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Simple Summary: Pancreatic ductal adenocarcinoma continues to be one of the deadliest cancers worldwide. Preclinical studies involving animals rarely include sex as a major biological variable in testing the efficacy of new drugs. In an animal model of pancreatic cancer, we analyzed the impact of sex on the pathological features of the disease and on an experimental small molecule-based therapy tested in vivo for the first time. While the therapy shows potential, the obtained results are confounded by sex-specific effects. This study, therefore, highlights the importance of sex-inclusive research while simultaneously providing a basis for further studies of the therapy tested. Preclinical studies rarely test the efficacy of therapies in both sexes. The field of oncology is no exception in this regard. In a model of syngeneic, orthotopic, metastasized pancreatic ductal adenocarcinoma we evaluated the impact of sex on pathological features of this disease as well as on the efficacy and possible adverse side effects of a novel, small molecule-based therapy inhibiting KRAS:SOS1, MEK1/2 and PI3K signaling in male and female C57BL/6J mice. Male mice had less tumor infiltration of CD8-positive cells, developed bigger tumors, had more lung metastasis and a lower probability of survival compared to female mice. These more severe pathological features in male animals were accompanied by higher distress at the end of the experiment. The evaluated inhibitors BI-3406, trametinib and BKM120 showed synergistic effects in vitro. This combinatorial therapy reduced tumor weight more efficiently in male animals, although the drug concentrations were similar in the tumors of both sexes. These results underline the importance of sex-specific preclinical research and at the same time provide a solid basis for future studies with the tested compounds. [ABSTRACT FROM AUTHOR]

Background: Although extensive efforts have been made to improve the treatment of colorectal cancer (CRC) patients, the prognosis for these patients remains poor. A wide range of anti-cancer agents has been applied to ameliorate the clinical management of CRC patients; however, drug resistance develops in nearly all patients. Based on the prominent role of PI3K/AKT signaling in the development of CRC and current interest in the application of PI3K inhibitors, we aimed to disclose the exact mechanism underlying the efficacy of BKM120, a well-known pan-class I PI3K inhibitor, in CRC-derived SW480 cells. Materials and methods: The effects of BKM120 on SW480 cells were studied using MTT assay, cell cycle assay, Annexin V/PI apoptosis tests, and scratch assay. In the next step, qRT-PCR was used to investigate the underlying molecular mechanisms by which the PI3K inhibitor could suppress the survival of SW480 cells. Result: The results of the MTT assay showed that BKM120 could decrease the metabolic activity of SW480 cells in a concentration and time-dependent manner. Investigating the exact mechanism of BKM120 showed that this PI3K inhibitor induces its anti-survival effects through a G2/M cell cycle arrest and apoptosis-mediated cell death. Moreover, the scratch assay demonstrated that PI3K inhibition led to the inhibition of cancer invasion and inhibition of PI3K/AKT signaling remarkably sensitized SW480 cells to Cisplatin. Conclusion: Based on our results, inhibition of PI3K/AKT signaling can be a promising approach, either as a single modality or in combination with Cisplatin. However, further clinical studies should be performed to improve our understanding. [ABSTRACT FROM AUTHOR]

Purpose: Although the complex structure of acute lymphoblastic leukemia (ALL) andinvolvement of diverse pathways in its pathogenesis have put an obstacle in the way of efficienttreatments, identification of strategies to manipulate the genome of neoplastic cells has madethe treatment prospective more optimistic.Methods: To evaluate whether the transduction of apoptin __a gene encoding a protein thatparticipates in the induction of apoptosis__ could reduce the survival of leukemic cells, wegenerated recombinant lentivirus expressing apoptin, and then, MTT assay, flow cytometricanalysis of DNA content, western blotting, and quantitative reverse transcription polymerasechain reaction (qRT-PCR) were applied.Results: Transduction of apoptin into different leukemic cells was coupled with the reductionin the viability and proliferative capacity of the cells. Among all tested cell lines, Nalm-6 andC8166 were more sensitive to the anti-leukemic property of apoptin. Moreover, we found thatthe transduction of apoptin in the indicated cell lines not only induced G2/M cell cycle arrestbut also induced apoptotic cell death by altering the balance between pro- and anti-apoptotictarget genes. The efficacy of apoptin transduction was not limited to these findings, as wereported for the first time that the overexpression of this gene could potentiate the anti-leukemicproperty of pan PI3K inhibitor BKM120.Conclusion: The results of this study showed that the transduction of apoptin into lymphoblasticleukemia cell lines induced cytotoxic effects and enhanced therapeutic value of PI3K inhibition;however, further investigations are demanded to ascertain the safety and the efficacy of apoptintransduction in patients with ALL.

Abstract Background The critical role of phosphoinositide 3-kinase (PI3K) activation in tumor cell biology has prompted massive efforts to develop PI3K inhibitors (PI3Kis) for cancer therapy. However, recent results from clinical trials have shown only a modest therapeutic efficacy of single-agent PI3Kis in solid tumors. Targeting autophagy has controversial context-dependent effects in cancer treatment. As a FDA-approved lysosomotropic agent, hydroxychloroquine (HCQ) has been well tested as an autophagy inhibitor in preclinical models. Here, we elucidated the novel mechanism of HCQ alone or in combination with PI3Ki BKM120 in the treatment of cancer. Methods The antitumor effects of HCQ and BKM120 on three different types of tumor cells were assessed by in vitro PrestoBlue assay, colony formation assay and in vivo zebrafish and nude mouse xenograft models. The involved molecular mechanisms were investigated by MDC staining, LC3 puncta formation assay, immunofluorescent assay, flow cytometric analysis of apoptosis and ROS, qRT-PCR, Western blot, comet assay, homologous recombination (HR) assay and immunohistochemical staining. Results HCQ significantly sensitized cancer cells to BKM120 in vitro and in vivo. Interestingly, the sensitization mediated by HCQ could not be phenocopied by treatment with other autophagy inhibitors (Spautin-1, 3-MA and bafilomycin A1) or knockdown of the essential autophagy genes Atg5/Atg7, suggesting that the sensitizing effect might be mediated independent of autophagy status. Mechanistically, HCQ induced ROS production and activated the transcription factor NRF2. In contrast, BKM120 prevented the elimination of ROS by inactivation of NRF2, leading to accumulation of DNA damage. In addition, HCQ activated ATM to enhance HR repair, a high-fidelity repair for DNA double-strand breaks (DSBs) in cells, while BKM120 inhibited HR repair by blocking the phosphorylation of ATM and the expression of BRCA1/2 and Rad51. Conclusions Our study revealed that HCQ and BKM120 synergistically increased DSBs in tumor cells and therefore augmented apoptosis, resulting in enhanced antitumor efficacy. Our findings provide a new insight into how HCQ exhibits antitumor efficacy and synergizes with PI3Ki BKM120, and warn that one should consider the “off target” effects of HCQ when used as autophagy inhibitor in the clinical treatment of cancer.

Purpose: Although the complex structure of acute lymphoblastic leukemia (ALL) andinvolvement of diverse pathways in its pathogenesis have put an obstacle in the way of efficienttreatments, identification of strategies to manipulate the genome of neoplastic cells has madethe treatment prospective more optimistic.Methods: To evaluate whether the transduction of apoptin __a gene encoding a protein thatparticipates in the induction of apoptosis__ could reduce the survival of leukemic cells, wegenerated recombinant lentivirus expressing apoptin, and then, MTT assay, flow cytometricanalysis of DNA content, western blotting, and quantitative reverse transcription polymerasechain reaction (qRT-PCR) were applied.Results: Transduction of apoptin into different leukemic cells was coupled with the reductionin the viability and proliferative capacity of the cells. Among all tested cell lines, Nalm-6 andC8166 were more sensitive to the anti-leukemic property of apoptin. Moreover, we found thatthe transduction of apoptin in the indicated cell lines not only induced G2/M cell cycle arrestbut also induced apoptotic cell death by altering the balance between pro- and anti-apoptotictarget genes. The efficacy of apoptin transduction was not limited to these findings, as wereported for the first time that the overexpression of this gene could potentiate the anti-leukemicproperty of pan PI3K inhibitor BKM120.Conclusion: The results of this study showed that the transduction of apoptin into lymphoblasticleukemia cell lines induced cytotoxic effects and enhanced therapeutic value of PI3K inhibition;however, further investigations are demanded to ascertain the safety and the efficacy of apoptintransduction in patients with ALL. [ABSTRACT FROM AUTHOR]

Apart from BCR/ABL which is the main player in the pathogenesis of chronic myeloid leukemia (CML), the role of other signaling cascades should not be underestimated especially for the maintenance of leukemic cells survival. The results of the present study indicate that either an isoform-specific or a pan-PI3K inhibitor could potently reduce the survival of CML-derived K562 cells, shedding more light on the involvement of the PI3K axis in the pathogenesis of CML. Of particular interest, the importance of the PI3K pathway in this disease became more evident when we found that there was a more remarkable reduction in the viability of K562 cells when BKM120 was used in combination with imatinib. Moreover, BKM120 robustly enhanced the growth-suppressive effect of imatinib through p21-mediated induction of G2/M cell cycle arrest and induction of apoptotic cell death. Despite the favorable anti-survival effects of the drug combination, these agents failed to induce inhibitory effects on the expression of c-Myc and NF-κB anti-apoptotic target genes. However, the ability of combinational therapy in diminishing K562 cell survival was potentiated either in the presence of 10058-F4 (c-Myc inhibitor) or Bortezomib (proteasome inhibitor), suggestive of the role of both NF-κB and c-Myc in overshadowing the therapeutic value of drugs combination. Taken together, the results of this study showed that inhibition of the PI3K pathway is a suitable approach to enhance the therapeutic value of imatinib in the treatment of CML. [ABSTRACT FROM AUTHOR]

Abstract Background Treatment options for triple-negative breast cancer remain limited. Activation of the PI3K pathway via loss of PTEN and/or INPP4B is common. Buparlisib is an orally bioavailable, pan-class I PI3K inhibitor. We evaluated the safety and efficacy of buparlisib in patients with metastatic triple-negative breast cancer. Methods This was a single-arm phase 2 study enrolling patients with triple-negative metastatic breast cancer. Patients were treated with buparlisib at a starting dose of 100 mg daily. The primary endpoint was clinical benefit, defined as confirmed complete response (CR), partial response (PR), or stable disease (SD) for ≥ 4 months, per RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. A subset of patients underwent pre- and on-treatment tumor tissue biopsies for correlative studies. Results Fifty patients were enrolled. Median number of cycles was 2 (range 1–10). The clinical benefit rate was 12% (6 patients, all SD ≥ 4 months). Median PFS was 1.8 months (95% confidence interval [CI] 1.6–2.3). Median OS was 11.2 months (95% CI 6.2–25). The most frequent adverse events were fatigue (58% all grades, 8% grade 3), nausea (34% all grades, none grade 3), hyperglycemia (34% all grades, 4% grade 3), and anorexia (30% all grades, 2% grade 3). Eighteen percent of patients experienced depression (12% grade 1, 6% grade 2) and anxiety (10% grade 1, 8% grade 2). Alterations in PIK3CA/AKT1/PTEN were present in 6/27 patients with available targeted DNA sequencing (MSK-IMPACT), 3 of whom achieved SD as best overall response though none with clinical benefit ≥ 4 months. Of five patients with paired baseline and on-treatment biopsies, reverse phase protein arrays (RPPA) analysis demonstrated reduction of S6 phosphorylation in 2 of 3 patients who achieved SD, and in none of the patients with progressive disease. Conclusions Buparlisib was associated with prolonged SD in a very small subset of patients with triple-negative breast cancer; however, no confirmed objective responses were observed. Downmodulation of key nodes in the PI3K pathway was observed in patients who achieved SD. PI3K pathway inhibition alone may be insufficient as a therapeutic strategy for triple-negative breast cancer. Trial registration NCT01790932 . Registered on 13 February 2013; NCT01629615 . Registered on 27 June 2012.

Objective: 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. Materials and Methods: 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. Results: We found that PI3K inhibition diminished cell viability and metabolic activity and exerted a concentration-dependent growthsuppressive 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 c-Myc; however, the capability of BKM120 to reduce the survival rate of AML cells was potentiated upon c-Myc inhibition using 10058-F4, suggestive of the plausible contribution of c-Myc in leukemic cell response to the PI3K inhibitor. Conclusion: 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.

Background: The critical role of phosphoinositide 3-kinase (PI3K) activation in tumor cell biology has prompted massive efforts to develop PI3K inhibitors (PI3Kis) for cancer therapy. However, recent results from clinical trials have shown only a modest therapeutic efficacy of single-agent PI3Kis in solid tumors. Targeting autophagy has controversial context-dependent effects in cancer treatment. As a FDA-approved lysosomotropic agent, hydroxychloroquine (HCQ) has been well tested as an autophagy inhibitor in preclinical models. Here, we elucidated the novel mechanism of HCQ alone or in combination with PI3Ki BKM120 in the treatment of cancer. Methods: The antitumor effects of HCQ and BKM120 on three different types of tumor cells were assessed by in vitro PrestoBlue assay, colony formation assay and in vivo zebrafish and nude mouse xenograft models. The involved molecular mechanisms were investigated by MDC staining, LC3 puncta formation assay, immunofluorescent assay, flow cytometric analysis of apoptosis and ROS, qRT-PCR, Western blot, comet assay, homologous recombination (HR) assay and immunohistochemical staining. Results: HCQ significantly sensitized cancer cells to BKM120 in vitro and in vivo. Interestingly, the sensitization mediated by HCQ could not be phenocopied by treatment with other autophagy inhibitors (Spautin-1, 3-MA and bafilomycin A1) or knockdown of the essential autophagy genes Atg5/Atg7, suggesting that the sensitizing effect might be mediated independent of autophagy status. Mechanistically, HCQ induced ROS production and activated the transcription factor NRF2. In contrast, BKM120 prevented the elimination of ROS by inactivation of NRF2, leading to accumulation of DNA damage. In addition, HCQ activated ATM to enhance HR repair, a high-fidelity repair for DNA double-strand breaks (DSBs) in cells, while BKM120 inhibited HR repair by blocking the phosphorylation of ATM and the expression of BRCA1/2 and Rad51. Conclusions: Our study revealed that HCQ and BKM120 synergistically increased DSBs in tumor cells and therefore augmented apoptosis, resulting in enhanced antitumor efficacy. Our findings provide a new insight into how HCQ exhibits antitumor efficacy and synergizes with PI3Ki BKM120, and warn that one should consider the "off target" effects of HCQ when used as autophagy inhibitor in the clinical treatment of cancer. [ABSTRACT FROM AUTHOR]

Multiple primary cancers (MPC) occurring in the same individual is considered rare but being increasingly recognized owing to the longer cancer survival nowadays. Despite of accumulating experience in diagnosis, effective treatment remains to be problematic in many scenarios. Genetic testing-based targeted therapy could be an invaluable option for both diagnosis and treatment of such patients. Here we present a 74-year-old male with triple primary cancers including kidney, prostate, and lung with metastatic tumor on the costal bones. The patient visited the hospital for persistent cough and hemoptysis, and a diagnosis of squamous cell carcinoma of the left lung was made by bioptic fiberoptic bronchoscopy. A previous history included renal cancer controlled by Sorafenib and prostate cancer controlled by Goserelin. Radiotherapy and platinum-based chemotherapy failed to help the patient and the tumor size increased over a period of 6 months. In order to seek better therapeutical options, we performed targeted sequencing using the cancerous tissues from his lung, kidney, and prostate cancers. Briefly, the results identified VHL, EGFR, PIK3CA, TP53, and AKT1 mutations in lung cancer, AKT1, FGFR2, and TP53 mutations in renal cancer, and FGFR2 mutations in prostate cancer. A combined medication targeting PIK3CA and AKT1 signaling was recommended and the patient was given BKM120 (PIK3CA, Phase III clinical trial) and MK2206 (AKT, phase III clinical trial). Revisit chest CTs after 4 months and 9 months showed a significant shrinkage of tumor size by 40% and 80%, respectively. Our experience demonstrated a good example that genetic analysis could be valuable to diagnose and precisely treat multiple primary cancers. [ABSTRACT FROM AUTHOR]

Background/Aims: PI3KCA and mutant p53 are associated with tumorigenesis and the development of cancers. NVP-BKM120, a selective pan-PI3K inhibitor, exerts the antitumor activity by suppressing the PI3K signaling pathway. Prima-1Met, a low molecular weight compound, can rescue the gain-of-function of mutant p53 by restoring its transcriptional function. In this study, we investigated whether PI3K inhibition combined with mutant p53 reactivation could enhance the antitumor effect in thyroid cancer cells. Methods: The effects of BKM120 and Prima-1Met on the proliferation, apoptosis, migration and invasion of thyroid cancer cells were measured by MTT, colony formation, flow cytometry, wound-healing and transwell assays, respectively. Thyroid differentiation was assessed by detecting the expression levels of specific markers using RT-PCR and Western blot. The in vivo antitumor efficacy was analyzed in a mouse xenograft model. Results: The combinational treatment of BKM120 and Prima-1Met significantly enhanced the inhibitions of cell viability, colony formation, migration and invasion, and the induction of apoptosis in thyroid cell lines, and synergistically suppressed tumor xenograft growth by inhibiting the PI3K/Akt/mTOR and EMT signaling pathways, up-regulating p53 targeted genes, and triggering the release of cytochrome c. Moreover, the combination of BKM120 and Prima-1Met suppressed the stemlike traits of thyroid cancer cells and promoted their differentiation by upregulating the expression of thyroid-specific differentiation markers and repressing the expression of cancer stem cell markers. Furthermore, the mechanism study demonstrated that the combinational treatment synergistically abrogated the binding of CPSF4 at the promoter of hTERT and thus suppressed hTERT expression. Consistently, overexpression of hTERT rescued the inhibitions of cell viability, invasion and stem-like traits mediated by the combination of BKM120 and Prima-1Met. Conclusion: Our results showed that the combination of BKM120 with Prima-1Met synergistically suppressed the growth of thyroid cancer cells and tumor xenografts via inhibiting PI3K/Akt/mTOR and CPSF4/hTERT signaling and reactivating mutant p53.

Background: Treatment options for triple-negative breast cancer remain limited. Activation of the PI3K pathway via loss of PTEN and/or INPP4B is common. Buparlisib is an orally bioavailable, pan-class I PI3K inhibitor. We evaluated the safety and efficacy of buparlisib in patients with metastatic triple-negative breast cancer.Methods: This was a single-arm phase 2 study enrolling patients with triple-negative metastatic breast cancer. Patients were treated with buparlisib at a starting dose of 100 mg daily. The primary endpoint was clinical benefit, defined as confirmed complete response (CR), partial response (PR), or stable disease (SD) for ≥ 4 months, per RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. A subset of patients underwent pre- and on-treatment tumor tissue biopsies for correlative studies.Results: Fifty patients were enrolled. Median number of cycles was 2 (range 1-10). The clinical benefit rate was 12% (6 patients, all SD ≥ 4 months). Median PFS was 1.8 months (95% confidence interval [CI] 1.6-2.3). Median OS was 11.2 months (95% CI 6.2-25). The most frequent adverse events were fatigue (58% all grades, 8% grade 3), nausea (34% all grades, none grade 3), hyperglycemia (34% all grades, 4% grade 3), and anorexia (30% all grades, 2% grade 3). Eighteen percent of patients experienced depression (12% grade 1, 6% grade 2) and anxiety (10% grade 1, 8% grade 2). Alterations in PIK3CA/AKT1/PTEN were present in 6/27 patients with available targeted DNA sequencing (MSK-IMPACT), 3 of whom achieved SD as best overall response though none with clinical benefit ≥ 4 months. Of five patients with paired baseline and on-treatment biopsies, reverse phase protein arrays (RPPA) analysis demonstrated reduction of S6 phosphorylation in 2 of 3 patients who achieved SD, and in none of the patients with progressive disease.Conclusions: Buparlisib was associated with prolonged SD in a very small subset of patients with triple-negative breast cancer; however, no confirmed objective responses were observed. Downmodulation of key nodes in the PI3K pathway was observed in patients who achieved SD. PI3K pathway inhibition alone may be insufficient as a therapeutic strategy for triple-negative breast cancer.Trial Registration: NCT01790932 . Registered on 13 February 2013; NCT01629615 . Registered on 27 June 2012. [ABSTRACT FROM AUTHOR]

Objective: The association between PI3K overexpression and the acquisition of che mo resistance 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. Materials and Methods: 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 BKM 120 in combination with idarubicin. Results: 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 BKM 120 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 BKM 120 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 BKM 120 are mediated, at least partly, through the modulation of the NF-kB pathway. Interestingly, we found that the single agent of BKM 120 was unable to significantly alter the expression level of c-Myc; however, the capability of BKM 120 to reduce the survival rate of AML cells was potentiated upon c-Myc inhibition using 10058-F4, suggestive of the plausible contribution of c-Myc in leukemic cell response to the PI3K inhibitor. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Summary: Background Resistance to Epidermal Growth Factor inhibition (EGFRi) in patients with KRAS wild-type (wt) Colorectal Cancer (CRC) may occur as a result of PI3K/AKT/mTOR signaling. We conducted a study to establish the recommended phase II dose (RP2D) and response rate of panitumumab, an EGFRi, plus BKM120, a PI3K inhibitor, in advanced CRC. Methods Patients with chemotherapy refractory KRAS wt CRC, who were EGFRi naive were enrolled. A 3 + 3 dose escalation design was utilized. The starting dose of panitumumab was 6 mg/kg iv every 2 weeks with BKM120 at 60 mg oral daily. Results Nineteen patients were treated and 17 were evaluable for response. The starting dose was not tolerable (mucositis, fatigue). At dose level (DL) 1, three of six patients discontinued treatment due to toxicity, DL − 1 had no significant toxicity. Panitumumab 6 mg/kg iv q 2 weeks with BKM120 60 mg given 5 out of 7 days per week was declared the RP2D. One patient (5.9%) who was PTEN and PIK3CA negative by IHC had a partial response, seven had stable disease, and nine had disease progression. Conclusion Panitumumab (6 mg/kg iv q 2 weeks) with BKM120 60 mg given 5 out of 7 days per week was declared the RP2D. Toxicities including fatigue, rash and mucositis. There was little evidence of activity in this biomarker unselected cohort. [ABSTRACT FROM AUTHOR]

The success in the identification of BCR/ABL tyrosine kinase role in the pathogenesis of chronic myeloid leukemia (CML) went as far as to find a path to cure this leukemia; however, compensatory activation of leukomogenic signals get across the message that the small molecule inhibitors of oncogenic pathways, along with tyrosine kinase inhibitors, might be a beneficial approach in CML treatment. The results of the present study showed that the abrogation of the phosphoinositide 3‐kinase (PI3K) pathway using pan‐PI3K inhibitor BKM120 exerted a cytotoxic effect against CML‐derived K562 cells through both the induction of p21‐mediated G2/M arrest and the stimulation of apoptosis. Notably, the apoptotic effect of the inhibitor was further confirmed by the molecular analysis showing that BKM120 significantly increased the expression of pro‐apoptotic genes. To the best of our knowledge, the involvement of autophagy in resistance to BKM120 has not been yet described and our study suggests for the first time that the elevation of autophagy‐related genes might serve as a compensatory pathway to cease the anti‐leukemic effect of BKM120 in K562; since we found a reinforced anti‐survival event when the cells were treated with BKM120 in combination with autophagy inhibitor. In conclusion, the results of the present study showed that the abrogation of PI3K using BKM120 might be a befitting approach in CML treatment, either as a single agent or in a combined‐modal strategy; however, further evaluations including clinical trials and in vivo investigations are demanded to ascertain the safety and the efficacy of the inhibitor in treatment strategies. [ABSTRACT FROM AUTHOR]

Sarcoidosis is a systemic granulomatous disease associated with Th1/ regulatory T cells (Treg) paradigm. PI3K/Akt signaling, critical for maintaining Treg's homeostasis, is aberrantly activated in sarcoidosis patients. Here we tested the role of the PI3K inhibitors, LY294002 and BKM120, in immune modulation in experimental pulmonary sarcoidosis, concerning Th1/Th17/Treg immune profile detected by fluorescence‐activated cell sorting analysis or quantitative polymerase chain reaction, as well as the effect on Treg's suppressive functions. Our investigation showed abnormal activation of PI3K/Akt signaling both in lung and Treg in pulmonary sarcoidosis, along with decreased frequency and damaged function of Treg. Blockage of PI3K suppressed this signaling in Treg, rebalanced Th1/Treg, inhibited the production of inflammatory cytokines, and enhanced Treg's function. These results demonstrate the key role of the PI3K/Akt signaling in regulating Th1/Th2 rebalances and indicates that PI3K/Akt signaling is critical for the optimal Treg responses in pulmonary sarcoidosis. Thus, PI3K inhibitors have potential for therapeutic translation, and can be candidate for add‐on drugs to treat pulmonary sarcoidosis. [ABSTRACT FROM AUTHOR]

Background: Current bevacizumab-based regimens have failed to improve survival in patients with recurrent glioblastoma. To improve treatment efficacy, we evaluated bevacizumab + BKM120, an oral pan-class I PI3K inhibitor, in this patient population. Methods: A brief phase I study established the optimal BKM120 dose to administer with standard-dose bevacizumab. BKM120 60 mg PO daily + bevacizumab 10 mg/kg IV every 2 weeks in 28-day cycles was then administered to patients with relapsed/refractory glioblastoma in the phase II portion. Results: Eighty-eight patients enrolled (phase I, 12; phase II, 76). In phase I, BKM120 80 mg PO daily produced dose limiting toxicity in 3 of 6 patients; a BKM120 dose of 60 mg PO daily was established as the maximum tolerated dose. In phase II, the median progression-free survival (PFS) was 4.0 months (95% CI 3.4, 5.4), PFS at 6 months was 36.5%, and the overall response rate was 26%. Forty-two patients (57%) experienced one or more serious treatment related toxicities. The most common CNS toxicities included mood alteration (17%) and confusion (12%); however, these were often difficult to classify as treatment- versus tumor-related. Conclusions: The efficacy seen in this study is similar to the efficacy previously reported with single-agent bevacizumab. This regimen was poorly tolerated, despite the low daily dose of BKM120. Further development of this combination for the treatment of glioblastoma is not recommended. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is the most common pediatric malignant neoplasia of the skeletal system. It is characterized by a high degree of malignancy and a severe tendency to metastasize. In the past decade, many studies have provided evidence that the phosphoinositide 3‐kinase (PI3K) signaling pathway is one of the most frequently altered pathways in human cancer, and has a critical role in driving tumor initiation and progression. Here, we have analyzed the therapeutic potential of the pan‐PI3K inhibitor NVP‐BKM120, which has recently entered clinical Phase II for treatment of PI3K‐dependent cancers on three OS cell lines. We observed a concentration‐ and time‐dependent decrease of Ser473 p‐Akt as well as reduced levels of Thr37/46 p‐4E‐BP1, an indicator of the mammalian target of rapamycin complex 1 activity. All OS cell lines used in this study responded to BKM120 treatment with an arrest of cell proliferation, an increase in cell mortality, and an increase in caspase‐3 activity. MG‐63 cells were the most responsive cell line, demonstrating a significant increase in sub‐G1 cells, and a rapid induction of cell death. Furthermore, we demonstrate that BKM120 is more effective when used in combination with other standard chemotherapeutic drugs. Combining BKM120 with vincristine demonstrated a more synergistic effect than BKM120 with doxorubicin in all the lines. Hence, we suggest that BKM120 may be a novel therapy for the treatment of OS presenting with anomalous upregulation of the PI3K signaling pathway. We have analyzed the therapeutic potential of the pan‐PI3K inhibitor NVP‐BKM120, which has recently entered clinical Phase II for treatment of PI3K‐dependent cancers on three osteosarcoma cell lines. We observed a concentration‐ and time‐dependent decrease of Ser473 p‐Akt as well as reduced levels of Thr37/46 p‐4E‐BP1. All OS cell lines used in this study responded to BKM120 treatment with an arrest of cell proliferation, an increase in cell mortality, and an increase in caspase‐3 activity. [ABSTRACT FROM AUTHOR]

Abstract The correlation between the Phosphoinositide 3-kinase (PI3K) axis and crucial mechanisms involved in the maintenance of the neoplastic nature of multiple myeloma (MM) has recently evolved a general agreement that PI3K inhibition-based therapies could construct an exciting perspective for the future treatment strategies. Our results outlined that abrogation of PI3K using pan-PI3K inhibitor BKM120 decreased survival of MM cells through induction of a caspase-3-dependent apoptosis coupled with SIRT1-mediated G2/M arrest in both KMM-1 and RPMI 8226 cell lines; however, the cell responses to the inhibitor was quite different, introducing wild-type PTEN-expressing RPMI 8226 as less sensitive cells. By investigating the sensitivity extent of a panel of hematological cell lines to BKM120, we found no significant association with respect to PTEN status. As far as we are aware, the results of the present study propose for the first time that the inhibitory effect of BKM120 was overshadowed, at least partially, through over-expression of either c-Myc or nuclear factor (NF)-κB in less sensitive MM cells. While there was no significant effect of the inhibitor on the expression of c-Myc in RPMI 8226, we found an enhanced cytotoxic effect when BKM120 was used in combination with a small molecule inhibitor of c-Myc. Noteworthy, the results of the synergistic experiments also revealed that BKM120 could produce a synergistic anti-cancer effect with carfilzomib (CFZ) and provided an enhanced therapeutic efficacy in MM cells, highlighting that PI3K inhibition might be a befitting approach in MM both in mono and combined therapy. [ABSTRACT FROM AUTHOR]

Abstract The latest molecular investigations leading to the discovery of the brand-new mechanisms associated to immortalized nature of cancer cells have questioned the efficacy of the conventional therapies and have increased the demand for more influential approaches, especially in the context of synergistic strategies. In an effort to enhance the effectiveness of acute promyelocytic leukemia (APL) treatment and to investigate the potential therapeutic value of Phosphoinositide 3-kinase (PI3K) inhibition synergism with chemotherapy, we designed experiments to evaluate the effect of Arsenic trioxide (ATO) in combination with BKM120 for the treatment of APL-derived NB4 cells. The results of the present study highlighted the favorable outcome of the PI3K inhibition using BKM120 in potentiating the anti-cancer effect of ATO, while reducing its cytotoxic concentration. Investigating the molecular mechanisms leading to this synergistic effect showed that probably down-regulation of the transcription factor SIRT1 coupled with suppression of c-Myc might halt the progression of the cell cycle from the G1 phase, resulting in the enhanced growth suppressive effect in ATO-plus-BKM120 combination. Moreover, we found that the positive regulatory role of the PI3K inhibition in augmenting the intracellular level of reactive oxygen species disturbed the balance between the death promoter and death repressor genes, which in turn amplified the caspase-3-dependent apoptotic activity of ATO in NB4. By and large, this study laid a therapeutic value on BKM120 in combination with ATO and suggested this combination as a novel therapeutic strategy that may be clinically accessible in the near future. [ABSTRACT FROM AUTHOR]

Background/Aims: PI3KCA and mutant p53 are associated with tumorigenesis and the development of cancers. NVP-BKM120, a selective pan-PI3K inhibitor, exerts the antitumor activity by suppressing the PI3K signaling pathway. Prima-1Met, a low molecular weight compound, can rescue the gain-of-function of mutant p53 by restoring its transcriptional function. In this study, we investigated whether PI3K inhibition combined with mutant p53 reactivation could enhance the antitumor effect in thyroid cancer cells. Methods: The effects of BKM120 and Prima-1Met on the proliferation, apoptosis, migration and invasion of thyroid cancer cells were measured by MTT, colony formation, flow cytometry, wound-healing and transwell assays, respectively. Thyroid differentiation was assessed by detecting the expression levels of specific markers using RT-PCR and Western blot. The in vivo antitumor efficacy was analyzed in a mouse xenograft model. Results: The combinational treatment of BKM120 and Prima-1Met significantly enhanced the inhibitions of cell viability, colony formation, migration and invasion, and the induction of apoptosis in thyroid cell lines, and synergistically suppressed tumor xenograft growth by inhibiting the PI3K/Akt/mTOR and EMT signaling pathways, up-regulating p53 targeted genes, and triggering the release of cytochrome c. Moreover, the combination of BKM120 and Prima-1Met suppressed the stemlike traits of thyroid cancer cells and promoted their differentiation by upregulating the expression of thyroid-specific differentiation markers and repressing the expression of cancer stem cell markers. Furthermore, the mechanism study demonstrated that the combinational treatment synergistically abrogated the binding of CPSF4 at the promoter of hTERT and thus suppressed hTERT expression. Consistently, overexpression of hTERT rescued the inhibitions of cell viability, invasion and stem-like traits mediated by the combination of BKM120 and Prima-1Met. Conclusion: Our results showed that the combination of BKM120 with Prima-1Met synergistically suppressed the growth of thyroid cancer cells and tumor xenografts via inhibiting PI3K/Akt/mTOR and CPSF4/hTERT signaling and reactivating mutant p53. [ABSTRACT FROM AUTHOR]

Glioblastoma is the most common type of malignant intracranial tumor in adults. Temozolomide (TMZ), as the first‑line chemotherapy agent used in patients with glioblastoma, has demonstrated different effects in patients due to the expression of O6‑methylguanine‑DNA methyltransferase (MGMT) which is able to repair the DNA lesions induced by TMZ. The phosphatidylinositol 3‑kinase (PI3K)/Akt signaling pathway is over‑activated in glioblastoma and has been revealed to be potentially implicated in resistance to TMZ. BKM120, a selective pan class I PI3K inhibitor, has been reported to facilitate apoptosis and reverse drug resistance in advanced solid tumors. The present study aims to investigate whether BKM120 is able to sensitize glioma cells to TMZ. C6 glioma cells were treated with BKM120 and/or TMZ for 12, 24 and 48 h, respectively. Cell Counting Kit‑8 assays were performed to determine cell viability. The level of apoptosis was evaluated by Hoechst 33342 and TUNEL staining, and the levels of cleaved caspase-3 and Bcl‑2‑like protein 4 (Bax) expression was measured. Furthermore, the present study investigated the possible mechanism underlying BKM120 reverse chemoresistance to TMZ. The downstream targets of PI3K, including phosphorylated (p)‑Akt, nuclear factor (NF)‑B p65, were analyzed by western blotting. The MGMT transcription levels in monotherapy and combination therapy were demonstrated by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). The present study revealed that monotherapy treatments with either drug required a high concentration found reduction in cell viability. However, a low concentration of BKM120 inhibited the PI3K/Akt/NF‑κB signaling pathway activity in glioma cells and significantly increased TMZ cytotoxicity. The coefficient of drug interaction was ~0.7. Results from the TUNEL assay, Hoechst 33342 staining and evaluation of the levels of cleaved caspase-3 and Bax expression also confirmed the finding that the combination treatment induced a higher level of apoptosis compared with the TMZ monotherapy. RT‑qPCR demonstrated that the combination strategy reversed the TMZ‑induced MGMT over‑transcription. The reduction of NF‑κB p65 in combination treatment supported the hypothesis that BKM120 may mediate MGMT transcription via inhibition of NF‑κB p65. In conclusion, BKM120 and TMZ demonstrated strong synergistic cytotoxicity in C6 glioma cells. The BKM120‑induced NF‑κB p65 inhibition may be involved in the mediation of MGMT transcription to reverse TMZ‑resistance in C6 glioma cells. [ABSTRACT FROM AUTHOR]

Malignant rhabdoid tumor of the kidney (MRTK) has an inferior prognosis and is insensitive to radiotherapy and chemotherapy. Search for novel, potent medicinal agents is urgent. Herein, data on the gene expression and clinical characteristics of malignant rhabdoid tumors (MRT) were retrieved from the TARGET database. Prognosis-related genes were identified by differential analysis and one-way cox regression analysis, and prognosis-related signalling pathways were identified by enrichment analysis. The prognosis-related genes were imported into the Connectivity Map database for query, and BKM120 was predicted and screened as a potential therapeutic agent for MRTK. A combination of high-throughput RNA sequencing and Western blot verified that the PI3K/Akt signaling pathway is associated with MRTK prognosis and is overactivated in MRTK. Our results outlined that BKM120 inhibited the proliferation, migration, and invasion ability of G401 cells and induced apoptosis and cell cycle G0/G1 phase arrest. In vivo, BKM120 inhibited tumor growth and had no significant toxic side effects. Western blot and immunofluorescence results confirmed that BKM120 could reduce the expression of PI3K and p-AKT, critical proteins of the PI3K/Akt signaling pathway. BKM120 inhibits MRTK by inhibiting PI3K/Akt signalling pathway to induce apoptosis and cell cycle G0/G1 phase arrest, which is anticipated to give the clinical treatment of MRTK a new direction. [ABSTRACT FROM AUTHOR]

The intertwining between cancer pathogenesis and perturbation of multitude signaling pathways ushered the cancer therapeutic approaches into an unbounded route of targeted therapies. For the nonce and among the plethora of promising inhibitors, intense interest has focused on small molecules targeting different component of PI3K axis. Intrigued by the constant activation of PI3K in leukemia, this study aimed to investigate the effects of BKM120, as the excelled member of pan PI3K inhibitors, in a panel of hematologic malignant cell lines. The resulting data showed that BKM120 exerted a concentration-dependent growth suppressive effect; however, IC 50 values varied among the tested cells. Our results outlined that the blockage of PI3K in NB4, as the most sensitive cell line, resulted in a caspase-3-dependent apoptosis probably through NFκB-mediated suppression of c-Myc and hTERT. As far we are aware, to date, there have been no reports of BKM120 effect on enzymatic repression of telomerase, and this study represents for the first time that the anti-proliferative effect of the inhibitor on NB4 is mediated by down-regulation of telomerase; shedding new light on the novel mechanism of action of BKM120. [ABSTRACT FROM AUTHOR]

Background: Based upon preclinical synergy in murine models, we carried out a phase I trial to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and biomarkers of response for the combination of BKM120, a PI3K inhibitor, and olaparib, a PARP inhibitor. Patients and methods: Olaparib was administered twice daily (tablet formulation) and BKM120 daily on a 28-day cycle, both orally. A 3+3 dose-escalation design was employed with the primary objective of defining the combination MTD, and secondary objectives were to define toxicities, activity, and pharmacokinetic profiles. Eligibility included recurrent breast (BC) or ovarian cancer (OC); dose-expansion cohorts at the MTD were enrolled for each cancer. Results: In total, 69 of 70 patients enrolled received study treatment; one patient never received study treatment because of ineligibility. Twenty-four patients had BC; 46 patients had OC. Thirty-five patients had a germline BRCA mutation (gBRCAm). Two DLTs (grade 3 transaminitis and hyperglycemia) were observed at DL0 (BKM120 60 mg/olaparib and 100mg b.i.d.). The MTD was determined to be BKM120 50mg q.d. and olaparib 300mg b.i.d. (DL8). Additional DLTs included grade 3 depression and transaminitis, occurring early in cycle 2 (DL7). Anticancer activity was observed in BC and OC and in gBRCAmand gBRCA wild-type (gBRCAwt) patients. Conclusions: BKM120 and olaparib can be co-administered, but the combination requires attenuation of the BKM120 dose. Clinical benefit was observed in both gBRCAm and gBRCAwt pts. Randomized phase II studies will be needed to further define the efficacy of PI3K/PARP-inhibitor combinations as compared with a PARP inhibitor alone. [ABSTRACT FROM AUTHOR]

Proteasome inhibitor bortezomib has proven efficacy against multiple myeloma. However, bortezomib activates the phosphatidylinositol 3-kinase/AKT (PI3K/AKT) pathway (which is essential to the development of myeloma), often resulting in drug resistance and disease recurrence. The addition of BKM120 significantly enhanced the apoptotic effects of bortezomib in both bortezomib-sensitive and bortezomib-resistant cells. Treatment with bortezomib alone increased the phosphorylation of AKT (P-AKT), whereas the addition of BKM120 markedly downregulated P-AKT in both bortezomib-sensitive and bortezomib-resistant cells. The clinical relevance of combined treatment with bortezomib and BKM120 was investigated in a xenograft mouse model and in myeloma patients, and the synergy of the combination was confirmed. In conclusion, the addition of BKM120 enhanced the sensitivity of myeloma cells to bortezomib. [ABSTRACT FROM AUTHOR]

Mutations in the catalytic subunit of phosphoinositide 3-kinase (PIK3CA) and other PI3K-AKT pathway components have been associated with cancer and a wide spectrum of brain and body overgrowth. In the brain, the phenotypic spectrum of PIK3CA-related segmental overgrowth includes bilateral dysplastic megalencephaly, hemimegalencephaly and focal cortical dysplasia, the most common cause of intractable pediatric epilepsy. We generated mouse models expressing the most common activating Pik3ca mutations (H1047R and E545K) in developing neural progenitors. These accurately recapitulate all the key human pathological features including brain enlargement, cortical malformation, hydrocephalus and epilepsy, with phenotypic severity dependent on the mutant allele and its time of activation. Underlying mechanisms include increased proliferation, cell size and altered white matter. Notably, we demonstrate that acute 1 hr-suppression of PI3K signaling despite the ongoing presence of dysplasia has dramatic anti-epileptic benefit. Thus PI3K inhibitors offer a promising new avenue for effective anti-epileptic therapy for intractable pediatric epilepsy patients.

Objective Combined inhibition of PI3K and PARP has been shown to be effective in the treatment of preclinical models of breast cancer and prostate cancer independent of BRCA or PIK3CA mutational status. However, the knowledge about this combination treatment in ovarian cancer is limited. The aim of this study was to evaluate the therapeutic effect of PI3K inhibitor BKM120 and PARP inhibitor Olaparib on ovarian cancer cell lines bearing wild-type PIK3CA genes. Methods We exposed three wild-type PIK3CA ovarian cancer cell lines to a PI3K inhibitor BKM120 and/or a PARP inhibitor Olaparib. The effect of BKM120 as a single-agent or in combination with Olaparib was evaluated by Cell Count Kit (CCK8) assay, immunoblotting, comet assay, flow cytometry and immunofluorescence staining assay. The combination indexes for synergistic effect on cell viability were calculated with the Chou-Talalay method. Ex vivo cultured ovarian cancer tissues from patients were analyzed by histological and immunohistochemical analyses. Results Combined inhibition of PI3K and PARP effectively synergized to block the growth of three wild-type PIK3CA ovarian cancer cell lines and explants of a primary ovarian tumor specimen. Mechanistically, dual blockade of PI3K and PARP in these ovarian cancer cell lines resulted in substantially attenuated PI3K/AKT/mTOR signaling, impaired DNA damage response and deficient homologous recombination repair, with remarkable BRCA downregulation. Conclusions The combined use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib may be effective in ovarian cancers with a broader spectrum of cancer-associated genetic alterations but not limited to those with mutant PIK3CA or BRCA genes. BRCA downregulation may be a potential biomarker for the effective response to the proposed combination treatment. [ABSTRACT FROM AUTHOR]

Metastatic colorectal cancer ( CRC) patients with v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ( KRAS) mutations are resistant to monoclonal antibody that targets the epidermal growth factor receptor such as cetuximab. BKM120 targets phosphatidylinositide-3-kinase ( PIK3 CA), but it is unknown whether BKM120 can reverse cetuximab resistance in KRAS mutant CRC. Human CRC cell lines with KRAS mutations ( DLD-1, HCT116, and LoVo) were used to test the effect of cetuximab, BKM120, and cetuximab plus BKM120 on cell proliferation in vitro and in vivo. BKM120 reduced cell proliferation in a concentration-dependent manner in the LoVo ( PI3 KCA wild type) as well as the HCT116 and DLD1 cells (that carry a PI3 KCA mutation). BKM120 only inhibited ERK phosphorylation in LoVo cells ( PIK3 CA wild type), but not in DLD1 or HCT116 cells at a concentration of 1 μmol/L. Treatment with cetuximab and BKM120 significantly reduced the growth of xenograft tumors originating from KRAS mutant cells compared with cetuximab alone ( P = 0.034). BKM120 may overcome cetuximab resistance in colon cancer cells with KRAS mutation. [ABSTRACT FROM AUTHOR]

Human non-small cell lung cancer (NSCLC) displays activated MEK/ERK signaling due to a high frequency of K-Ras mutation and is thus a potential candidate for MEK-targeted therapy. The current study focuses on demonstrating the activity of MEK162 (binimetinib), a MEK inhibitor under clinical testing, against NSCLC and exploring possible mechanism-driven strategies to enhance its therapeutic efficacy. MEK162 inhibits the growth of human NSCLC cell lines with varied potencies through induction of G1 cell cycle arrest and apoptosis. Moreover, it induces autophagy and accordingly the combination of MEK162 with the autophagy inhibitor, chloroquine, synergistically inhibits the growth of NSCLC cells and enhances apoptosis. MEK162 activates Akt signaling while effectively inhibiting MEK/ERK signaling. Accordingly, the combination of MEK162 and BKM120 (buparlisib), a pan-PI3K inhibitor, abrogates induced Akt activation and significantly augments therapeutic efficacy against the growth of NSCLC cells both in vitro and in vivo . Hence our findings warrant further evaluation of these rational combinations in the clinic. [ABSTRACT FROM AUTHOR]

The plasma cell malignancy multiple myeloma (MM) is unique amongst haematological malignancies in its capacity to cause osteoclast-mediated skeletal destruction. The PI3K/Akt pathway mediates proliferation, survival and drug resistance in MM plasma cells and is also involved in regulating the formation and activity of bone-forming osteoblasts and bone-resorbing osteoclasts. NVP-BKM120 (Buparlisib, Novartis) is a PI3K inhibitor that is currently undergoing clinical evaluation in several tumour settings. In this study, we have examined the anti-tumorigenic effects of BKM120 in an immunocompetent mouse model of MM and its effects on osteoblast and osteoclast formation and function. BKM120 treatment (40 mg/kg) resulted in a significant decrease in serum paraprotein and tumour burden, and μCT analysis of the proximal tibia revealed a significant reduction in the number of osteolytic bone lesions in BKM120-treated animals. BKM120 also mediated a significant increase in serum levels of the osteoblast marker P1NP, and a significant decrease in serum levels of the osteoclast marker TRAcP5. In vitro , BKM120 decreased MM plasma cell proliferation, osteoclast formation and function, and promoted osteoblast formation and function. These findings suggest that, in addition to its anti-tumour properties, BKM120 could be used to treat osteolytic bone disease in MM patients. [ABSTRACT FROM AUTHOR]

Purpose The pan-Class I PI3K inhibitor buparlisib (BKM120) has shown activity in a range of preclinical cancer models. This first-in-man study was initiated to identify the maximum tolerated dose (MTD) of buparlisib (100 mg/day) and to assess safety and preliminary efficacy. Methods Patients with advanced solid tumors ( N = 83) enrolled in a Phase I dose-escalation and -expansion study of single-agent buparlisib. Patients in the dose-expansion arm ( n = 43) had tumor samples with PIK3CA and/or PTEN alterations. Results The most common cancers were colorectal ( n = 31) and breast cancer ( n = 21). Median number of prior antineoplastic regimens was four (range: 1-12). Grade 3/4 adverse events (AEs) included asthenia (12.0 %) and performance status decrease (9.6 %). Treatment-related AEs (all grades) included decreased appetite, diarrhea, nausea (each in 33 % of patients), hyperglycemia (31 %) and rash (29 %). One confirmed partial response (PR; triple-negative breast cancer) and three unconfirmed PRs (parotid gland carcinoma, epithelioid hemangiothelioma, ER + breast cancer) were reported. Tumor molecular status did not predict clinical benefit in the full study cohort, or among the colorectal or breast cancer subpopulations. Pharmacodynamic biomarkers (F-FDG-PET, C-peptide, pS6) demonstrated dose-dependent changes; however, tumor heterogeneity precluded a clear correlation with clinical benefit. Conclusion Buparlisib was well tolerated up to the 100 mg/day dose and showed preliminary activity in patients with advanced cancers. Future studies in more homogeneous patient populations will evaluate buparlisib in combination with other agents and further investigate the use of predictive biomarkers. [ABSTRACT FROM AUTHOR]

Breast cancer is the second leading cause of cancer death in women. Targeted therapies are available for HER2-positive and endocrine-sensitive disease while chemotherapy remains the mainstay of treatment for triple-negative breast cancer. The efficacy of all targeted interventions is, however, limited by primary or secondary resistance. Preclinical data show that active PI3K/AKT/mTOR signaling contributes to therapy resistance in HER2-positive and hormone-receptor-positive breast cancer. In line with these preclinical observations, clinical trials such as BOLERO-2 demonstrated a benefit of additional inhibition of mTOR signaling in advanced estrogen-receptor-positive breast cancer patients refractory to prior aromatase-inhibitor therapy. Besides the mTOR, several other proteins involved in the PI3K-pathway serve as potential therapeutic targets, such as PI3K and AKT. In this review, we summarize the current available knowledge and experimental and clinical research results about targeting the PI3K-pathway in breast cancer and, thus, provide the rationale for PI3K- and AKT-inhibitor use in the clinic. [ABSTRACT FROM AUTHOR]

Purpose: Combined targeting with a PI3-kinase inhibitor, BKM120, and an Hsp90 inhibitor, HSP990, was investigated as a multi-targeted approach to potentiate cell death in glioblastoma (GBM). Additionally, the effect of dual drug treatment combined with cytotoxic stress (radiation therapy) was examined. Methods: Four human GBM cell lines containing wild-type or mutated PTEN and/or p53 were studied. The effects of drug treatments on cell viability, apoptosis induction, pAKt activity, cell cycle arrest, clonogenicity, and tumor growth delay were studied. Results: Combined concurrent treatment with both drugs produced more cell killing in cell viability and apoptosis assays than either drug alone. BKM120 plus HSP990 induced suppression of baseline Akt signaling as well as radiation (RT)-induced pAkt signaling in all cell lines. Cell cycle analysis revealed that HSP990 and BKM120, singly or combined, induced G2/M arrest leading to apoptosis/necrosis and polyploidy. Additionally, the drugs radiosensitized GBM cells in clonogenic assays. In vivo tumor growth delay studies demonstrated the effectiveness of combined drug treatment with HSP990 and BKM120 over single drug treatment, as well as the effectiveness of combined drug treatment in enhancing the effectiveness of radiation therapy. Conclusions: In conclusion, HSP990 and BKM120, with and without RT, are active agents against glioma tumors. The sensitivity to these agents does not appear to depend on PTEN/p53status in the cell lines tested. We suggest that the combined action of both drugs is a viable multi-targeted strategy with the potential to improve clinical outcome for patients with high-grade glioma. [ABSTRACT FROM AUTHOR]

Buparlisib ( BKM120) is an oral pan-phosphatidylinositol 3-kinase inhibitor, targeting all four isoforms of class I PI3K (α, β, γ and δ). This open-label Phase I dose-escalation study was conducted to determine the maximum tolerated dose of continuous daily buparlisib in Japanese patients with advanced solid tumors. Secondary objectives included safety and tolerability, pharmacokinetics, antitumor activity and pharmacodynamic marker changes. Fifteen patients were treated at 25 mg/day ( n = 3), 50 mg/day ( n = 3) and 100 mg/day ( n = 9) dose levels. One dose-limiting toxicity of Grade 4 abnormal liver function occurred at 100 mg/day. Considering the safety profile and the maximum tolerated dose in the first-in-man study of buparlisib in non-Japanese patients, further dose escalation was stopped and 100 mg/day was declared the recommended dose. The most common treatment-related adverse events were rash, abnormal hepatic function (including increased transaminase levels), increased blood insulin levels and increased eosinophil count. Hyperglycemia was experienced by two patients, one Grade 1 and one Grade 4, and mood alterations were experienced by three patients, two Grade 1 and one Grade 2. Pharmacokinetic results showed that buparlisib was rapidly absorbed in a dose-proportional manner. Best overall response was stable disease for six patients, including one unconfirmed partial response. In these Japanese patients with advanced solid tumors, buparlisib had a manageable safety profile, with similar pharmacokinetics to non-Japanese patients. The recommended dose of 100 mg/day will be used in future studies of buparlisib in Japanese patients. [ABSTRACT FROM AUTHOR]

BKM120 is an inhibitor of class I phosphoinositide 3-kinases and its anti-cancer effects have been demonstrated in various solid cancer models. BKM120 is highly brain permeable and has been reported to induce mood disturbances in clinical trials. Therefore, we examined whether BKM120 produces anxiety- and depression-like behaviors in mice, as with patients receiving BKM120 in clinical trials. In this study, repeated BKM120 treatment (2.0 or 5.0 mg/kg, i.p., five times at 12-h interval) significantly induced anxiety- and depression-like behaviors in mice. Although abnormal changes in hippocampal neurogenesis have been suggested to, at least in part, associated with the pathogenesis of depression and anxiety, BKM120 did not affect the incorporation of 5-bromo-2′-deoxyuridine or the expression of doublecortin (DCX); however, it significantly enhanced the radial migration of DCX-positive cells in the dentate gyrus. BKM120-induced changes in migration were not accompanied by obvious neuronal damage in the hippocampus. Importantly, BKM120-induced anxiety- and depression-like behaviors were positively correlated with the extent of DCX-positive cell migration. Concomitantly, p-Akt expression was significantly decreased in the dentate gyrus. Moreover, the expression of p-c-Jun N-terminal kinase (JNK), p-DCX, and Ras homolog family member A (RhoA)-GTP decreased significantly, particularly in aberrantly migrated DCX-positive cells. Together, the results suggest that repeated BKM120 treatment enhances the radial migration of DCX-positive cells and induces anxiety- and depression-like behaviors by regulating the activity of Akt, JNK, DCX, and RhoA in the dentate gyrus. It also suggests that the altered migration of adult-born neurons in the dentate gyrus plays a role in mood disturbances. [Display omitted] • BKM120 has been reported to induce mood disturbances in clinical trials. • Repeated BKM120 produces anxiety- and depression-like behaviors in mice. • Repeated BKM120 enhanced the radial migration of DCX+ cells in the dentate gyrus. • Enhanced migration of DCX+ cells positively correlated with altered mood behaviors. • Alterations in PI3K/Akt, JNK, and RhoA signaling may be involved in these changes. [ABSTRACT FROM AUTHOR]

Highlights: [•] The novel PI3K inhibitor, BKM120, induces apoptosis and enhance TRAIL-induced apoptosis. [•] BKM120 induces GSK3-dependent and FBXW7-mediated Mcl-1 degradation. [•] Mcl-1 reduction contributes to induction of apoptosis and enhancement of TRAIL-induced apoptosis by BKM120. [ABSTRACT FROM AUTHOR]

BKM120, a pan class I PI3K inhibitor, was cytotoxic in the majority of primary B-chronic lymphocytic leukemia (CLL) lymphocytes, including samples from patients who have a high-risk for poor response to treatment (patient with del11 and del17) at clinically obtainable concentrations. The PI3Kδ inhibitor Cal-101 is cytotoxic in B-CLL lymphocytes in vitro and is active in the treatment of CLL in vivo. Interestingly, we demonstrated that BKM120 is 3.6 fold more toxic than Cal-101 in malignant B-CLL lymphocytes in vitro. BKM120 cytotoxicity correlated with the basal expression of proteins involved in the PI3K/Akt pathway. A protein signature of PI3K pathway proteins predicts the response to BKM120 treatment. In the primary B-CLL lymphocytes tested in vitro, BKM120 decreased the phosphorylation status of molecular biomarkers used as indicators of PI3K pathway inhibition in vivo. Also, BKM120 induced apoptosis in primary B-CLL cells culture in the presence and absence of stromal cell support. Our findings suggest that BKM120 should be tested clinically in CLL. [ABSTRACT FROM AUTHOR]

Abstract: This study focuses on determining whether the combination of NYP-BKM120 (BKM120) and RAD001 exerts enhanced therapeutic effect against lung cancer. The combination of BKM120 and RAD001 exerted synergistic inhibitory effects on the growth of lung cancer cells both in culture and in mouse xenograft model. This combination abrogated RAD001-induced Akt phosphorylation and exerted enhanced suppressive effect on 4EBP1 phosphorylation. Collectively, we suggest that the combination of RAD001 and BKM120 may be an effective regimen for treatment of lung cancer, hence warranting further evaluation of the combination in the clinic. [Copyright &y& Elsevier]

NVP-BKM120 is a novel phosphatidylinositol 3-kinase (PI3K) inhibitor and is currently being investigated in phase I clinical trials in solid tumors. This study aimed to evaluate the therapeutic efficacy of BKM120 in multiple myeloma (MM). BKM120 induces cell growth inhibition and apoptosis in both MM cell lines and freshly isolated primary MM cells. However, BKM120 only shows limited cytotoxicity toward normal lymphocytes. The presence of MM bone marrow stromal cells, insulin-like growth factor, or interleukin-6 does not affect BKM120-induced tumor cell apoptosis. More importantly, BKM120 treatment significantly inhibits tumor growth in vivo and prolongs the survival of myeloma-bearing mice. In addition, BKM120 shows synergistic cytotoxicity with dexamethasone in dexamethasone-sensitive MM cells. Low doses of BKM120 and dexamethasone, each of which alone has limited cytotoxicity, induce significant cell apoptosis in MM.1S and ARP-1. Mechanistic study shows that BKM120 exposure causes cell cycle arrest by upregulating p27 (Kip1) and downregulating cyclin D1 and induces caspase-dependent apoptosis by downregulating antiapoptotic XIAP and upregulating expression of cytotoxic small isoform of Bim, BimS. In summary, our findings demonstrate the in vitro and in vivo anti-MM activity of BKM120 and suggest that BKM120 alone or together with other MM chemotherapeutics, particularly dexamethasone, may be a promising treatment for MM. [ABSTRACT FROM AUTHOR]

The reputation of conventional treatment in acute lymphoblastic leukemia (ALL) has recently been questioned due to the considerable increment in the number of relapsed patients. The remarkable role of histone deacetylase (HDAC) enzymes in induction of chemo-resistance has provided an opportunity for HDAC inhibitors to be used as a treatment strategy in ALL; however, the compensatory activation of oncogenic pathways may negatively affect their promising effects. In the present study, we found an attenuating effect for PI3K axis on the anti-leukemic effects of panobinostat in pre-B ALL-derived Nalm-6 cells, as the harnessing of this pathway using BKM120 or CAL-101 resulted in a significant reduction in the number of viable cells as well as the metabolic activity. Moreover, we found the altered expression of p21, p27, c-Myc, and CDK4 upon co-treatment of the cells with panobinostat and BKM120, which was associated with a substantial blockage of cell cycle progression at G2/M phase. The companionship of the PI3K inhibitor with HDAC inhibitor also potentiated panobinostat-induced apoptotic cell death and enhanced the mRNA of Foxo3a and Foxo4. Conclusively, this study sheds light on the adjuvantive effects of BKM120 on panobinostat efficacy and outlined that the simultaneous inhibition of PI3K and HDACs may be a promising therapeutic approach to improve the cure rates of ALL.

Background: Type 1 diabetes (T1D) is a multiple factor autoimmune disease characterized by T cell-mediated immune destruction of islet β cells. Autologous hematopoietic stem cell transplantation (AHSCT) has been a novel strategy for patients with new-onset T1D, but not for those with a later diagnosis. Disturbance of regulatory T cells (Tregs) likely contributes to poor response after transplantation in later-stage T1D. Inhibition of phosphoinositide 3-kinases (PI3K)/Akt signaling maintains Tregs' homeostasis., Methods: We built a later-stage streptozotocin (STZ)-induced T1D mouse model. Syngeneic bone marrow transplantation (syn-BMT) was performed 20 days after the onset of diabetes in combination with BKM120 (a PI3K inhibitor). Meanwhile, another group of STZ-diabetic mice were transplanted with bone marrow cells cocultured with BKM120 in vitro for 24 h. Fasting glucose and glucose tolerance were recorded during the entire experimental observation after syn-BMT. Samples were collected 126 days after syn-BMT. Hematoxylin and eosin (H&E) staining was used to detect the effect of PI3K inhibitor combined with syn-BMT on morphology of the T1D pancreas. CD4 + CD25 - T cells and CD4 + CD25 + T cells were sorted by magnetic cell sorting (MACS), then fluorescence activated cell sorting (FACS) and quantitative real-time PCR (qPCR) were used to detect the effect of PI3K inhibitor on modulating immune disorder and restoring the function of Treg cells., Results: Our investigation showed syn-BMT in combination with BKM120 effectively maintained normoglycemia in later-stage T1D. The disease remission effects may be induced by the rebalance of Th17/Tregs dysregulation and restoration of Tregs' immunosuppressive function by BKM120 after syn-BMT., Conclusions: These results may reveal important connections for PI3K/Akt inhibition and Tregs' homeostasis in T1D after transplantation. AHSCT combining immunoregulatory strategies such as PI3K inhibition may be a promising therapeutic approach in later-stage T1D., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-3329). SL, Y Wang, YZ, Y Wen received funding from the Independent and Open Grant of Jiangsu Key Laboratory of Molecular Medicine and Innovation and Entrepreneurship Training Program for College Students (G201910284011). DC, NZ, Y Wen received funding from the Independent and Open Grant of Jiangsu Key Laboratory of Molecular Medicine and Innovation and Entrepreneurship Training Program for College Students (202010284016Z). JD received funding from the National Natural Science Foundation of China (81400046). Y Wen received funding from the National Natural Science Foundation of China (81100386). The other authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)