graves’ orbitopathy is the most common extrathyroidal manifestation of Graves’ disease. Up to now, curative treatment modalities for the most severe sight-threatening cases have not been developed. Here the authors summarize the treatment protocol of Graves’ orbitopathy and review novel therapeutic options. They review the literature on this topic and present their own clinical experience. The authors point out that anti-CD20 antibody could positively influence the clinical course of Graves’ orbitopathy. Selenium is efficient in mild cases. Further prospective investigations are warranted. Orv. Hetil., 2014, 155(33), 1295–1300.

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Herbal Medicine for Glioblastoma: Current and Future Prospects

Medicinal Chemistry ◽

10.2174/1573406416666200130100833 ◽

2020 ◽

Vol 16 (8) ◽

pp. 1022-1043

Author(s):

Imran Khan ◽

Sadaf Mahfooz ◽

Mustafa A. Hatiboglu

Keyword(s):

Cell Proliferation ◽

Survival Rates ◽

Standard Of Care ◽

Natural Compounds ◽

Treatment Modalities ◽

Normal Brain ◽

The Central Nervous System ◽

Cycle Regulation ◽

Immense Potential

Background: Glioblastoma is one of the most aggressive and devastating tumours of the central nervous system with short survival time. Glioblastoma usually shows fast cell proliferation and invasion of normal brain tissue causing poor prognosis. The present standard of care in patients with glioblastoma includes surgery followed by radiotherapy and temozolomide (TMZ) based chemotherapy. Unfortunately, these approaches are not sufficient to lead a favorable prognosis and survival rates. As the current approaches do not provide a long-term benefit in those patients, new alternative treatments including natural compounds, have drawn attention. Due to their natural origin, they are associated with minimum cellular toxicity towards normal cells and it has become one of the most attractive approaches to treat tumours by natural compounds or phytochemicals. Objective: In the present review, the role of natural compounds or phytochemicals in the treatment of glioblastoma describing their efficacy on various aspects of glioblastoma pathophysiology such as cell proliferation, apoptosis, cell cycle regulation, cellular signaling pathways, chemoresistance and their role in combinatorial therapeutic approaches was described. Methods: Peer-reviewed literature was extracted using Pubmed, EMBASE Ovid and Google Scholar to be reviewed in the present article. Conclusion: Preclinical data available in the literature suggest that phytochemicals hold immense potential to be translated into treatment modalities. However, further clinical studies with conclusive results are required to implement phytochemicals in treatment modalities.

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Current and Future Treatments for Classic Galactosemia

Journal of Personalized Medicine ◽

10.3390/jpm11020075 ◽

2021 ◽

Vol 11 (2) ◽

pp. 75 ◽

Cited By ~ 1

Author(s):

Britt Delnoy ◽

Ana I. Coelho ◽

Maria Estela Rubio-Gozalbo

Keyword(s):

Standard Of Care ◽

Type I ◽

Therapeutic Approaches ◽

Restricted Diet ◽

Galactose Metabolism ◽

Galt Activity ◽

Classic Galactosemia ◽

Pathogenic Factors ◽

Future Treatments ◽

Novel Therapeutic

Type I (classic) galactosemia, galactose 1-phosphate uridylyltransferase (GALT)-deficiency is a hereditary disorder of galactose metabolism. The current therapeutic standard of care, a galactose-restricted diet, is effective in treating neonatal complications but is inadequate in preventing burdensome complications. The development of several animal models of classic galactosemia that (partly) mimic the biochemical and clinical phenotypes and the resolution of the crystal structure of GALT have provided important insights; however, precise pathophysiology remains to be elucidated. Novel therapeutic approaches currently being explored focus on several of the pathogenic factors that have been described, aiming to (i) restore GALT activity, (ii) influence the cascade of events and (iii) address the clinical picture. This review attempts to provide an overview on the latest advancements in therapy approaches.

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COVD-25. THE PARADOXICAL EFFECTS OF COVID-19 ON CANCER CARE IN THE NEURO-ONCOLOGY SETTING

Neuro-Oncology ◽

10.1093/neuonc/noaa215.106 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii26-ii26

Author(s):

Nicole Cort ◽

Alex Broom ◽

Katherine Kenny ◽

Alexander Page ◽

Jennifer Durling ◽

...

Keyword(s):

Cancer Care ◽

Standard Of Care ◽

Adult Brain ◽

Evidence Based ◽

Negative Consequences ◽

Traditional Practice ◽

Delivery Of Care ◽

Paradoxical Effects ◽

Oncology Care ◽

The Impact

Abstract COVID-19 has caused ongoing interruptions to healthcare systems worldwide, shifting care to virtual platforms, and placing significant economic and logistical burdens on clinical practice. The pandemic has created uncertainty in delivering the standard of care, both in areas of cancer diagnosis and treatment, especially within neuro-oncology. Due to the pandemic, care and operational planning goals have shifted to infection prevention, modifying recommendations to decrease viral transmission and increasing telemedicine use, potentially creating a burden on implementing evidence-based medicine. These dynamics have since begun to redefine traditional practice and research regimens, impacting the comprehensive care that cancer patients can and should receive; and the enduring consequences for the delivery of healthcare. The impact of COVID-19 on oncology practice and trials might endure well beyond the short- to mid-term of the active pandemic. Therefore, these shifts must be accompanied by improved training and awareness, enhanced infrastructure, and evidence-based support to harness the positives and offset the potential negative consequences of the impacts of COVID-19 on cancer care. To address these paradoxical effects, we will conduct iterative, qualitative (face-to-face/video conference) interviews with neuro-oncology clinical and research professionals and adult brain tumor patients receiving care during the pandemic. We will capture unique aspects of oncology care: the lived, subjective, situated, and contingent accounts of patients and medical professionals, especially during a pandemic. We will also specifically compare the impact of telehealth during the pandemic on delivery of care to complex neuro-oncology patients. A summary of this in-depth, qualitative approach will result in a sophisticated understanding of neuro-oncology care on the frontline at a time of crisis, as experienced during a pandemic, to articulate best practices for future implementation.

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The evolution of alternative splicing in glioblastoma under therapy

Genome Biology ◽

10.1186/s13059-021-02259-5 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Lin Wang ◽

Karin Shamardani ◽

Husam Babikir ◽

Francisca Catalan ◽

Takahide Nejo ◽

...

Keyword(s):

Alternative Splicing ◽

Standard Of Care ◽

Surface Proteins ◽

Adult Brain ◽

Primary Tumors ◽

Cell Therapies ◽

Therapeutic Development ◽

Human Gbm ◽

Tissue Specimens ◽

Splicing Patterns

Abstract Background Alternative splicing is a rich source of tumor-specific neoantigen targets for immunotherapy. This holds promise for glioblastomas (GBMs), the most common primary tumors of the adult brain, which are resistant to standard-of-care therapy. Although most clinical trials enroll patients at recurrence, most preclinical studies have been done with specimens from primary disease. There are limited expression data from GBMs at recurrence and surprisingly little is known about the evolution of splicing patterns under therapy. Result We profile 37 primary-recurrent paired human GBM specimens via RNA sequencing. We describe the landscape of alternative splicing in GBM at recurrence and contrast that to primary and non-malignant brain-tissue specimens. By screening single-cell atlases, we identify cell-type-specific splicing patterns and novel splicing events in cell-surface proteins that are suitable targets for engineered T cell therapies. We identify recurrent-specific isoforms of mitogen-activated kinase pathway genes that enhance invasiveness and are preferentially expressed by stem-like cells. Conclusion These studies shed light on gene expression in recurrent GBM and identify novel targets for therapeutic development.

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New Therapeutics for Ulcerative Colitis

Annual Review of Medicine ◽

10.1146/annurev-med-052919-120048 ◽

2021 ◽

Vol 72 (1) ◽

pp. 199-213

Author(s):

Robert P. Hirten ◽

Bruce E. Sands

Keyword(s):

Ulcerative Colitis ◽

Inflammatory Disease ◽

Clinical Remission ◽

Treatment Options ◽

Treatment Modalities ◽

Therapeutic Approaches ◽

Stages Of Development ◽

The Future ◽

New Treatment ◽

Novel Therapeutic

Ulcerative colitis (UC) is a relapsing and remitting inflammatory disease of the colon with a variable course. Despite advances in treatment, only approximately 40% of patients achieve clinical remission at the end of a year, prompting the exploration of new treatment modalities. This review explores novel therapeutic approaches to UC, including promising drugs in various stages of development, efforts to maximize the efficacy of currently available treatment options, and non-medication-based modalities. Treatment approaches which show promise in impacting the future of UC management are highlighted.

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Potent pro-apoptotic combination therapy is highly effective in a broad range of cancers

Cell Death and Differentiation ◽

10.1038/s41418-021-00869-x ◽

2021 ◽

Author(s):

Antonella Montinaro ◽

Itziar Areso Zubiaur ◽

Julia Saggau ◽

Anna-Laura Kretz ◽

Rute M. M. Ferreira ◽

...

Keyword(s):

Combination Therapy ◽

Cancer Cells ◽

Standard Of Care ◽

Therapy Resistance ◽

Treatment Modalities ◽

Cancer Resistance ◽

Therapeutic Approaches ◽

Highly Effective ◽

Drastic Increase ◽

New Treatment

AbstractPrimary or acquired therapy resistance is a major obstacle to the effective treatment of cancer. Resistance to apoptosis has long been thought to contribute to therapy resistance. We show here that recombinant TRAIL and CDK9 inhibition cooperate in killing cells derived from a broad range of cancers, importantly without inducing detectable adverse events. Remarkably, the combination of TRAIL with CDK9 inhibition was also highly effective on cancers resistant to both, standard-of-care chemotherapy and various targeted therapeutic approaches. Dynamic BH3 profiling revealed that, mechanistically, combining TRAIL with CDK9 inhibition induced a drastic increase in the mitochondrial priming of cancer cells. Intriguingly, this increase occurred irrespective of whether the cancer cells were sensitive or resistant to chemo- or targeted therapy. We conclude that this pro-apoptotic combination therapy has the potential to serve as a highly effective new treatment option for a variety of different cancers. Notably, this includes cancers that are resistant to currently available treatment modalities.

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Immunotherapy Advances for Epithelial Ovarian Cancer

Cancers ◽

10.3390/cancers12123733 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3733

Author(s):

Erin G. Hartnett ◽

Julia Knight ◽

Mackenzy Radolec ◽

Ronald J. Buckanovich ◽

Robert P. Edwards ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Gynecologic Cancer ◽

Single Agent ◽

Standard Of Care ◽

Treatment Modalities ◽

Cancer Type ◽

Immune Effector ◽

Effector Cells ◽

Immune Therapies

New treatment modalities are needed in order to improve the prognosis of women diagnosed with epithelial ovarian cancer (EOC), the most aggressive gynecologic cancer type. Most ovarian tumors are infiltrated by immune effector cells, providing the rationale for targeted approaches that boost the existing or trigger new anti-tumor immune mechanisms. The field of immuno-oncology has experienced remarkable progress in recent years, although the results seen with single agent immunotherapies in several categories of solid tumors have yet to extend to ovarian cancer. The challenge remains to determine what treatment combinations are most suitable for this disease and which patients are likely to benefit and to identify how immunotherapy should be incorporated into EOC standard of care. We review here some of the most promising immune therapies for EOC and focus on those currently tested in clinical trials.

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