Eine EZH2-Inhibition sensitiviert BRCA1-defiziente Mammakarzinome gegenüber einer Therapie mit dem PI3K-Inhibitor BKM120

2017 ◽  
Vol 14 (02) ◽  
pp. A1-A53
Author(s):  
J Puppe ◽  
M van den Ven ◽  
E van der Burg ◽  
U Boon ◽  
O van Tellingen ◽  
...  
Keyword(s):  
Pi3k Inhibitor

scholarly journals A novel PI3K inhibitor XH30 suppresses orthotopic glioblastoma and brain metastasis in mice models

2021 ◽  
Author(s):  
Ming Ji ◽  
Dongjie Wang ◽  
Songwen Lin ◽  
Chunyang Wang ◽  
Ling Li ◽  
...  
Keyword(s):  
Brain Metastasis ◽  
Pi3k Inhibitor

First PI3k inhibitor launches into crowded hematology markets

2014 ◽  
Vol 32 (10) ◽  
pp. 963-964 ◽  
Author(s):  
Chris Morrison
Keyword(s):  
Pi3k Inhibitor

scholarly journals Safety and efficacy of low-dose PI3K inhibitor taselisib in adult patients with CLOVES and Klippel–Trenaunay syndrome (KTS): the TOTEM trial, a phase 1/2 multicenter, open-label, single-arm study

2021 ◽  
Author(s):  
M. Luu ◽  
P. Vabres ◽  
H. Devilliers ◽  
R. Loffroy ◽  
A. Phan ◽  
...  
Keyword(s):  
Low Dose ◽  
Phase 1 ◽  
Pi3k Inhibitor ◽  
Functional Improvement ◽  
Open Label ◽  
Tissue Volume ◽  
Pathogenic Variants ◽  
Patient Reported ◽  
Affected Tissue ◽  
Phosphoinositide 3 Kinase

ABSTRACT Purpose PIK3CA pathogenic variants in the PIK3CA-related overgrowth spectrum (PROS) activate phosphoinositide 3-kinase signaling, providing a rationale for targeted therapy, but no drug has proven efficacy and safety in this population. Our aim was to establish the six-month tolerability and efficacy of low-dose taselisib, a selective class I PI3K inhibitor, in PROS patients. Methods Patients over 16 years with PROS and PIK3CA pathogenic variants were included in a phase IB/IIA multicenter, open-label single-arm trial (six patients at 1 mg/day of taselisib, then 24 at 2 mg/day). The primary outcome was the occurrence of dose limiting toxicity (DLT). Efficacy outcomes were the relative changes after treatment of (1) tissue volume at affected and unaffected sites, both clinically and on imaging; (2) cutaneous vascular outcomes when relevant; (3) biologic parameters; (4) quality of life; and (5) patient-reported outcomes. Results Among 19 enrolled patients, 2 experienced a DLT (enteritis and pachymeningitis) leading to early trial termination (17 treated, 10 completed the study). No serious adverse reaction occurred in the 1 mg cohort (n = 6). No significant reduction in affected tissue volume was observed (mean −4.2%; p = 0.81; SD 14.01). Thirteen (76.4%) participants reported clinical improvement (pain reduction, chronic bleeding resolution, functional improvement). Conclusion Despite functional improvement, the safety profile of low-dose taselisib precludes its long-term use.

scholarly journals An open-label, single-arm, phase II trial of buparlisib in patients with melanoma brain metastases not eligible for surgery or radiosurgery—the BUMPER study

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Teresa Amaral ◽  
Heike Niessner ◽  
Tobias Sinnberg ◽  
Ioannis Thomas ◽  
Andreas Meiwes ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Local Therapy ◽  
Progression Free Survival ◽  
Pi3k Inhibitor ◽  
Open Label ◽  
Preclinical Data ◽  
Overall Response ◽  
Intracranial Disease ◽  
Dismal Prognosis

Abstract Background Patients with melanoma brain metastasis (MBM) still carry a dismal prognosis. Preclinical data originated in xenograft models showed that buparlisib therapy was highly effective in therapy-naïve MBM. Patients and Methods In this open-label, phase II trial, we investigate the safety and efficacy of monotherapy with buparlisib, a PI3K inhibitor, in patients with asymptomatic MBM who were not candidates for local therapy. These patients had also progressed under immunotherapy if BRAF wild-type or under targeted therapy with BRAF/MEK inhibitors if carrying a BRAFV600E/K mutation. The primary endpoint was the intracranial disease control rate assessed by the investigators. The secondary endpoints were overall response rate, duration of response (DOR) of intracranial disease, overall response, progression-free survival (PFS), overall survival (OS), safety, and tolerability of buparlisib. Results A total of 20 patients were screened and 17 patients were treated with buparlisib. Twelve patients had progressed under more than 2 systemic therapy lines and 17 had received at least 1 previous local therapy. There were no intracranial responses. Three patients achieved intracranial stable disease; the median DOR was 117 days. The median PFS was 42 days (95% confidence interval [CI]: 23–61 days) and the median OS was 5.0 months (95% CI: 2.24–7.76 months). No new safety signs were observed. Conclusions Buparlisib was well tolerated but no intracranial responses were observed. These results might be explained in part by the inclusion of only heavily pretreated patients. However, preclinical data strongly support the rationale to explore PI3K inhibitor-based combinations in patients with MBM displaying hyperactivation of the PI3K–AKT pathway.

scholarly journals Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer

2020 ◽  
Vol 15 (2) ◽  
pp. 163-174 ◽  
Author(s):  
Ramesh K. Ramanathan ◽  
Daniel D. Von Hoff ◽  
Ferry Eskens ◽  
George Blumenschein ◽  
Donald Richards ◽  
...  
Keyword(s):  
Advanced Cancer ◽  
Mek Inhibitor ◽  
Pi3k Inhibitor ◽  
Phase Ib

scholarly journals A phase 1 study of BYL719, an α-isoform selective PI3K inhibitor, in Japanese patients with advanced solid malignancies

2017 ◽  
Vol 28 ◽  
pp. v83
Author(s):  
J. Tomomatsu ◽  
S. Iwasa ◽  
H. Saka ◽  
S. Takahashi ◽  
K. Nakano ◽  
...  
Keyword(s):  
Phase 1 ◽  
Japanese Patients ◽  
Pi3k Inhibitor ◽  
Phase 1 Study ◽  
Solid Malignancies

scholarly journals GnRH Neuronal Migration and Olfactory Bulb Neurite Outgrowth Are Dependent on FGF Receptor 1 Signaling, Specifically via the PI3K p110α Isoform in Chick Embryo

Endocrinology ◽  
2013 ◽  
Vol 154 (1) ◽  
pp. 388-399 ◽  
Author(s):  
Youli Hu ◽  
Subathra Poopalasundaram ◽  
Anthony Graham ◽  
Pierre-Marc Bouloux
Keyword(s):  
Chick Embryo ◽  
Olfactory Bulb ◽  
Neurite Outgrowth ◽  
Neuronal Migration ◽  
Glycogen Synthase ◽  
Kallmann Syndrome ◽  
Pi3k Inhibitor ◽  
Fgf Signaling ◽  
In Ovo ◽  
Fgf Receptor

Fibroblast growth factor (FGF) signaling is essential for both olfactory bulb (OB) morphogenesis and the specification, migration, and maturation of the GnRH-secreting neurons. Disruption of FGF signaling contributes to Kallmann syndrome characterized by both anosmia and sexual immaturity. However, several unanswered questions remain as to which specific FGF receptor (FGFR)-1 signaling pathways are necessary for OB and GnRH neuronal development. Here, using pharmacological phosphatidylinositol 3-kinase (PI3K) isoform-specific inhibitors, we demonstrate a central role for the PI3K p110α isoform as a downstream effector of FGFR1 signaling for both GnRH neuronal migration and OB development. We show that signaling via the PI3K p110α isoform is required for GnRH neuronal migration in explant cultures of embryonic day (E) 4 chick olfactory placodes. We also show that in ovo administration of LY294002, a global PI3K inhibitor as well as an inhibitor to the PI3K p110α isoform into the olfactory placode of E3 chick embryo impairs GnRH neuronal migration toward the forebrain. In contrast, in ovo PI3K inhibitor treatment produced no obvious defects on primary olfactory sensory neuron axonal targeting and bundle formation. We also demonstrate that anosmin-1 and FGF2 induced neuronal migration of immortalized human embryonic GnRH neuroblast cells (FNC-B4-hTERT) is mediated by modulating FGFR1 signaling via the PI3K p110α isoform, specifically through phosphorylation of the PI3K downstream effectors, Akt and glycogen synthase kinase-3β. Finally, we show that neurite outgrowth and elongation of OB neurons in E10 chick OB explants are also dependent on the PI3K p110α isoform downstream of FGFR1. This study provides mechanistic insight into the etiology of Kallmann syndrome.

scholarly journals Salvianolic Acid B Prevents Iodinated Contrast Media-Induced Acute Renal Injury in Rats via the PI3K/Akt/Nrf2 Pathway

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Liu Tongqiang ◽  
Liu Shaopeng ◽  
Yu Xiaofang ◽  
Song Nana ◽  
Xu Xialian ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Contrast Media ◽  
Renal Injury ◽  
Salvianolic Acid B ◽  
Pi3k Inhibitor ◽  
Iodinated Contrast Media ◽  
Acute Renal Injury ◽  
Nrf2 Pathway ◽  
Salvianolic Acid ◽  
Iodinated Contrast

Contrast-induced acute renal injury (CI-AKI) has become a common cause of hospital-acquired renal failure. However, the development of prophylaxis strategies and approved therapies for CI-AKI is limited. Salvianolic acid B (SB) can treat cardiovascular-related diseases. The aim of the present study was to assess the effect of SB on prevention of CI-AKI and explore its underlying mechanisms. We examined its effectiveness of preventing renal injury in a novel CI-AKI rat model. Compared with saline, intravenous SB pretreatment significantly attenuated elevations in serum creatinine and the histological changes of renal tubular injuries, reduced the number of apoptosis-positive tubular cells, activated Nrf2, and lowered the levels of renal oxidative stress induced by iodinated contrast media. The above renoprotection of SB was abolished by the PI3K inhibitor (wortmannin). In HK-2 cells, SB activated Nrf2 and decreased the levels of oxidative stress induced by hydrogen peroxide and subsequently improved cell viability. The above cytoprotection of SB was blocked by the PI3K inhibitor (wortmannin) or siNrf2. Thus, our results demonstrate that, due to its antioxidant properties, SB has the potential to effectively prevent CI-AKI via the PI3K/Akt/Nrf2 pathway.

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