P2, N=35, Active, not recruiting, National Cancer Institute (NCI)

In conclusion, we developed a novel T cell exhaustion-associated signature, which holds considerable predictive value for both the prognosis of patients with HNSCC and the effectiveness of tumor immunotherapy.

TGX-221, a PIK3CB-selective inhibitor, which can block this signaling transduction pathway, was found to inhibit the growth of GC cells and induce apoptosis in vitro, implying that it may act as a potential development agent for GC. These collective findings provide a new insight into PI3K/AKT signaling that SP1 may function as an upstream factor on PI3K, forming a new signaling axis to promote the progression of GC or other malignancies.

Oral cancer patients with higher ZIC2 expression showed higher drug sensitivity to two compounds including AZD8186 and ERK_2240. We demonstrated the upregulation of ZIC2 in oral cancer and its promoting effect on the clinical advancement of oral cancer. The potential clinical value of ZIC2 in oral cancer deserves attention.

Low-score glioma patients were sensitive to AZD3759_1915, AZD5582_1617, AZD8186_1918, Dasatinib_1079, and Temozolomide_1375, while high-score patients were less sensitive to these drugs. Silencing COL8A1 inhibited the malignant characterization. Temozolomide and AZD3759 inhibited COL8A1 expression and cell viability and promoted apoptosis and parthanatos gene expression, which is a target to improve glioma.

P2, N=35, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Nov 2023 --> Nov 2024

P2, N=35, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Nov 2023 --> Nov 2024 | Trial primary completion date: Nov 2023 --> Nov 2024

P1, N=23, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2024 --> Sep 2024

The low-risk group was sensitive to the immune checkpoint PD-1 inhibitor, and the high-risk group exhibited lower inhibitory concentration values by 50% for 24 drugs, including AG.014699, AMG.706, and AZD6482. The prognostic stratification framework of patients with OS based on ARGs, such as BNIP3 and CXCL12, may lead to more efficient clinical management.

We hypothesized that GEMIN4 may be the potential target for the treatment of BLBC.

P1/2, N=27, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2025

CENPO was found to be positively associated with the expression levels of immune checkpoints and drug IC50 value (Roscovitine and TGX221), but negatively associated with the fraction levels of several immature cells and drug IC50 value (CCT018159, GSK1904529A, Lenaildomide, and PD-173074). The removal of CENPO significantly suppressed metastasis and induced arrest and apoptosis of LUAD cells. The involvement of CENPO in the immunosuppression of LUAD provides a prognostic signature for LUAD patients.

G6PD is highly expressed in gastrointestinal cancers. It is a carcinogenic indicator related to prognosis and can be used as a potential diagnostic marker of gastrointestinal cancers, so as to provide new strategy for cancer treatment.

This study elucidated the role and mechanism of BNIP3, PTGIS, and ZYX in OS progression and was well verified by the experimental results, enabling reliable prognostic means and treatment strategies to be proposed for OS patients.

Although the combination of AZD8186 and paclitaxel was well tolerated, limited clinical efficacy was observed.ClinicalTrials.gov Identifier: NCT04001569.

P1, N=21, Active, not recruiting, National Cancer Institute (NCI) | N=58 --> 21 | Trial completion date: Apr 2023 --> Mar 2024 | Trial primary completion date: Apr 2023 --> Jul 2022

In PTEN-present tumors, BYL719 (BYL, a PI3Kα inhibitor) synergized with αPD1 to delay tumor growth and extend survival (median survival of MC38-bearing mice in control (Ctrl), BYL, αPD1, and combination (Comb) groups: 30, 36, 33, and >45 respectively; p<0.05: Ctrl/BYL/αPD1 vs Comb). However, a limited combinatorial effect between GSK2636771(a PI3Kβ inhibitor) and αPD1 was observed in PTEN-present tumor models...Collectively, our results demonstrate that PI3Kα inhibitor can potentiate T cell-mediated antitumor immune responses regardless of PTEN status, providing a strong rationale for the clinical development of the BYL-based IO combination. In collaboration with Novartis, MD Anderson Cancer Center will launch a Phase I/II trial of the FDA-approved BYL in combination with αPD1 in advanced melanoma and breast cancer patients.

The sensitivity of 5-fluorouracil was positively correlated with VEGF-C, and the sensitivity of TGX221 was negatively correlated with VEGF-C. The activity of BI-2536 and BRD-A94377914 was positively correlated with VEGF-C. Novel LUAD prognostic biomarkers such as VEGF-C mRNA may aid diagnosis and treatment, and may help identify optimal LUAD populations for therapeutic treatments.

P1/2, N=27, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Dec 2022 --> Dec 2023

Moreover, AZD5363 and AZD8186 were the inhibitors of AKT and PI3K, respectively, and had lower IC50 and AUC in the low-score CSS group than it in the high-score CSS group. Besides, a scoring system based on CRGs can predict the efficacy of targeted drugs and immune response. These findings may improve our understanding of CRGs in LUAD and pave a new path for the assessment of prognosis and the development of more effective targeted therapy and immunotherapy strategies.

The PI3K inhibitors which are under clinical trial studies include GDC-0032, INK1117 for PI3K-α, and AZD8186 for PI3K-β. This review primarily focuses on the structural insights and structure anticancer activity relationship studies of recent PI3K inhibitors including their clinical stages of development and therapeutic values.

P2, N=35, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Nov 2022 --> Nov 2023

P2, N=35, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Nov 2022 --> Nov 2023

The combinatorial effect was seen also in the background of TP53 mutations and in epithelial-to-mesenchymal transformed cells. In conclusion, combinatorial ALK- and PI3Kβ-inhibitor treatment carries promise as a treatment for ALK-rearranged NSCLC.

We demonstrate that pan Bcl-2 family inhibition (ABT-263, rER: 1.52-1.56) or Bcl-xL specific inhibition (WEHI-539, A-1331852; rER: 1.31-2.00) radiosensitized wild-type PIK3CA/PTEN TNBC (MDA-MB-231, CAL-120) but failed to radiosensitize mutant PIK3CA/PTEN TNBC (rER: 0.90 - 1.07; MDA-MB-468, CAL-51, SUM-159). In vivo, ABT-263 or A-1331852 in combination with RT decreased tumor growth and increased tumor tripling time (p < 0.0001) in PIK3CA/PTEN wild-type TNBC cell line and patient-derived xenografts. Collectively, this study provides the preclinical rationale for early phase clinical trials testing the safety, tolerability, and efficacy of Bcl-xL inhibition and RT in women with wild-type PIK3CA/PTEN wild-type TNBC at high risk for recurrence.

The combined treatment with AZD8186 and the mTOR inhibitor AZD2014 overcame resistance to PI3Kβ/δ inhibition and completely prevented outgrowth of lymphoma cells in vivo in cell line- and patient-derived xenograft mouse models. Collectively, our study reveals that subsets of DLBCLs are addicted to PI3Kβ/δ signaling and thus identifies a previously unappreciated role of the PI3Kβ isoform in DLBCL survival. Furthermore, our data demonstrate that combined targeting of PI3Kβ/δ and mTOR is effective in all major DLBCL subtypes supporting the evaluation of this strategy in a clinical trial setting.

Parallel CRISPR screens in 3 PTEN-null breast cancer cell lines identified genes mediating resistance to capivasertib (AKT inhibitor) and AZD8186 (PI3Kβ inhibitor). The Mcl-1i + PI3Kβ/AKTi combination was effective across a panel of breast cancer cell lines with PIK3CA and PTEN mutations, and delivered increased anti-tumor benefit in vivo. This study demonstrates that different resistance drivers to PI3Kβi and AKTi converge to reactivate PI3K-AKT or mTOR signalling and combined inhibition of Mcl-1 and PI3K-AKT has potential as a treatment strategy for PI3Kβi/AKTi sensitive and resistant breast tumours.

Here, we demonstrate this workflow in a PTEN (phosphatase and tensin homolog) null breast cancer cell line (MDA-MB-468) exploring metabolic pathway activities in the absence and presence of the selective PI3Kβ inhibitor AZD8186...Besides pathways in central metabolism, known to be changed our workflow revealed additional pathways, like pyrimidine metabolism or hexosamine pathway. All pathways identified represent key metabolic processes associated with cancer metabolism and therapy.

In conclusion, m6A-related genes are important participants in LC and the expression levels of ZC3H13, CBLL1, ELAVL1 and YTHDF1 are significant for prediction and treatment of LC. Researches of drug resistance based on m6A-related genes need to pay more attention for producing new therapeutic strategies of LC and CBLL1 may contribute to target treatment for further research.

No-significant associations between the PPI dysreg magnitude of the drug-associated leading-edge genes and PIK3CA mutational status was observed (AZD6482 FDR=0.736 and A66 FDR=0.95). No significant genetic alteration, including PIK3CA mutational status, was identified between H/I-high and H/I-low groups. Thus, protein- protein interaction (PPI) dysregulation analysis identifies H/I-low BC tumors as those that are predicted to response to PIK3CA inhibitors independent of PIK3CA mutational status.

Notably, given the immunosuppressive and inflammatory microenvironment in HCC, we screened four candidate drugs, including dasatinib, vemurafenib, topotecan and AZD6482, and corroborated in two pharmacogenomics databases, which might have potential therapeutic implications in specific HCC patients. Our results enhanced the understanding of linkage in PD-L1 expression patterns with macrophages and inflammation, which may provide new insight into the pathogenic mechanisms and potential therapeutic strategy for HCC.

We found that AKT phosphorylation and PIK3CB mRNA data together performed better as a biomarker in predicting therapeutic response to p110β-selective inhibitors than each variable alone, specifically we found that AKT phosphorylation at T308 was negatively related to p110β-selective inhibitor AZD6482 sensitivity at low PIK3CB expression levels (B = -0.069, p = 0.0513) and this relationship disappeared at higher expression levels (B = 0.04, p = 0.176) with an interaction at near statistical significance (p = 0.0674). While AKT phosphorylation is currently used as a biomarker for PI3K pathway inhibitors, in this study, we demonstrate that both PIK3CB mRNA and AKT phosphorylation together was a significant biomarker in sensitivity to p110β inhibitors as compared to assessing each independently. Furthermore, PIK3CB was implicated in TMZ resistance in GBM as compared to other catalytic isoforms.

P2, N=400, Active, not recruiting, Yonsei University | Phase classification: P=N/A --> P2 | Trial completion date: Jun 2022 --> Dec 2022

Our results showed that CDRs modulate the AKT pathway in Hep3B cells. Since CDRs were not observed in other HCC and hepatocyte cell lines, we propose that CDRs in Hep3B would determine the carcinoma characteristic of the cell by aberrantly triggering the AKT pathway. Signaling molecules involved in CDR formation are promising therapeutic targets for some types of HCC. Video abstract.

Indeed, we detected increased activation of AKT accompanied by upregulation of MYC/BCL2 in post-therapy CLL cells from patients treated with idelalisib/ofatumumab. Interestingly, a stronger inhibitory effect of idelalisib on P-AKT (T308) than S473 was discernible in idelalisib-treated cells despite increased recruitment of PI3Kδ/PI3Kβ and accumulation of phosphatidylinositol-3,4,5-triphosphate; which could be attributed to reduced PDK1 activity. Thus, administration of isoform-specific inhibitors may prove more effective strategy for treating CLL patients.

The altered expression level shifts the primary function of SAA1 from cell cycle and mitosis to immune activity. High expression of SAA1 is associated with poor survival and upregulates the expression of LAIR1 and TNFSF14, thereby deeming it as the drug sensitivity indicator for XAV939, TGX-221, and lapatinib in GBM immune therapy.

We observed that KMT2A-r cell lines were more sensitive to 5-Fluorouracil (5FU), Gemcitabine (both antimetabolite chemotherapy drugs), WHI-P97 (JAK-3 inhibitor), Foretinib (MET/VEGFR inhibitor), SNX-2112 (Hsp90 inhibitor), AZD6482 (PI3Kβ inhibitor), KU-60019 (ATM kinase inhibitor), and Pevonedistat (NEDD8-activating enzyme (NAE) inhibitor). Moreover, IC50 data from analyses of ex-vivo drug sensitivity to small-molecule inhibitors reveals that Foretinib is a promising drug option for AML patients carrying FLT3 activating mutations. Thus, we provide novel and accurate options for the diagnostic screening and therapy of KMT2A-r leukemia, regardless of leukemia subtype.

We demonstrated the clinical utility of this integrated metabolic gene signature in LUAD by using it to guide repurposing of AZD-6482, a PI3Kβ inhibitor which significantly inhibited three genes from the 28-gene signature. Overall, we have integrated metabolomics and transcriptomics analyses to show that LUAD and LUSC have distinct profiles, inferred gene signatures with prognostic value for patient survival, and identified therapeutic targets and repurposed drugs for potential use in NSCLC treatment.

In the study reported here, a panel of five compounds targeting the catalytic subunits of the four class I PI3K isoforms (p110α, BYL-719 inhibitor; p110β, TGX-221 inhibitor; p110γ, CZC24832; p110δ, CAL-101 inhibitor) and the dual p110α/p110δ, AZD8835 inhibitor, were tested on the RMS cell lines RD, A204, and SJCRH30. When combined with CAL-101, BYL-719 decreased cell viability and induced apoptosis in a synergistic manner, equaling or surpassing results achieved with AZD8835. In conclusion, our findings indicate that BYL-719, either alone or in combination with the p110δ inhibitor, CAL-101, could represent an efficient treatment for human rhabdomyosarcoma presenting with aberrant upregulation of the PI3K signaling pathway.