A phase I study of vistusertib (dual mTORC1/2 inhibitor) in patients with previously treated glioblastoma multiforme: a CCTG study

SummaryThe PI3K/AKT/mTOR pathway activation plays a central role in glioblastoma multiforme (GBM) development and progression, and in resistance to anti-cancer therapies. Inhibition of the PI3K pathway has been shown to sensitize cultured glioma cells and tumor xenografts to the effects of temozolomide (TMZ) and radiation. Vistusertib is an oral inhibitor of mTORC1/2 complexes. The primary objective of this Canadian Cancer Trials Group phase I study was to determine the recommended phase II dose (RP2D) of vistusertib in patients with GBM receiving TMZ at first progression following primary treatment. Vistusertib was administered at a starting dose of 100  mg bid 2 days on/5 days off weekly with TMZ 150 mg/m2 daily for 5  days/28-days cycle. Dose escalation was according to a 3 + 3 design. Secondary objectives included assessment of vistusertib safety and toxicity profile, and preliminary efficacy. 15 patients were enrolled in the study (median age 66 (range 51–77), females 8). Vistusertib 125 mg BID in com bination with TMZ 150 mg/m2 daily for 5  days was well tolerated. Vistusertib treatment-related adverse events were generally grade 1–2, with the most frequently reported being fatigue, gastrointestinal symptoms, and rash. Of 13 response evaluable patients, 1 patient (8%) had a partial response ongoing at 7.6 months of follow-up, and 5 patients had stable disease (38%) as best response (median durat...
Source: Investigational New Drugs - Category: Drugs & Pharmacology Source Type: research

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Abstract PURPOSE: Pediatric low-grade glioma (pLGG) is the most prevalent childhood brain tumor. Patients with BRAF V600 mutation-positive pLGG may benefit from treatment with dabrafenib. Part 2 of a phase I/IIa study, open-label study (NCT01677741) explores the activity and safety of dabrafenib treatment in these patients. PATIENTS AND METHODS: Patients ages 1 to
Source: Clinical Cancer Research - Category: Cancer & Oncology Authors: Tags: Clin Cancer Res Source Type: research
Conclusions. In summary, RES529, the first dual TORC1/TORC2 dissociative inhibitor, lacking affinity for ABCB1/ABCG2 and having good brain penetration, was active in GBM preclinical/murine models giving credence to its use in clinical trial for patients with GBM treated in association with anti-angiogenetic compounds.
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
Abstract PURPOSE: The 2-part, phase 1/2a, open-label study (NCT01677741) sought to determine the safety, tolerability, pharmacokinetics, and preliminary activity of dabrafenib in pediatric patients with advanced BRAF V600-mutated cancers. EXPERIMENTAL DESIGN: This phase 1 dose-finding part treated patients aged 1 to 52 weeks and 52% undergoing treatment at data cutoff date. The most common grade 3/4 adverse events suspected to be related to study drug were maculopapular rash and arthralgia (2 patients each). No dose-limiting toxicities were observed. Pharmacokinetic analyses showed a dose-dependent increase i...
Source: Clinical Cancer Research - Category: Cancer & Oncology Authors: Tags: Clin Cancer Res Source Type: research
Park Chung Kang Despite the presence of aggressive treatment strategies, glioblastoma remains intractable, warranting a novel therapeutic modality. An oral antipsychotic agent, penflurido (PFD), used for schizophrenia treatment, has shown an antitumor effect on various types of cancer cells. As glioma sphere-forming cells (GSCs) are known to mediate drug resistance in glioblastoma, and considering that antipsychotics can easily penetrate the blood-brain barrier, we investigated the antitumor effect of PFD on patient-derived GSCs. Using five GSCs, we found that PFD exerts an antiproliferative effect in a time- an...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
miR‑378a‑3p inhibits cellular proliferation and migration in glioblastoma multiforme by targeting tetraspanin 17. Oncol Rep. 2019 Aug 20;: Authors: Guo XB, Zhang XC, Chen P, Ma LM, Shen ZQ Abstract Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor and patients with this disease tend to have poor clinical outcome. MicroRNAs (miRs) are important regulators of a number of key pathways implicated in tumor pathogenesis. Recently, the expression of miR‑378 was shown to be dysregulated in several different types of cancer, including gastric cancer, colorectal cancer and oral ca...
Source: Oncology Reports - Category: Cancer & Oncology Tags: Oncol Rep Source Type: research
ConclusionsThe CNS penetration observed was encouraging enough to move ribociclib forward with preclinical efficacy studies in models of pediatric brain tumors.
Source: Cancer Chemotherapy and Pharmacology - Category: Cancer & Oncology Source Type: research
The objective of our study is to unfold function and mechanism investigation on LINC00958 in OSCC. First, TCGA database showed the upregulation and prognostic significance of LINC00958 in head and neck squamous carcinoma. Then, we discovered in OSCC clinical samples that LINC00958 presented high expression and predicted poor prognosis. Also, LINC00958 was elevated in OSCC cells. In vitro gain- and loss-function experiments proved that LINC00958 facilitated cell growth, retarded apoptosis, accelerated migration, and epithelial-to-mesenchymal transition (EMT) in OSCC. Mechanistically, we confirmed the cytoplasmic expression ...
Source: Cancer Biology and Therapy - Category: Cancer & Oncology Authors: Tags: Cancer Biol Ther Source Type: research
Alla S. Koltsova1,2, Anna A. Pendina1, Olga A. Efimova1*, Olga G. Chiryaeva1, Tatyana V. Kuznetzova1 and Vladislav S. Baranov1,2 1D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Saint Petersburg, Russia 2Department of Genetics and Biotechnology, Saint Petersburg State University, Saint Petersburg, Russia In the present review, we focus on the phenomenon of chromothripsis, a new type of complex chromosomal rearrangements. We discuss the challenges of chromothripsis detection and its distinction from other chromoanagenesis events. Along with already known causes and mechanisms, we introdu...
Source: Frontiers in Genetics - Category: Genetics & Stem Cells Source Type: research
In this study, to improve our understanding of the role of ATP1A1 in the malignant phenotype and pathogenesis of GSCs, we evaluated ATP1A1 expression in GBMs of different grades and in two primary GSC lines established from human GBM tissues. We evaluated the role of ATP1A1 in GSC growth, its interactions with Src, and the activation of the ERK1/2 and AKT pathways. Our results revealed that ATP1A1 acts as an oncogene in our GSC models and targeting ATP1A1/Src may suppress GSC proliferation and growth. Materials and Methods Cell Isolation and Culture Human brain GBM tissues were from pathologically confirmed surgical spe...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Conclusion: Taken together, lncRNA OIP5-AS1 acted as a ceRNA to drive proliferation, migration and invasion of HemECs through regulating miR-195-5p/NOB1 axis. Introduction Infant hemangioma (IH) is a benign neoplasm commonly seen in childhood, which is more common in premature infants and infants with low birth weight (Smith et al., 2017). There are three distinct clinical histological stages in IH: the early proliferative stage, when undeveloped blood vessels are rapidly growing; plateau stage and final regressive stage, with scattered capillaries and large drainage vessels (Csoma et al., 2017). IH is characterize...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
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