PDTM-44. ROLE OF ONC-206 IN REGULATING MEDULLOBLASTOMA TUMOR PROGRESSION

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children. Of the four different sub-groups, the Sonic Hedgehog (SHH) subgroup accounts for about 30% of human MBs. The current standard of care (resection, cranio-spinal irradiation, and chemotherapy) for MB is typically ineffective for SHH MB in non-infants and those with metastatic disease. Survivors are frequently beset with long-term side effects including cognitive deficiencies and a severely impaired quality of life. Taken together, there is a critical need for novel targeted therapies for SHH MB. Recently, promising preclinical and clinical results have been obtained in a variety of cancers treated with a small molecule antagonist, ONC-201, which acts against DRD2, a G-protein coupled receptor that is widely expressed in MBs and regulates pro-survival pathways in tumors. In the present study we report the activity of ONC-201 and another DRD2 antagonist, ONC-206, which binds DRD2 with increased affinity. We tested three different MB cell lines with varied levels of DRD2 expression against these drugs, and consistently observed increased cell death at lower doses of ONC-206 compared to ONC-201. Following literature reports about the mechanism of action of ONC-201, we also evaluated the role of ClpP gene in MB cell lines. ClpP is a mitochondrial protease that has been shown to directly bind ONC 201. We observed a decrease in the expression of this gene after treatment of MB cell lines with ONC-206. Current studies are focusing on exploring the mechanism by which ONC-206 affects MB growth and metastasis. Dissecting this mechanism will be pivotal in predicting the role of this small molecule as a pre-clinical therapeutic for MB treatment.

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Radiotherapy in the treatment of gastrointestinal stromal tumor

Rare Tumors ◽

10.4081/rt.2011.e35 ◽

2011 ◽

Vol 3 (4) ◽

pp. 111-113 ◽

Cited By ~ 13

Author(s):

Christin A. Knowlton ◽

Luther W. Brady ◽

Rebecca C. Heintzelman

Keyword(s):

Kinase Inhibitor ◽

Standard Of Care ◽

High Rate ◽

Viable Option ◽

Current Standard ◽

Mesenchymal Tumors ◽

Palliative Setting ◽

Term Response

Gastrointestinal stromal tumors (GISTs) are uncommon mesenchymal tumors of the gastrointestinal tract. Up to one-third of GISTs are malignant with a high rate of metastasis. Surgical resection is the mainstay of care for patients with resectable disease. Imatinib mesylate, a selective tyrosine kinase inhibitor, is the current standard of care for GISTs that cannot be completely resected or in cases of metastatic GIST. Although often overlooked, radiation therapy is a viable option for select patients with GIST. We report the case of a patient with unresectable GIST who was treated with local radiotherapy and achieved long-term response. We also present a review of the literature regarding the use of radiotherapy in the treatment of GIST. GIST has been shown to be a radiosensitive tumor. Radiotherapy can offer long-term local control and should be considered in the adjuvant or palliative setting. The role of radiotherapy delivered concurrently with imatinib in the treatment of GIST may warrant further investigation.

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Patient-individual cancer cell lines and tissue analysis delivers no evidence for a role of DNA virus infection on colorectal cancer oncogenesis

10.21203/rs.2.13448/v1 ◽

2019 ◽

Author(s):

Michael Gock ◽

Marcel Kordt ◽

Stephanie Matschos ◽

Christina S. Mullins ◽

Michael Linnebacher

Keyword(s):

Cell Lines ◽

Molecular Subtypes ◽

Morphological Changes ◽

Tissue Analysis ◽

Oncogenic Viruses ◽

Dna Viruses ◽

Viral Particles ◽

Specific Sequences

Abstract Background Several DNA viruses are highly suspicious to have oncogenic effects in humans. This study investigates the presence of potentially oncogenic viruses such as SV40, JCV, BKV and EBV in patient-derived colorectal carcinoma (CRC) cells typifying all molecular subtypes of CRC. Methods Sample material (gDNA and cDNA) of a total of 49 patient-individual CRC cell lines and corresponding primary material from 11 patients, including normal, tumor-derived and metastasis-derived tissue were analyzed for sequences of SV40, JVC, BKV and EBV using endpoint PCR. In addition, the susceptibility of CRC cells to JCV and BKV was examined using a long-term cultivation approach of patient-individual cells in the presence of viruses. Results No virus-specific sequences could be detected in all specimens. Likewise, no morphological changes were observed and no evidence for viral infection or integration could be provided after long term CRC cell cultivation in presence of viral particles. Conclusions In summary, the presented data suggest that there is no direct correlation between tumorigenesis and viral load and consequently no evidence for a functional role of the DNA viruses included into this analysis in CRC development.

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The Yin and the Yang of Treatment for Chronic Hepatitis B—When to Start, When to Stop Nucleos(t)ide Analogue Therapy

Viruses ◽

10.3390/v12090934 ◽

2020 ◽

Vol 12 (9) ◽

pp. 934 ◽

Cited By ~ 1

Author(s):

Samuel Hall ◽

Jessica Howell ◽

Kumar Visvanathan ◽

Alexander Thompson

Keyword(s):

Chronic Hepatitis ◽

Hepatitis B ◽

Chronic Hepatitis B ◽

Antiviral Agents ◽

Standard Of Care ◽

Current Standard ◽

Hbsag Loss ◽

Personalised Treatment ◽

Treat All

Over 257 million individuals worldwide are chronically infected with the Hepatitis B Virus (HBV). Nucleos(t)ide analogues (NAs) are the first-line treatment option for most patients. Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are both potent, safe antiviral agents, have a high barrier to resistance, and are now off patent. They effectively suppress HBV replication to reduce the risk of cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Treatment is continued long-term in most patients, as NA therapy rarely induces HBsAg loss or functional cure. Two diverging paradigms in the treatment of chronic hepatitis B have recently emerged. First, the public health focussed “treat-all” strategy, advocating for early and lifelong antiviral therapy to minimise the risk of HCC as well as the risk of HBV transmission. In LMICs, this strategy may be cost saving compared to monitoring off treatment. Second, the concept of “stopping” NA therapy in patients with HBeAg-negative disease after long-term viral suppression, a personalised treatment strategy aiming for long-term immune control and even HBsAg loss off treatment. In this manuscript, we will briefly review the current standard of care approach to the management of hepatitis B, before discussing emerging evidence to support both the “treat-all” strategy, as well as the “stop” strategy, and how they may both have a role in the management of patients with chronic hepatitis B.

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Towards Personalization in the Curative Treatment of Gastric Cancer

Frontiers in Oncology ◽

10.3389/fonc.2020.614907 ◽

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.

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Role of the G-Protein-Coupled Receptor Signaling Pathway in Insecticide Resistance

International Journal of Molecular Sciences ◽

10.3390/ijms20174300 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4300 ◽

Cited By ~ 2

Author(s):

Ting Li ◽

Nannan Liu

Keyword(s):

Insecticide Resistance ◽

Cell Line ◽

Signaling Pathway ◽

G Protein ◽

Cell Lines ◽

Sf9 Cells ◽

Camp Production ◽

G Protein Coupled Receptor ◽

G Protein Coupled

The G-protein-coupled receptor (GPCR) regulated intracellular signaling pathway is known to be involved in the development of insecticide resistance in the mosquito, Culex quinquefasciatus. To elucidate the specific role of each effector in the GPCR regulating pathway, we initially expressed a GPCR, G-protein alpha subunit (Gαs), adenylate cyclase (AC), and protein kinase A (PKA) in insect Spodoptera frugiperda (Sf9) cells and investigated their regulation function on cyclic AMP (cAMP) production and PKA activity. GPCR, Gαs, and AC individually expressed Sf9 cells showed higher cAMP production as the expression of each effector increased. All the effector-expressed cell lines showed increased PKA activity however. Moreover, Sf9 cytochrome P450 gene expression and cell tolerance to permethrin were examined. The relative expression of CYP9A32gene in Sf9 cells tested was significantly increased in all effector-expressed cell lines compared to a control cell line; these effector-expressed cell lines also showed significantly higher tolerance to permethrin. Inhibitor treatments on each effector-expressed cell line revealed that Bupivacaine HCl and H89 2HCl robustly inhibited cAMP production and PKA activity, respectively, resulting in decreased tolerance to permethrin in all cell lines. The synergistic functions of Bupivacaine HCl and H89 2HCl with permethrin were further examined in Culex mosquito larvae, providing a valuable new information for mosquito control strategies.

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Radiotherapy of glioblastoma 15 years after the landmark Stupp’s trial: more controversies than standards?

Radiology and Oncology ◽

10.2478/raon-2018-0023 ◽

2018 ◽

Vol 52 (2) ◽

pp. 121-128 ◽

Cited By ~ 17

Author(s):

Tomas Kazda ◽

Adam Dziacky ◽

Petr Burkon ◽

Petr Pospisil ◽

Marek Slavik ◽

...

Keyword(s):

Concurrent Chemoradiotherapy ◽

Standard Of Care ◽

Primary Brain Tumor ◽

Current Standard ◽

Tumor Treating Fields ◽

Integrated Boost ◽

Hippocampal Sparing ◽

New Treatment ◽

Personalized Approach

Abstract Background The current standard of care of glioblastoma, the most common primary brain tumor in adults, has remained unchanged for over a decade. Nevertheless, some improvements in patient outcomes have occurred as a consequence of modern surgery, improved radiotherapy and up-to-date management of toxicity. Patients from control arms (receiving standard concurrent chemoradiotherapy and adjuvant chemotherapy with temozolomide) of recent clinical trials achieve better outcomes compared to the median survival of 14.6 months reported in Stupp’s landmark clinical trial in 2005. The approach to radiotherapy that emerged from Stupp’s trial, which continues to be a basis for the current standard of care, is no longer applicable and there is a need to develop updated guidelines for radiotherapy within the daily clinical practice that address or at least acknowledge existing controversies in the planning of radiotherapy. The goal of this review is to provoke critical thinking about potentially controversial aspects in the radiotherapy of glioblastoma, including among others the issue of target definitions, simultaneously integrated boost technique, and hippocampal sparing. Conclusions In conjunction with new treatment approaches such as tumor-treating fields (TTF) and immunotherapy, the role of adjuvant radiotherapy will be further defined. The personalized approach in daily radiotherapy practice is enabled with modern radiotherapy systems.

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Radiomics for the Diagnosis and Differentiation of Pancreatic Cystic Lesions

Diagnostics ◽

10.3390/diagnostics10070505 ◽

2020 ◽

Vol 10 (7) ◽

pp. 505

Author(s):

Jorge D. Machicado ◽

Eugene J. Koay ◽

Somashekar G. Krishna

Keyword(s):

Predictive Accuracy ◽

Quantitative Imaging ◽

Standard Of Care ◽

Small Sample ◽

Cystic Lesions ◽

Current Standard ◽

Cross Sectional ◽

Small Sample Sizes ◽

Insight Into

Radiomics, also known as quantitative imaging or texture analysis, involves extracting a large number of features traditionally unmeasured in conventional radiological cross-sectional images and converting them into mathematical models. This review describes this approach and its use in the evaluation of pancreatic cystic lesions (PCLs). This discipline has the potential of more accurately assessing, classifying, risk stratifying, and guiding the management of PCLs. Existing studies have provided important insight into the role of radiomics in managing PCLs. Although these studies are limited by the use of retrospective design, single center data, and small sample sizes, radiomic features in combination with clinical data appear to be superior to the current standard of care in differentiating cyst type and in identifying mucinous PCLs with high-grade dysplasia. Combining radiomic features with other novel endoscopic diagnostics, including cyst fluid molecular analysis and confocal endomicroscopy, can potentially optimize the predictive accuracy of these models. There is a need for multicenter prospective studies to elucidate the role of radiomics in the management of PCLs.

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Adjuvant Treatments for Localized Advanced Gastric Cancer: Differences among Geographic Regions

American Society of Clinical Oncology Educational Book ◽

10.14694/edbook_am.2012.32.17 ◽

2012 ◽

pp. e31-e34

Author(s):

Yoon-Koo Kang ◽

Changhoon Yoo

Keyword(s):

Gastric Cancer ◽

Adjuvant Therapy ◽

Standard Of Care ◽

Current Standard ◽

The West ◽

The United Kingdom ◽

Group B ◽

Leukemia Group ◽

Postoperative Chemoradiation

Overview: After much debate, adjuvant therapy has become the standard of care worldwide for resected localized gastric cancer. However, geographic differences exist in standard adjuvant treatments: postoperative chemoradiation in North America, perioperative chemotherapy in the United Kingdom, and postoperative chemotherapy in East Asia. Now that D2 gastrectomy has been recognized as the optimal surgery for localized gastric cancer in the West as well as in Asia, the standard adjuvant treatments used in the West may need to be reconsidered. One of the most important issues in adjuvant therapy for localized gastric cancer is how to improve the clinical outcomes of current standard treatments. Recent Cancer and Leukemia Group B (CALGB) and AMC studies suggest that simply intensifying chemotherapy by adding more agents or prolonging treatment duration is insufficient. However, new strategies like early initiation of chemotherapy and/or intraperitoneal chemotherapy may further improve the current standard adjuvant therapy. In the era of targeted therapy, the role of biologic agents for gastric cancer should also be explored in the adjuvant setting. With a deeper understanding of the molecular biology of gastric cancer, adjuvant therapy for patients with localized gastric cancer can be optimized and individualized.

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Needleless Ablation of Osteoid Osteoma and Osteoblastoma: The Emergent Role of MRgFUS

Journal of Clinical Medicine ◽

10.3390/jcm11010128 ◽

2021 ◽

Vol 11 (1) ◽

pp. 128

Author(s):

Flavia Cobianchi Bellisari ◽

Pierpaolo Palumbo ◽

Carlo Masciocchi ◽

Carmine Zoccali ◽

Antonio Barile ◽

...

Keyword(s):

Osteoid Osteoma ◽

Focused Ultrasound ◽

Standard Of Care ◽

Current Standard ◽

Ultrasound Surgery ◽

Focused Ultrasound Surgery ◽

Poor Tolerance ◽

Microscopic Features ◽

Technical Details

Osteoblastoma (OB) and osteoid osteoma (OO) are benign bone-forming tumors, with nearly identical basic microscopic features. The main difference is dimension (OO has usually a nidus measuring <2 cm in diameter). In addition, OB is biologically more active than OO, with a tendency to grow in size. Historically, treatments have included surgical resection and analgesics, although invasiveness and poor tolerance have led to the current standard of care moving toward interventional radiology, where radiofrequency ablation (RFA) represents the most diffuse technique. Magnetic resonance-guided focused ultrasound surgery (MRgFUS) has recently emerged as another innovative alternative treatment, providing tumor ablation through a needleless and ionizing radiation-free modality. In addition, this technique has the ability to guarantee a very precise and controlled increase in temperature, delivering small amounts of energy that can accurately destroy only the lesion, avoiding healthy surrounding tissues. The present review focuses on MRgFUS as the less invasive, safe, effective, and durable treatment option for the management of osteoid osteoma and osteoblastoma, including a description of technical details, indications and outcomes.

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Successful Treatment of Tumor-Induced Osteomalacia by Multidisciplinary Therapy with Radiation to Intracranial Fibromyxoid Tumor

Case Reports in Endocrinology ◽

10.1155/2021/8841259 ◽

2021 ◽

Vol 2021 ◽

pp. 1-5

Author(s):

Mariangela Massaccesi ◽

Francesco Miccichè ◽

Mario Rigante ◽

Gianluigi Petrone ◽

Elisabetta Lepre ◽

...

Keyword(s):

Paraneoplastic Syndrome ◽

Bone Fractures ◽

External Beam Radiotherapy ◽

Fibroblast Growth Factor 23 ◽

Tumor Resection ◽

Rare Condition ◽

Standard Of Care ◽

Tumor Control ◽

Current Standard

Background. Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by protein fibroblast-growth-factor-23 (FGF-23) secreting tumors. Complete tumor resection is the current standard of care for TIO; however, some patients may develop tumor recurrence. Due to the rarity of this paraneoplastic syndrome, the role of radiotherapy is unclear. This case is worth reporting because it adds to our knowledge some insights about the potential role of radiotherapy in this rare condition. Case Presentation. After multidisciplinary consultation, in July 2015, postoperative adjuvant radiotherapy was offered to a 52-year-old man with a multiple recurrent ossifying fibromyxoid tumor in the right frontal sinus causing TIO. The patient had a history of multiple bone fractures and pain since more than 20 years. The tumor had been removed in 2003 for the first time. Subsequent endoscopic resections of the tumor had been performed for recurrences of TIO in May 2012, October 2013, and July 2015. Starting from October 2015, external beam radiotherapy was delivered with a volumetric modulated arc technique to the tumor bed with a daily dose of 2 Gy up to a total dose of 60 Gy. After five years from treatment, the patient is free from local tumor relapse, TIO progression, and radiation-induced side effects. Conclusions. Radiotherapy may provide long-term TIO remission and tumor control, thus being a treatment option in cases where surgery is unfeasible or unsuccessful.

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