buparlisib and Leukemia--Myeloid--Acute

Phosphatidylinositol-3-kinase (PI3K) signaling plays a crucial role in oncogene-mediated tumor growth and proliferation. Buparlisib (BKM120) is an oral pan-class I PI3K inhibitor. This phase I study was conducted to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of BKM120 in patients (pts) with relapsed/refractory acute leukemias. Fourteen pts (12 acute myeloid leukemia, 1 acute lymphoblastic leukemia, and 1 mixed phenotype leukemia) were enrolled. Twelve pts received BKM-120 80 mg/day and two 100 mg/day. The MTD was 80 mg/day. Of the 14 patients treated, the best response was stable disease in one patient that lasted 82 days. The median survival for all patients was 75 days (range 10-568). Three patients with a 3q26 chromosome abnormality had a significantly improved median survival of 360 days (range 278-568) as compared to a median survival of 57 days (range, 10-125) among the 11 other patients. The most frequent drug-related toxicities included confusion, mucositis, dysphagia, and fatigue. Western blot profiling revealed a decrease in p-pS6K/total pS6K in 5/7 (71%) available patient samples with a mean quantitative inhibition of 65% (range, 32-100%) and a decrease in p-FOXO3/total FOXO3 in 4/6 (67%) samples with a mean quantitative inhibition of 93% (range, 89-100%). BKM120 administered at 80 mg/day showed modest efficacy and was tolerable in advanced acute leukemias. Am. J. Hematol. 92:7-11, 2017. © 2016 Wiley Periodicals, Inc.

Topics: Adult; Aged; Aged, 80 and over; Aminopyridines; Antineoplastic Agents; Disease-Free Survival; Humans; Leukemia, Myeloid, Acute; Maximum Tolerated Dose; Middle Aged; Morpholines; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Precursor Cell Lymphoblastic Leukemia-Lymphoma

The association between PI3K overexpression and the acquisition of chemoresistance has attracted tremendous attention to this axis as an appealing target to revolutionize the conventional treatment strategies of human cancers. In the present study, we aimed to survey the inhibitory impact of the pan-PI3K inhibitor BKM120 on both cellular and molecular aspects of acute myeloid leukemia (AML)-derived KG-1 and U937 cells.. We designed various assays to survey the antitumor impacts and molecular mechanisms underlying the action of BKM120 for the treatment of AML, and we performed experiments to check the effect of BKM120 in combination with idarubicin.. We found that PI3K inhibition diminished cell viability and metabolic activity and exerted a concentration-dependent growth-suppressive effect on the cells. Moreover, we suggested that the ability of BKM120 to induce its antiproliferative properties was mediated through the induction of p21-mediated G2/M cell-cycle arrest. Investigating the effect of inhibitor on the molecular features revealed not only that BKM120 reduced the expression of NF-κB antiapoptotic targets, but also that NF-κB suppression using bortezomib profoundly enhanced the cytotoxicity of the inhibitor, highlighting that the antileukemic effects of BKM120 are mediated, at least partly, through the modulation of the NF-κB pathway. Interestingly, we found that the single agent of BKM120 was unable to significantly alter the expression level of. Taken together, the results of this study reveal the efficacy of BKM120 as a therapeutic approach for AML; however, further investigations should be undertaken to determine the expediency of this inhibitor.. PI3K aşırı ifadesi ile kemoterapiye direnç kazanılması arasındaki ilişki insan kanserlerinin konvansiyonel tedavi stratejilerinde devrim yaratmak yolunda cazip bir hedef oluşturarak bu yolağa olan ilgiyi büyük ölçüde artırmıştır. Bu çalışmamızda pan-PI3K inhibitörü BKM120’nin akut myeloid lösemi (AML) kökenli KG-1 ve U937 hücreleri üzerine hücresel ve moleküler inhibitor etkisini araştırmayı amaçladık.. AML tedavisinde BKM120’nin etkisinin altında yatan moleküler mekanizmalar ve antitümör tesirini araştırmak için çeşitli yöntemler oluşturduk ve BKM120 idarubisin kombinasyonunun etkisini kontrol etmek için deneyler yaptık.. PI3K inhibisyonunun hücre canlılığı ve metabolik aktiviteyi azalttığını ve hücrelerde konsantrasyona bağımlı olarak büyümeyi baskılayıcı etki gösterdiğini bulduk. Ayrıca, BKM120’nin antiproliferatif etkilerini p21 aracılı G2/M hücre döngüsünü durdurmak yoluyla gösterdiğini ileri sürdük. İnhibitörün moleküler özellikler üzerindeki etkisinin araştırılması sadece BKM120’nin antiapoptotik NF-κB’nin hedeflerinin ifadesini azalttığını değil, fakat aynı zamanda bortezomib kullanarak NF-κB baskılanmasının inhibitörün sitotoksisitesini belirgin artırdığını ortaya koyarak BKM120’nin antilösemik etkisinin en azından kısmen NF-κB yolağı modülasyonuyla olduğunu gösterdi. İlginç olarak, tek başına BKM120’nin. Birlikte değerlendirildiğinde bu çalışmanın sonuçları AML için terapötik yaklaşımda BKM120’nin etkililiğini göstermektedir. Ancak bu inhibitörün uygunluğunu belirlemek için ek çalışmalar yapılmalıdır.

Topics: Aminopyridines; Antineoplastic Agents; Apoptosis; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; G2 Phase Cell Cycle Checkpoints; Humans; Leukemia, Myeloid, Acute; Morpholines; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Structure-Activity Relationship; Tumor Cells, Cultured; U937 Cells

Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cytokines; Drug Discovery; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Lung Neoplasms; Mice; Molecular Targeted Therapy; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proteomics; Xenograft Model Antitumor Assays

Aberrant activation of the PI3K/Akt/mTOR pathway is a common feature of acute myeloid leukemia (AML) patients contributing to chemoresistance, disease progression and unfavourable outcome. Therefore, inhibition of this pathway may represent a potential therapeutic approach in AML. The aim of this study was to evaluate the pre-clinical activity of NVP-BKM120 (BKM120), a selective pan-class I PI3K inhibitor, on AML cell lines and primary samples. Our results demonstrate that BKM120 abrogates the activity of the PI3K/Akt/mTOR signaling, promoting cell growth arrest and significant apoptosis in a dose- and time-dependent manner in AML cells but not in the normal counterpart. BKM120-induced cytotoxicity is associated with a profound modulation of metabolic behaviour in both cell lines and primary samples. In addition, BKM120 synergizes with the glycolitic inhibitor dichloroacetate enhancing apoptosis induction at lower doses. Finally, in vivo administration of BKM120 to a xenotransplant mouse model of AML significantly inhibited leukemia progression and improved the overall survival of treated mice. Taken together, our findings indicate that BKM120, alone or in combination with other drugs, has a significant anti-leukemic activity supporting its clinical development as a novel therapeutic agent in AML.

Topics: Adult; Aged; Aminopyridines; Animals; Blotting, Western; Cell Line, Tumor; Cell Survival; Class I Phosphatidylinositol 3-Kinases; Dose-Response Relationship, Drug; Female; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Male; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Middle Aged; Morpholines; Proto-Oncogene Proteins c-akt; Signal Transduction; Time Factors; TOR Serine-Threonine Kinases; U937 Cells; Xenograft Model Antitumor Assays