buparlisib (AN2025)

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.

Moreover, they inhibited the PI3K/Akt signalling pathway, leading to activation of the FoxO3a/Puma signalling in NSCLC cells. Our findings suggest that combined treatment of metformin and buparlisib might provide a promising strategy for treating NSCLC.

P1, N=63, Recruiting, Adlai Nortye Biopharma Co., Ltd. | Phase classification: P1a --> P1 | Trial completion date: Dec 2023 --> Jun 2024 | Trial primary completion date: Sep 2023 --> Mar 2024

Our findings suggested that the rs10889677 variant as a critical initiator of the PI3K signaling pathway, and buparlisib had the ability to prevent PI3K-non-AKT activation in the pathophysiology of CAC.

P3, N=483, Active, not recruiting, Adlai Nortye Biopharma Co., Ltd. | Recruiting --> Active, not recruiting

Moreover, FD2056 showed more efficacious anti-TNBC activity than the corresponding drugs BKM120 and CYC202 at an oral dose of 15 mg/kg in the MDA-MB-231 xenograft model, inhibiting tumor growth by 43% with no observable toxic effects. All these results suggest that FD2056 has potential for further development as a promising anticancr compound, and co-targeting PI3K and CDK2 pathways may provide an alternative therapeutic strategy for the treatment of TNBC.

Compound 4w exhibited superior anti-tumor activity against the A549 cells with IC values of 1.55±0.18 μM, and better than the BKM120 (IC = 9.75±1.25 µM). Further studies indicated that 4w could induce G/G phase arrest, cell apoptosis, and down-regulate expression of p-PI3K and p-Akt. These results indicate that 4w could be served as a lead compound of PI3K inhibitor for the treatment of human lung cancers.

The presence of Buparlisib in plasma and CSF was confirmed 2h post-treatment with a median CSF concentration below the EC50 defined in the cell line All four patients were evaluated for response and the median time to progression was 39 days. Buparlisib monotherapy did not lead to meaningful responses and the trial was prematurely stopped.Clinical Trial Registration: NCT02301364.

As monotherapy, the pan-PI3K inhibitor BKM120 can induce growth inhibition and apoptosis in most of the melanoma models tested, but shows severe side effects in patients...Initial in ovo test results (on chick chorioallantoic membrane (CAM)) showed reduced tumor burden by using BYL719 in combination with the MEKi trametinib. These data suggest that the combination of PI3Ki with MEKi may be a new therapeutic option for BRAF wild-type melanoma patients.

The IT and BKM-120 were used in the BBB-model showing preliminary results of permeability. Conclusions Targeted innovative scFv-based immunotherapy as highly specific and less immunogenic therapy for MB or RMS was established, also as combination therapy approach.

Reducing insulin feedback improves the efficacy of PI3K inhibition in glioblastoma in mice, and hyperglycemia worsens progression-free survival in patients with glioblastoma treated with PI3K inhibition. These findings indicate that hyperglycemia is a critical resistance mechanism associated with PI3K inhibition in glioblastoma and that anti-hyperglycemic therapy may enhance PI3K inhibitor efficacy in glioblastoma patients.

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.

Furthermore, buparlisib inhibited the effects of ARHGAP30 upregulation on OC cell growth and invasiveness. In conclusion, ARHGAP30 regulated the PI3K/AKT/mTOR pathway to promote progression of OC.

Furthermore, buparlisib inhibited the effects of ARHGAP30 upregulation on OC cell growth and invasiveness. In conclusion, ARHGAP30 regulated the PI3K/AKT/mTOR pathway to promote progression of OC.

In monotherapy, the pan-PI3K inhibitor BKM120 (activity against p110 alpha, beta, gamma, and delta isoforms) is able to induce growth inhibition and apoptosis in most of the melanoma models tested to date, whereas BYL719, an alpha-specific inhibitor, has limited antitumor activity as monotherapy...Initial in vivo test results (in ovo) on chick chorioallantoic membrane (CAM) showed reduced tumor burden and micrometastases by using the p110alpha-specific BYL719 in combination with trametinib...These data show that the combination of PI3K inhibitors with MEK inhibitors could be a new therapeutic option for melanoma patients. By using PI3Kα-selective inhibitors, potential side effects could be reduced compared to pan-PI3K inhibitors.

Treating these chordoma cells with palbociclib (CDK4/6 inhibitor), rapamycin (mTOR inhibitor) or the pan-PI3K inhibitor buparlisib significantly reduced cell viability. Synergistic effects were observed when combining palbociclib with rapamycin. In conclusion, we show that patients with PTEN-/p16-negative chordomas have poor prognoses and provide strong preclinical evidence that these patients might benefit from a Palbociclib/rapamycin combination treatment.

Totally, we initially identified the smoking-related epigenetic modifications in bladder cancer and constructed a corresponding prognostic model, which was also linked to disparate sensitivities to chemotherapeutics. Our findings would provide novel insights into the carcinogenesis, prognosis, and therapies in bladder cancer.

PI3K inhibitor buparlisib exerted selective activity against Lin-cKit+ NUP98-PMX1;Abl1-/- cells when compared to the Abl1 + /+ counterparts...Moreover, ABL1 kinase inhibitor enhanced the sensitivity to PI3K, DNA-PKcs and ATR inhibitors. In conclusion, we showed that ABL1 kinase plays a tumor suppressor role in hematological malignancies induced by AML1-ETO and NUP98-PMX1 and modulates the response to PI3K and/or DDR inhibitors.

P1a, N=63, Recruiting, Adlai Nortye Biopharma Co., Ltd. | Trial completion date: Nov 2022 --> Dec 2023 | Trial primary completion date: Sep 2022 --> Sep 2023

Of note, all tested combinations (venetoclax + PI3K inhibitors idelalisib or BKM-120, as well as AKT inhibitors MK-2206 or perifosine) achieved comparable anti-leukemic effects. The present study provides rational combination strategies involving selective BCL-2 and PI3K/AKT inhibition in B-ALL cell lines. Furthermore, we identified a potential mechanistic background of the synergistic activity of combined venetoclax and perifosine application.

Cells were challenged with: AKT inhibitor MK-2206; multikinase inhibitors Sorafenib, Lenvatinib and Dasatinib; PI3-kinase inhibitors BKM-120, Wortmannin, LY294002, and CAL-101; and mTOR inhibitor Rapamycin. Our studies show that the nine inhibitors differentially target ICC, ECC, and HCC/hepatoblastoma lines. Caution should be taken with Lenvatinib and Sorafenib administration in patients with cHCC/CC as the drugs may have no effects on, or might even stimulate, ICC.

Our analyses demonstrate that HRD can be detected reliably from panel sequencing data that are obtained as part of routine clinical care, and that this approach can identify patients beyond those with germline BRCA12 mut who might benefit from PARP inhibitors. Prospective clinical utility testing is warranted.

We also find that HOIP depletion sensitizes PCa cells to therapeutic agents BKM120 and Enzalutamide. Furthermore, the clinical data analyses confirm that HOIP is upregulated and positively correlated with AKT activation in PCa patient specimen, which may promote PCa progression and increase the risk of PCa biochemical relapse. Together, our study reveals a key role of PTEN M1-Ubi in regulation of AKT activation and PCa progression, which may propose a new strategy for PCa therapy.

We investigated the anti-tumor efficacy of two KRAS inhibitors BI-3406 (KRAS::SOS1 inhibitor) and sotorasib (KRAS G12C inhibitor) alone or in combination with MEK1/2 inhibitor trametinib and/or PI3K inhibitor buparlisib in seven PDAC cell lines. As well as directly involved in RAF/MEK/ERK pathway and PI3K/AKT pathway affect cell survival. Our current study confirmed inhibition of KRAS and its downstream pathways as a potential novel therapy for PDAC and provides fundamental data for in vivo evaluations.

KW-2478, buparlisib, and minocycline hydrochloride (MH) promoted maximal expression of the junctional protein β-catenin and induced 4T1 cells nucleus changes...MH was the most promising in preventing 4T1 migration and BBB disruption, tumour and endothelial cytoskeleton-associated proteins modifications, and miRNA deregulation. Our data revealed MH's ability to improve BBB properties, while compromising BCCs viability and interaction with BBB endothelial cells, besides restoring miRNAs' homeostasis, paving the way for MH repurposing for BCBM prevention.

P1, N=18, Completed, Kami Maddocks, MD | Active, not recruiting --> Completed

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.

Aims To characterize functional responses to 10 PI3Ki in CLL To study PI3Ki drug class activity in idelalisib-refractory CLL To investigate whether ex vivo drug sensitivity can predict in vivo treatment responses Methods CLL cells from patients that were treatment naïve (n=7), idelalisib refractory (n=9), or on idelalisib treatment (longitudinal samples from n=6 patients) were screened against 10 PI3Ki (buparlisib, compound 7n, copanlisib, duvelisib, idelalisib, nemiralisib, pictilisib, pilaralisib, umbralisib, ZSTK474), both alone and in combination with the B-cell lymphoma 2 (Bcl-2) antagonist venetoclax...Ex vivo drug testing on CLL cells from a patient who presented with relapsed disease after sequential treatment with FCR, ibrutinib, idelalisib and venetoclax revealed sensitivity to PI3Ki+venetoclax treatment...Conclusion Our findings indicate PI3Ki drug class activity in idelalisib-refractory CLL, and suggest that ex vivo drug sensitivity may guide precision medicine and predict treatment responses. These results warrant further testing in larger cohorts and in clinical trials.

In conclusion, the present study reveals the distinct antitumor effects of PI3K/AKT pathway inhibitors against PDAC cell lines. Aberrations in specific target genes, as well as KRAS and TP53, individually or together, affect the efficacy of the two PI3K/AKT pathway inhibitors.

This study identified that the Luminal androgen receptor subtype of triple-negative breast cancer with PIK3CA mutation may be targeted with PIK3CA inhibitors with a favorable outcome.

Furthermore, inhibition of USP28 via a small-molecule inhibitor resets the proteome of transformed cells towards a 'pre-malignant' state, and its inhibition synergises with clinically established compounds used to target EGFR -, BRAF - or PI3K -driven tumor cells. Targeting USP28 protein abundance at an early stage via inhibition of its activity is therefore a feasible strategy for the treatment of early-stage lung tumours, and the observed synergism with current standard-of-care inhibitors holds the potential for improved targeting of established tumors.

The three kinase inhibitors, osimertinib, erlotinib, and BKM120, all have evidence of some brain penetrance. In fact, several treatment combinations of EGFR/PI3K inhibitors and LSD1 inhibitors resulted in synergistic effects in multiple GSC lines.In summary, our results highlight the need for effective therapy combinations that can reduce the population of GSCs and avoid the adaptive resistance that is typical of kinase inhibitors. Future studies will focus on evaluating the efficacy and tolerability of the most promising treatment combinations in vivo using orthotopic xenograft models of the GSCs.

The aim of our study was to investigate the efficacy of PI3K/AKT/mTOR pathway inhibitors (PI3Ki) (alpelisib, buparlisib and gedatolisib) and CDK4/6 inhibitors (CDKi) (palbociclib and ribociclib) in HPV-positive and -negative HNSCC cell lines. The efficacy of the inhibitors was assessed using MTT assays and changes in PI3K and Cyclin D1/CDK pathway protein expression were determined by Western blotting. PI3Ki and CDKi efficiently inhibit their respective pathways and HNSCC cell growth in vitro, the latter only in HPV-negative cell lines. Whereas PI3Ki especially show an effect on oxidative and glycolytic metabolism, CDKi particularly lead to cell cycle arrest. Further research should elucidate whether these inhibitors may be effective therapeutic agents in HNSCC patients.

A patient-derived xenograft established from osimertinib-resistant patient revealed KRAS p.G12D mutation which could be overcome with combination of osimertinib, trametinib, and buparlisib. In this study, we explored the genetic profiles of osimertinib-resistant NSCLC patient samples using targeted deep sequencing. In vitro and in vivo models harboring osimertinib resistance revealed potential novel treatment strategies after osimertinib failure.

P1a, N=63, Recruiting, Adlai Nortye Biopharma Co., Ltd. | Trial primary completion date: Dec 2021 --> Sep 2022

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. 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.

Several biological agents have been studied in combination with PARP inhibitors, including inhibitors of vascular endothelial growth factor (vascular endothelial growth factor; bevacizumab, cediranib), AKT (capivasertib), PI3K inhibitors (buparlisib, alpelisib), epidermal growth factor receptor and BET inhibitors. In general, PARP inhibitor and biological agent combinations are well tolerated, and early data suggest that they are clinically effective in both BRCA1/2 mutant and wild-type cancers. In this review, we discuss multiple clinical trials that are underway examining the antitumor activity of the most promising combination strategies.