The PI3K/AKT/mTOR signaling pathway in breast cancer: Review of clinical trials and latest advances.

Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer mortality in women. As the phosphatidylinositol 3-kinase (PI3K) signaling pathway is involved in a wide range of physiological functions of cells including growth, proliferation, motility, and angiogenesis, any alteration in this axis could induce oncogenic features; therefore, numerous preclinical and clinical studies assessed agents able to inhibit the components of this pathway in BC patients. To the best of our knowledge, this is the first study that analyzed all the registered clinical trials investigating safety and efficacy of the PI3K/AKT/mTOR axis inhibitors in BC. Of note, we found that the trends of PI3K inhibitors in recent years were superior as compared with the inhibitors of either AKT or mTOR. However, most of the trials entering phase III and IV used mTOR inhibitors (majorly Everolimus) followed by PI3K inhibitors (majorly Alpelisib) leading to the FDA approval of these drugs in the BC context. Despite favorable efficacies, our analysis shows that the majority of trials are utilizing PI3K pathway inhibitors in combination with hormone therapy and chemotherapy; implying monotherapy cannot yield huge clinical benefits, at least partly, due to the activation of compensatory mechanisms. To emphasize the beneficial effects of these inhibitors in combined-modal strategies, we also reviewed recent studies which investigated the conjugation of nanocarriers with PI3K inhibitors to reduce harmful toxicities, increase the local concentration, and improve their efficacies in the context of BC therapy.

APDS patients with immune-complex vasculitis and resolution with leniolisib.

Activated phosphoinositide 3-kinase delta syndrome (APDS) is an inborn error of immunity with heterogeneous clinical manifestations of infections, immune dysregulation, autoimmunity; lymphoproliferation; and malignancy. Immune complex-mediated vasculitides have not yet been described in APDS patients. Here we offer a case series of three patients with APDS who have refractory IgA vasculitis (also called Henoch-Schönlein purpura), a form of immune complex-mediated vasculitis that activates complement and attracts neutrophils, macrophages and eosinophils to cause local tissue injury. Leniolisib is an inhibitor of PI3K p110δ and an FDA-approved treatment for APDS. IgA vasculitis resolved upon treatment with leniolisib. Patients with immune dysregulation including IgA vasculitis should be screened for APDS.

AAV-mediated VEGFA overexpression promotes angiogenesis and recovery of locomotor function following spinal cord injury via PI3K/Akt signaling.

Spinal cord injury (SCI) is a disorder of the central nervous system resulting from various factors such as trauma, inflammation, tumors, and other etiologies. This condition leads to impairment in motor, sensory, and autonomic functions below the level of injury. Limitations of current therapeutic approaches prompt an investigation into therapeutic angiogenesis through persistent local expression of proangiogenic factors. Here, we investigated whether overexpression of adeno-associated virus (AAV)-mediated vascular endothelial growth factor A (VEGFA) in mouse SCI promoted locomotor function recovery, and whether the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway was mechanistically involved. Three weeks before SCI, AAV-VEGFA was injected at the T10 level to induce VEGFA overexpression. Neurofunctional, histological, and biochemical assessments were done to determine tissue damage and/or recovery of neuromuscular and behavioral impairments. Daily injections of the PI3K/Akt pathway inhibitor LY294002 were made to assess a possible mechanism. AAV-VEGFA overexpression dramatically improved locomotor function and ameliorated pathological injury caused by SCI. Improved motor-evoked potentials in hindlimbs and more spinal CD31-positive microvessels were observed in AAV-VEGFA-overexpressing mice. LY294002 reduced PI3K and Akt phosphorylation levels and attenuated AAV-VEGFA-related improvements. In conclusion, sustained local AAV-mediated VEGFA overexpression in spinal cord can significantly promote angiogenesis and ameliorate locomotor impairment after SCI in a contusion mouse model through activation of the PI3K/Akt signaling pathway.

Simultaneous inhibition of PI3K and PAK in preclinical models of neurofibromatosis type 2-related schwannomatosis.

Neurofibromatosis Type 2 (NF2)-related schwannomatosis is a genetic disorder that causes development of multiple types of nervous system tumors. The primary and diagnostic tumor type is bilateral vestibular schwannoma. There is no cure or drug therapy for NF2. Recommended treatments include surgical resection and radiation, both of which can leave patients with severe neurological deficits or increase the risk of future malignant tumors. Results of our previous pilot high-throughput drug screen identified phosphoinositide 3-kinase (PI3K) inhibitors as strong candidates based on loss of viability of mouse merlin-deficient Schwann cells (MD-SCs). Here we used novel human schwannoma model cells to conduct combination drug screens. We identified a class I PI3K inhibitor, pictilisib and p21 activated kinase (PAK) inhibitor, PF-3758309 as the top combination due to high synergy in cell viability assays. Both single and combination therapies significantly reduced growth of mouse MD-SCs in an orthotopic allograft mouse model. The inhibitor combination promoted cell cycle arrest and apoptosis in mouse merlin-deficient Schwann (MD-SCs) cells and cell cycle arrest in human MD-SCs. This study identifies the PI3K and PAK pathways as potential targets for combination drug treatment of NF2-related schwannomatosis.

Modulating the PI3K Signalling Pathway in Activated PI3K Delta Syndrome: a Clinical Perspective.

Activated phosphoinositide-3-kinase (PI3K) δ syndrome (APDS) is an inborn error of immunity characterised by immune dysregulation. Since the discovery of genetic mutations resulting in PI3Kδ overactivation, treatment of APDS patients has begun to focus on modulation of the PI3K pathway in addition to supportive therapies. The mTOR inhibitor sirolimus has been used effectively for some clinical manifestations of this condition, however the arrival of specific PI3Kδ inhibitor leniolisib has shown promising early results and may provide a more targeted approach. This review summarizes key aspects of PI3K pathway biology and discusses potential options for nuanced modulation of the PI3K pathway in APDS from a clinical perspective, highlighting differences from PI3K inhibition in haematological malignancies.

[Cheng's Juanbi Decoction alleviates the inflammation in collagen-induced arthritis (CIA) rats via inhibiting activation of PI3K/AKT/mTOR pathway].

Objective To investigate the potential mechanism of Cheng's Juanbi Decoction (JBT) for treating collagen-induced arthritis (CIA) in rats. Methods Female SD rats were divided into normal group, CIA model group, methotrexate (MTX) group, JBT group with different doses, and LY294002 (PI3K blocker) group. The effects of JBT on toe swelling and arthritis index of rats before and after treatment were evaluated. HE staining was used to observe the pathological changes of synovial tissues. ELISA was used to determine the levels of interleukin-1ß (IL-1ß) and tumor necrosis factor α(TNF-α) in synovium of rats. Real-time quantitative PCR was used to detect mRNA expression levels of phosphatidylinositol 3 kinase (PI3K), protein kinase B (AKT), mammalian target of rapamycin (mTOR), beclin-1, and P62. The expressions of AKT, phosphorylated AKT (p-AKT), mTOR, phosphorylated mTOR (p-mTOR), PI3K, phosphorylated PI3K (p-PI3K), P62, beclin-1, and microtubule-associated protein 1 light chain 3B (LC3B) were detected by Western blot analysis. Results Compared with the normal group, the toe of other groups was significantly swollen 1 hour before administration. Compared with the conditions 1 hour before administration, toe swelling in the high-dose JBT group, MTX group, and LY294002 group was significantly relieved 2 hours before blood collection after 30 days of administration. JBT can significantly reduce the degree of toe swelling, arthritis index(AI) score, and the destruction of synovial tissue. The levels of IL-1ß, TNF-α, mRNA expression of PI3K, AKT, mTOR and P62, and protein levels of p-PI3K, p-AKT, p-mTOR, and P62 in synovium samples of rats in the high-dose JBT group were significantly decreased. Beclin-1 mRNA and protein expression and LC3B protein level were significantly increased. Conclusion JBT may alleviate joint inflammation by inhibiting the activation of the PI3K/AKT/mTOR signaling pathway, and the therapeutic effect of high-dose JBT is comparable to that of MTX and LY294002.

Metabolic and toxicological considerations for phosphoinositide 3-kinase delta inhibitors in the treatment of chronic lymphocytic leukemia.

INTRODUCTION: Phosphoinositide 3-kinase delta (PI3Kδ) inhibitors are a class of novel agents that are mainly used to treat B-cell malignancies. They function by inhibiting one or more enzymes which are part of the PI3K/AKT/mTOR pathway. Idelalisib is a first-in-class PI3Kδ inhibitor effective in patients with B-cell lymphoid malignancies. AREAS COVERED: This article reviews the chemical structure, mechanism of action, and metabolic and toxicological properties of PI3Kδ inhibitors and discusses their clinical applications in monotherapy and in combination with other agents for the treatment of chronic lymphocytic leukemia (CLL). A search was conducted of PubMed, Web of Science, and Google Scholar for articles in English. RESULTS/CONCLUSION: PI3Kδ inhibitors hold potential for the treatment of B-cell malignancies, including CLL. However, their use is also associated with severe toxicities, including pneumonia, cytopenias, hepatitis, and rash. Newer drugs are in development to reduce toxicity with novel schedules and/or combinations. EXPERT OPINION: The development of novel PI3Kδ inhibitors might help to reduce toxicity and improve efficacy in patients with CLL and other B-cell lymphoid malignancies.

Inhibitors of the PI3K/AKT/mTOR pathway in human malignancies; trend of current clinical trials.

The phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway regulates proliferation, survival and metabolism, and its dysregulation is one of the most frequent oncogenic events across human malignancies. Over the last two decades, there has been significant focus on the clinical development of PI3K pathway inhibitors. More than 40 different inhibitors of this axis have reached various stages of clinical trials, but only a few of them have been approved by the Food and Drug Administration (FDA) for cancer treatment. These clinical results, however, could be improved given the importance of PI3K signaling in cancer and its role in linking cancer growth with metabolism. In this systematic review, after a glance at PI3K/AKT/mTOR pathway and its different inhibitors, we retrieved registered clinical trials evaluating the efficacy and safety of PI3K/AKT/mTOR inhibitors on Clinicaltrials.gov. Following the extraction of the data, finally we analyzed 2250 included studies in multiple steps, beginning with an overview and moving on to the details about type of malignancies, inhibitors, and treatment strategies. We also took a closer look at more than 100 phase III-IV clinical trials to pinpoint promising therapies, hoping that presenting a comprehensive picture of current clinical trials casts a flash of light on what remains to be done in future clinical trials of PI3K/AKT/mTOR inhibitors in human malignancies.

Cotargeting Phosphoinositide 3-Kinase and Focal Adhesion Kinase Pathways Inhibits Proliferation of NF2 Schwannoma Cells.

Neurofibromatosis Type 2 (NF2) is a tumor predisposition syndrome caused by germline inactivating mutations in the NF2 gene encoding the merlin tumor suppressor. Patients develop multiple benign tumor types in the nervous system including bilateral vestibular schwannomas (VS). Standard treatments include surgery and radiation therapy, which may lead to loss of hearing, impaired facial nerve function, and other complications. Kinase inhibitor monotherapies have been evaluated clinically for NF2 patients with limited success, and more effective nonsurgical therapies are urgently needed. Schwannoma model cells treated with PI3K inhibitors upregulate activity of the focal adhesion kinase (FAK) family as a compensatory survival pathway. We screened combinations of 13 clinically relevant PI3K and FAK inhibitors using human isogenic normal and merlin-deficient Schwann cell lines. The most efficacious combination was PI3K/mTOR inhibitor omipalisib with SRC/FAK inhibitor dasatinib. Sub-GI50 doses of the single drugs blocked phosphorylation of their major target proteins. The combination was superior to either single agent in promoting a G1 cell-cycle arrest and produced a 44% decrease in tumor growth over a 2-week period in a pilot orthotopic allograft model. Evaluation of single and combination drugs in six human primary VS cell models revealed the combination was superior to the monotherapies in 3 of 6 VS samples, highlighting inter-tumor variability between patients consistent with observations from clinical trials with other molecular targeted agents. Dasatinib alone performed as well as the combination in the remaining three samples. Preclinically validated combination therapies hold promise for NF2 patients and warrants further study in clinical trials.

HTRA3 transcriptionally inhibited by FOXP1 suppresses tumorigenesis of osteosarcoma via the PTEN/PI3K/AKT pathway.

Despite recent advances in understanding the biological behavior of osteosarcoma (OS), OS is still the most common primary bone sarcoma that endangers the health of children and adolescents. High-temperature requirement A (HTRA) protease family plays an important regulatory role in numerous malignancies and acts as a prognostic biomarker. However, the function and underlying mechanisms of the HTRA family in OS development remain unknown. Through analyzing the GSE126209 dataset obtained from different Gene Expression Omnibus (GEO) databases, we found that HTRA3 as a member of the HTRA family was downregulated in OS tissues compared with that in normal tissues. Functional experiments indicated that HTRA3 overexpression suppressed malignant behaviors of OS cells in vitro and tumor growth in vivo. Mechanistically, we found that HTRA3 co-localized with the X-linked inhibitor of apoptosis protein (XIAP) and decreased XIAP stability. Further investigation showed that XIAP knockdown inhibited the degradation of phosphatase and tensin homolog (PTEN) and that HTRA3 caused the blockage of PTEN/phosphoinositide 3-kinase (PI3K)/AKT pathway, characterized as the reverse of cell function caused by HTRA3 overexpression after PTEN inhibitor BpV (HOpic) treatment. Detailed investigations showed that forkhead box protein 1 (FOXP1), an oncogene in OS progression, downregulated HTRA3 expression and inhibited the transcriptional activity of HTRA3, suggesting that HTRA3 was regulated negatively by FOXP1. In conclusion, our study demonstrates that HTRA3 is a repressor involved in OS development via the PTEN/PI3K/AKT pathway under the modulation of transcription factor FOXP1, and it may provide a therapeutic direction for OS patients.

Immunodeficiency due to a novel variant in PIK3CD: a case report.

BACKGROUND: Primary immunodeficiencies are immunological disorders caused by gene mutations involved in immune system development and activation. Recently, activated phosphoinositide 3-kinase delta syndrome (APDS) due to mutations in the phosphoinositide 3-kinase (PI3K), phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit delta gene (PIK3CD), and phosphoinositide 3-kinase regulatory subunit 1 (PIK3R1) genes have been reported to induce a combined immunodeficiency syndrome leading to senescent T cells, lymphadenopathy, and immunodeficiency. The exact diagnosis of these deficiencies is essential for treatment and prognosis. In recent years, targeted treatment with selective PI3Kd inhibitors has had a significant effect on controlling the symptoms of these patients. CASE PRESENTATION: In this case report, we represent a 27-month-old girl with recurrent fever, an increased level of inflammatory markers, and erythema nodosum, who was referred to the rheumatology clinic. In the course of evaluations, because of the lack of clinical improvement with usual treatments, and a history of frequent respiratory infections, combined immunodeficiency was diagnosed in the immunological investigations. Moreover, whole-exome sequencing was performed for her. CONCLUSION: The genetic analysis found a novel variant of PIK3CD (c.1429 G > A) in the patient. Following daily antibiotic prophylaxis and monthly IV therapy, the patient's frequent infections and fevers were controlled.

Inhibitors of phosphoinositide 3-kinase (PI3K) and phosphoinositide 3-kinase-related protein kinase family (PIKK).

Phosphoinositide 3-kinases (PI3K) and phosphoinositide 3-kinase-related protein kinases (PIKK) are two structurally related families of kinases that play vital roles in cell growth and DNA damage repair. Dysfunction of PIKK members and aberrant stimulation of the PI3K/AKT/mTOR signalling pathway are linked to a plethora of diseases including cancer. In recent decades, numerous inhibitors related to the PI3K/AKT/mTOR signalling have made great strides in cancer treatment, like copanlisib and sirolimus. Notably, most of the PIKK inhibitors (such as VX-970 and M3814) related to DNA damage response have also shown good efficacy in clinical trials. However, these drugs still require a suitable combination therapy to overcome drug resistance or improve antitumor activity. Based on the aforementioned facts, we summarised the efficacy of PIKK, PI3K, and AKT inhibitors in the therapy of human malignancies and the resistance mechanisms of targeted therapy, in order to provide deeper insights into cancer treatment.

Insulin feedback is a targetable resistance mechanism of PI3K inhibition in glioblastoma.

BACKGROUND: Insulin feedback is a critical mechanism responsible for the poor clinical efficacy of phosphatidylinositol 3-kinase (PI3K) inhibition in cancer, and hyperglycemia is an independent factor associated with poor prognosis in glioblastoma (GBM). We investigated combination anti-hyperglycemic therapy in a mouse model of GBM and evaluated the association of glycemic control in clinical trial data from patients with GBM. METHODS: The effect of the anti-hyperglycemic regimens, metformin and the ketogenic diet, was evaluated in combination with PI3K inhibition in patient-derived GBM cells and in an orthotopic GBM mouse model. Insulin feedback and the immune microenvironment were retrospectively evaluated in blood and tumor tissue from a Phase 2 clinical trial of buparlisib in patients with recurrent GBM. RESULTS: We found that PI3K inhibition induces hyperglycemia and hyperinsulinemia in mice and that combining metformin with PI3K inhibition improves the treatment efficacy in an orthotopic GBM xenograft model. Through examination of clinical trial data, we found that hyperglycemia was an independent factor associated with poor progression-free survival in patients with GBM. We also found that PI3K inhibition increased insulin receptor activation and T-cell and microglia abundance in tumor tissue from these patients. CONCLUSION: Reducing insulin feedback improves the efficacy of PI3K inhibition in GBM in mice, and hyperglycemia worsens progression-free survival in patients with GBM treated with PI3K inhibition. These findings indicate that hyperglycemia is a critical resistance mechanism associated with PI3K inhibition in GBM and that anti-hyperglycemic therapy may enhance PI3K inhibitor efficacy in GBM patients.

Clinical practice guideline for activated phosphatidyl inositol 3-kinase-delta syndrome in Japan.

Activated phosphatidyl inositol 3-kinase-delta syndrome (APDS) due to gain-of-function variant in the class IA PI3K catalytic subunit p110δ (responsible gene: PIK3CD) was described in 2013. The disease is characterized by recurrent airway infections and bronchiectasis. It is associated with hyper-IgM syndrome due to the defect of immunoglobulin class switch recombination and decreased CD27-positive memory B cells. Patients also suffered from immune dysregulations, such as lymphadenopathy, autoimmune cytopenia or enteropathy. T-cell dysfunction due to increased senescence is associated with a decrease in CD4-positive T lymphocytes and CD45RA-positive naive T lymphocytes, along with increased susceptibility to Epstein-Barr virus/cytomegalovirus infections. In 2014, loss-of-function (LOF) mutation of p85α (responsible gene: PIK3R1), a regulatory subunit of p110δ, was identified as a causative gene, followed in 2016 by the identification of the LOF mutation of PTEN, which dephosphorylates PIP3, leading to the differentiation of APDS1 (PIK3CD-GOF), APDS2 (PIK3R1-LOF) and APDS-L (PTEN-LOF). Since the pathophysiology of patients with APDS varies with a wide range of severity, it is crucial that patients receive appropriate treatment and management. Our research group created a disease outline and a diagnostic flow chart and summarized clinical information such as the severity classification of APDS and treatment options.

LIPUS-SCs-Exo promotes peripheral nerve regeneration in cavernous nerve crush injury-induced ED rats via PI3K/Akt/FoxO signaling pathway.

OBJECTIVE: Clinical treatment of erectile dysfunction (ED) caused by cavernous nerve (CN) injury during pelvic surgery is difficult. Low-intensity pulsed ultrasound (LIPUS) can be a potential strategy for neurogenic ED (NED). However, whether Schwann cells (SCs) can respond to LIPUS stimulation signals is unclear. This study aims to elucidate the signal transmission between SCs paracrine exosome (Exo) and neurons stimulated by LIPUS, as well as to analyze the role and potential mechanisms of exosomes in CN repair after injury. METHODS: The major pelvic ganglion (MPG) neurons and MPG/CN explants were stimulated with LIPUS of different energy intensities to explore the appropriate LIPUS energy intensity. The exosomes were isolated and purified from LIPUS-stimulated SCs (LIPUS-SCs-Exo) and non-stimulated SCs (SCs-Exo). The effects of LIPUS-SCs-Exo on neurite outgrowth, erectile function, and cavernous penis histology were identified in bilateral cavernous nerve crush injury (BCNI)-induced ED rats. RESULTS: LIPUS-SCs-Exo group can enhance the axon elongation of MPG/CN and MPG neurons compared to SCs-Exo group in vitro. Then, the LIPUS-SCs-Exo group showed a stronger ability to promote the injured CN regeneration and SCs proliferation compared to the SCs-Exo group in vivo. Furthermore, the LIPUS-SCs-Exo group increased the Max intracavernous pressure (ICP)/mean arterial pressure (MAP), lumen to parenchyma and smooth muscle to collagen ratios compared to the SCs-Exo group in vivo. Additionally, high-throughput sequencing combined with bioinformatics analysis revealed the differential expression of 1689 miRNAs between the SCs-Exo group and the LIPUS-SCs-Exo group. After LIPUS-SCs-Exo treatment, the phosphorylated levels of Phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt) and forkhead box O (FoxO) in MPG neurons increased significantly compared to negative control (NC) and SCs-Exo groups. CONCLUSION: Our study revealed that LIPUS stimulation could regulate the gene of MPG neurons by changing miRNAs derived from SCs-Exo, then activating the PI3K-Akt-FoxO signal pathway to enhance nerve regeneration and restore erectile function. This study had important theoretical and practical significance for improving the NED treatment.

[Sivelestat protects acute kidney injury by inhibiting the PI3K/AKT pathway in septic rats].

OBJECTIVE: To explore the protective effect of sivelestat (SV) against sepsis-induced acute kidney injury (AKI) and its molecular mechanism. METHODS: According to the random number table method, 64 male Wistar rats were divided into sham operation group (Sham group), sepsis due to cecal ligation and puncture group (CLP group), low dose of SV treatment group (SL group, 50 mg/kg SV was injected into the tail vein at 12 hours and 24 hours after CLP), and high dose of SV treatment group (SH group, 100 mg/kg SV was injected into the tail vein at 12 hours and 24 hours after CLP), with 16 rats in each group. 48 hours after CLP, the 48-hour survival of rats were recorded, all rats were sacrificed and samples were harvested. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum levels of kidney injury molecule-1 (KIM-1), interleukins (IL-1ß, IL-6), tumor necrosis factor-α (TNF-α) and neutrophil elastase (NE). Hematoxylin-eosin (HE) staining was used to observe histopathological changes and assess renal tubule injury score. Masson staining was used to detect the collagen volume fraction (CVF) of kidney tissue. Western blotting was used to detect the protein expressions of phosphatidylinositol 3-kinase (PI3K), phosphorylation PI3K (p-PI3K), protein kinase B (AKT), phosphorylation AKT (p-AKT), nuclear factor-κB p65 (NF-κB p65) and NE. The protein expressions of p-PI3K, p-AKT, NF-κB p65 were detected by immunohistochemistry. RESULTS: Compared with Sham group, the 48-hour survival rate of CLP group was significantly reduced. Histopathological results showed that large tubular epithelial cells and brush margins were shed, tubular casts were formed, some tubular atrophy, glomerular hyperemia, renal interstitial inflammatory cell infiltration and increased renal tubular injury score. Renal interstitial fibrosis was obvious and CVF increased. The levels of KIM-1, IL-1ß, IL-6, TNF-α and NE in serum were significantly elevated in the CLP group. The proteins expression of inflammatory pathway-related p-PI3K/PI3K, p-AKT/AKT, NF-κB p65 and NE were significantly increased in kidney tissue. It suggested that septic rats had renal injury and the PI3K/AKT inflammatory pathway was activated. Compared with CLP group, there was no significant difference in 48-hour survival in SL group and SH group (68.75%, 75.00% vs. 56.25%, both P > 0.05), but kidney injury was significantly relieved. Specifically: renal tubular injury score and CVF significantly decreased [tubular injury score: 2 (1, 2), 1 (1, 1) vs. 2 (2, 3); CVF: (22.36±0.86)%, (18.74±1.05)% vs. (58.38±0.79)%, all P < 0.05]; the serum levels of KIM-1, IL-1ß, IL-6, TNF-α and NE also decreased significantly [KIM-1 (ng/L): 145.03±8.88, 117.58±7.02 vs. 158.22±12.00; IL-1ß (ng/L): 108.32±9.00, 92.98±8.06 vs. 133.78±8.48; IL-6 (ng/L): 124.33±10.11, 115.42±8.17 vs. 165.19±5.70; TNF-α (ng/L): 321.56±19.29, 289.68±21.57 vs. 424.88±22.76, NE (mol/L): 93.84±9.14, 75.01±10.56 vs. 113.45±6.39, all P < 0.05]; the proteins expression of inflammatory pathway-related p-PI3K/PI3K, p-AKT/AKT, NF-κB p65 and NE were significantly decreased (p-PI3K/PI3K: 0.93±0.06, 0.67±0.04 vs. 1.27±0.08; p-AKT/AKT: 0.78±0.09, 0.47±0.05 vs. 0.96±0.12; NF-κB p65/GAPDH: 1.43±0.13, 0.85±0.08 vs. 1.88±0.17; NE/GAPDH: 1.45±0.06, 0.91±0.04 vs. 1.71±0.08, all P < 0.05), the positive expressions of p-PI3K, p-AKT and NF-κB p65 in kidney tissue were decreased [p-PI3K positive expression area: (13.36±1.84)%, (8.03±1.12)% vs. (21.56±1.20)%; p-AKT positive expression area: (21.57±0.91)%, (15.21±2.76)% vs. (30.81±2.12)%; NF-κB p65 positive expression area: (25.17±1.38)%, (17.07±2.11)% vs. (37.85±2.50)%, all P < 0.05]. Serum inflammatory factor level, and PI3K/AKT pathway related protein, NF-κB p65, NE protein expression level and p-PI3K, p-AKT, NF-κB p65 positive area and other indicators in renal tissue in SH group were further lower than those in SL group (all P < 0.05). CONCLUSIONS: SV can ameliorate sepsis-induced AKI. The mechanism may be related to the inhibition of PI3K/AKT pathway, and high dose of SV has better efficacy.

Procyanidin B2 alleviates oxidative stress-induced nucleus pulposus cells apoptosis through upregulating Nrf2 via PI3K-Akt pathway.

Oxidative stress can lead to nucleus pulposus cell (NPC) apoptosis, which is considered to be one of the main contributors to intervertebral disc degeneration (IVDD). Procyanidin B2 is a natural antioxidant that protects against oxidative stress. However, whether procyanidin B2 protects NPCs from oxidative stress remains unknown. In this study, we demonstrated that procyanidin B2 could reduce tert-butyl hydroperoxide-induced reactive oxygen species in rat NPCs and attenuate rat NPC apoptosis. Further experiments revealed that procyanidin B2 upregulated the expression of both nuclear factor erythroid 2-related factor 2 (Nrf2) and phosphorylation of protein kinase B (Akt). We then used silencing of Nrf2 and LY294002 to silence Nrf2 expression and block the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, respectively, and found that the protective roles of procyanidin B2 in NPCs were inhibited. Therefore, we demonstrated that procyanidin B2 alleviated rat NPC apoptosis induced by oxidative stress by upregulating Nrf2 via activation of the PI3K/Akt signaling pathway. This study provides a potential therapeutic approach for procyanidin B2 in IVDD, which might help in the development of new drugs for IVDD treatment.

A phase 2 trial of buparlisib in patients with platinum-resistant metastatic urothelial carcinoma.

BACKGROUND: The phosphatidyl 3-inositol kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway frequently is activated in patients with urothelial carcinoma (UC). In the current study, the authors performed a phase 2 study evaluating the efficacy of the pan-isoform class I PI3K inhibitor buparlisib in patients with platinum-refractory metastatic UC. METHODS: Two cohorts were recruited: an initial genetically unselected cohort and a subsequent expansion cohort of patients with PI3K/Akt/mTOR pathway-altered tumors. The primary endpoint was the 2-month progression-free survival rate. A rate of ≥80% was considered promising using a Simon 2-stage minimax design. Secondary endpoints included safety and correlation of markers of PI3K pathway activation with outcome. RESULTS: Six of 13 evaluable patients within the initial cohort demonstrated stable disease and 1 demonstrated a partial response, which was below the cutoff of 9 patients required to proceed to stage 2. Three of the patients with stable disease and the patient with a partial response harbored somatic TSC1 alterations. Four patients subsequently were recruited onto an expansion cohort: 3 patients with TSC1 alterations and 1 patient with a PIK3CA-activating mutation. No patient achieved disease control at 8 weeks and accrual was halted. Of the 19 patients evaluable for toxicity, 17 demonstrated treatment-related toxicities, 2 of whom had to discontinue therapy. CONCLUSIONS: Buparlisib was found to demonstrate modest activity in patients with metastatic UC whose tumors harbored TSC1 loss of function alterations; however, this was not a robust predictor of response to buparlisib. The pattern of genetic coalterations likely influences drug sensitivity. Given the modest clinical activity and substantial toxicity of buparlisib, future trials of PI3K inhibitors in patients with UC should focus on isoform-selective PI3K inhibitors in genomically selected patients. LAY SUMMARY: The phosphatidyl 3-inositol kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway frequently is upregulated in patients with metastatic urothelial carcinoma (UC). This trial explored buparlisib, an inhibitor of the pathway, in patients with heavily pretreated metastatic UC. Although the drug was found to have modest efficacy, with 6 patients experiencing stable disease and 1 patient achieving a partial response at 8 weeks on therapy, significant side effects also were observed. Patients with specific genetic alterations responded to treatment. Further studies of PI3K pathway inhibition are warranted using newer agents that have superior toxicity profiles and are more selective inhibitors of the pathway.

Phase I study of BGT226, a pan-PI3K and mTOR inhibitor, in Japanese patients with advanced solid cancers.

The phosphatidylinositol 3-kinase (PI3K) pathway is a promising therapeutic target for various cancers. BGT226 is a pan-PI3K and mammalian target of rapamycin (mTOR) inhibitor. The tolerability and pharmacokinetics/pharmacodynamics of BGT226 were investigated in a phase I study in Japanese patients with advanced solid cancers. BGT226 was orally administered on days 1, 3, and 5 of each week. The initial dose of 10 mg was subsequently escalated to 20, 40, 80, and 100 mg in a cohort of three patients. Pharmacokinetics and pharmacodynamics were investigated using plasma, normal skin, and tumor samples. A total of 18 patients were enrolled and evaluated. The most frequently reported toxicities were diarrhea, nausea, decreased appetite, vomiting, and fatigue. They were all grade 1 or 2, and no dose-limiting toxicity was observed. However, all six patients treated at 100 mg experienced diarrhea and nausea, while two experienced a dose reduction and/or interruptions during the study. Two of five patients who exhibited stable disease continued the study treatment for ≥ 16 weeks. The absorption of BGT226 was rapid, and systemic exposure increased in a dose-dependent manner. Treatment with BGT226 did not change any of the biomarkers in neither normal skin nor tumor tissues. BGT226 was tolerated up to 100 mg three times a week in Japanese patients with solid cancers, without difference in toxicity profiles and pharmacokinetics compared to Western patients.