This study aims to comprehensively characterize ACOX3 as a novel pan-cancer biomarker by assessing its expression heterogeneity, clinical relevance, tumor-immune interactions and therapeutic potential across multiple cancer types.

METHODS:

The multi-omics analyses of the ACOX3 expression pattern were performed. Prognostic and diagnostic significance was evaluated by Cox regression, Kaplan-Meier survival and ROC analyses. Immune correlates were assessed in terms of immune cell infiltration, checkpoint and immunomodulatory activity. Drug sensitivity was predicted through molecular docking and molecular dynamics simulations to evaluate binding affinity and complex stability. Experimental validation was conducted in HNSCC cell lines.

RESULTS:

ACOX3 was significantly upregulated in KICH, PRAD and THCA, and downregulated in COAD, HNSCC, KIRP, LIHC and STAD. The OS Cox regression showed high ACOX3 expression was associated with a favorable prognosis in HNSCC but poor outcomes in LGG and UVM. The ROC curves showed that the AUC for ESCA, GBM, OV, PAAD, STES and WT exceeded 0.8. ACOX3 expression positively correlated with CD4⁺T, CD8⁺T and NK cells in HNSCC. Single-cell and spatial transcriptomics revealed ACOX3 enrichment in malignant regions, particularly in CD4⁺T, CD8⁺T and CD8⁺Tex cells. Drug screening prioritized AZD6482 and TGX-221 as high-affinity ACOX3 inhibitors, and the AZD6482 showed stable binding in MD simulations. Functional experiments confirmed that ACOX3 overexpression suppressed HNSCC cell proliferation, invasion and migration.

CONCLUSION:

ACOX3 represents a dual diagnostic and prognostic biomarker with broad pan-cancer relevance, exhibiting distinct immune correlates and therapeutic potential.

2025-06-01·APOPTOSIS

Migrasome-related ITGA5 for predicting prognosis, immune infiltration and drug sensitivity of hepatocellular carcinoma

Article

作者: Zhang, Hui ; Gao, Tingting ; Wang, Zhiling ; Liu, Yuting ; Cheng, Shengtao ; Su, Xiameng ; Chen, Xinyan ; Gu, Leirong ; Liu, Kailin ; Chen, Wanjin ; Tan, Ming

To clarify the biological functions and prognostic significance of migrasome-related integrin subunit alpha 5 (ITGA5) in hepatocellular carcinoma (HCC). We used The Cancer Genome Atlas datasets and RNA-seq data from nine sets of paired HCC and adjacent normal tissues to identify key migrasome-related genes through a comprehensive analysis and weighted correlation network analysis. We then confirmed their roles in HCC through analyses of gene mutations, methylation, and immune cell infiltration, as well as molecular docking, molecular dynamics, and cell experiments. A comprehensive analysis of migrasome-related genes showed that ITGA5 was a critical gene related to HCC, and it is highly expressed in HCC tissues, which is related to poor prognosis. Further enrichment analysis revealed that ITGA5 is involved in many pathways related to tumor occurrence and metastasis, such as the PI3K-AKT pathway. In addition, ITGA5 was found to be expressed in multiple types of immune cells and was closely associated with immune infiltration. Drug sensitivity, molecular docking, and molecular dynamics analyses indicated that ITGA5 may enhance the sensitivity of HCC to drug TGX221. Finally, cell phenotype experiments confirmed that ITGA5 knockdown suppressed the proliferation, migration, and invasion of HCC cells, and while overexpression exacerbated malignant phenotypes. Our analyses showed that ITGA5 is a key migrasome-related gene involved in the proliferation and metastasis of HCC that has promise as a therapeutic target and candidate prognostic indicator.

2024-05-01·Heliyon

Dual blockage of PI3K-mTOR and FGFR induced autophagic cell death in cholangiocarcinoma cells

Article

作者: Kongpetch, Sarinya ; Kukongviriyapan, Veerapol ; Mahaamnad, Narumon ; Prawan, Auemduan ; Pocasap, Piman ; Senggunprai, Laddawan

Purpose:

To assess the impact of concurrent inhibition of the FGFR and PI3K/mTOR signaling pathways on oncogenic characteristics in cholangiocarcinoma (CCA) cells, including proliferation, autophagy, and cell death.

Materials and methods:

KKU-213A, KKU-100, and KKU-213C cells were treated with either infigratinib or PKI-402 alone or in combination. Cell viability and cell death were evaluated using the sulforhodamine B (SRB) assay and acridine orange/ethidium bromide (AO/EB) staining. Cell cycle progression and apoptotic cell death were analyzed by flow cytometry. Western blotting was performed to assess the expression of proteins involved in cell cycle regulation and autophagy. Additionally, AO staining was employed to assess autophagic induction.

Results:

The combination of infigratinib and PKI-402 showed a remarked synergistic suppression in cell viability in both CCA cell lines compared to treatment with single inhibitors. This antiproliferative effect was associated with cell cycle arrest in the G2-M phase and a decrease in the expression of cyclin A and cyclin B1 in CCA cells. Furthermore, the combination treatment induced apoptotic cell death to a greater extent than treatment with a single inhibitor. Infigratinib enhanced the induction of autophagy by PKI-402, as evidenced by marked increases of autophagic vacuoles stained acridine orange, levels of LC3B-II and suppression of levels of p-mTOR and. Notably, inhibition of autophagic flux by chloroquine prevented cell death induced by the combination treatment.

Conclusions:

This study demonstrated that concurrent inhibition of the key FGFR/PI3K/mTOR pathways in CCA carcinogenesis enhances the suppression of CCA cells. The present findings indicate potential clinical implications for using combination treatment modalities in CCA therapy.

项与 PKI-402 相关的新闻（医药）

2025-12-28

·有驾

癌症治疗新希望：PI3K抑制剂的多样性及研究进展

PI3K与癌症治疗 PI3K信号通路的重要性 PI3K，作为一种关键的胞内磷脂酰肌醇激酶，与Src和RAS等癌基因产物紧密相关。该信号通路在人类癌症中频繁被激活，甚至牵涉到约半数恶性肿瘤的发病机制。众多研究揭示，PI3K信号通路的过度活跃会显著推动肿瘤的进展、提升肿瘤微血管密度，以及增强癌细胞的趋化性和侵袭性。因此，PI3K已成为治疗多种恶性肿瘤的关键靶点，涵盖乳腺癌和滤泡性淋巴瘤等众多疾病。尽管如此，针对PI3K的选择性抑制剂研发仍面临诸多挑战，尤其是毒性问题，这在一定程度上限制了其临床应用。尽管如此，全球范围内已经批准了五款PI3K抑制剂，为癌症治疗带来了新的希望。 PI3K抑制剂的种类与挑战泛PI3K抑制剂泛PI3K抑制剂，作为三磷酸腺苷（ATP）的竞争性抑制剂，能够同时阻断所有四种I类亚型，从而为限制癌细胞增殖和存活提供了有效手段（见图2）。但这类抑制剂往往缺乏选择性，可能导致整个通路受到非选择性抑制，进而引发严重的不良反应。 Wortmannin和LY294002是第一代泛PI3K抑制剂的代表。尽管LY294002在选择性和稳定性方面仍存在诸多不足，其在50μM的浓度下对PI3Kα、β、γ和δ四种亚型的活性展现出了显著的抑制作用。相比之下，buparisib克服了一些限制，是一种口服生物可利用的I类泛PI3K抑制剂，能够有效地抑制PI3Kα、β、γ和δ亚型。 PI3K异构体选择性抑制剂针对特定PI3K亚型的抑制剂，提高了安全性和效率。PI3Kα选择性抑制剂包括Serabelisib和Inavolisib，它们在体外研究中对细胞增殖和凋亡有显著的阻断效果。其中，Serabelisib能有效阻断细胞增殖和凋亡，而Inavolisib通过阻碍突变的PI3K信号通路和细胞活力，导致突变p110α蛋白降解。 PI3Kβ选择性抑制剂的目标是针对其在抗血栓及抗肿瘤治疗中的特性。TGX-221及其r-异构体TGX-221-R显示出对PI3Kβ的选择性抑制活性。GSK2636771和SAR260301也在临床试验中取得了一定的进展。 PI3Kγ选择性抑制剂在炎症、呼吸和代谢疾病以及癌症等疾病的治疗中有了显著的发现。喹唑啉-噻唑烷衍生物AS605240和三唑吡啶衍生物CZC24832都是有效的选择性PI3Kγ抑制剂。 PI3Kδ选择性抑制剂在血液系统恶性肿瘤和免疫疾病的治疗中展现出潜力。Idelalisib是首个有效的口服选择性抑制剂，对B细胞、T淋巴细胞、肥大细胞及中性粒细胞的PI3K/PKB/mTOR信号通路至关重要。双重PI3K抑制剂及应用双重PI3K抑制剂如Pictilisib在临床试验中展现潜力，为不同癌症提供新治疗选择。在PI3K异构体双重抑制剂中，口服活性Pictilisib和Duvelisib（IPI-145）能够有效抑制两种PI3K异构体，显示出明确的临床应用前景。研究进展与临床试验目前，PI3K抑制剂在临床试验中取得进展，新药研发聚焦于提高安全性和有效性。全球范围内，已有五款PI3K抑制剂获得批准，它们分别是吉利德的idelalisib、拜耳的copanlisib（Zydelig）等，为患者带来了新的治疗选择。新药研发正致力于优化药代动力学特征和毒性特点，以期提供更为安全有效的临床用药方案。正处于临床阶段的多种泛PI3K抑制剂，正在为癌症治疗提供更多选择。

临床结果临床终止

2025-01-30

·PMLiVE

Roche shares positive overall survival results for Itovebi in advanced breast cancer

Roche has shared positive top-line overall survival results from a late-stage study of its oral PI3K inhibitor Itovebi (inavolisib) in a subset of advanced breast cancer patients. The phase INAVO120 trial has been evaluating the drug in combination with Pfizer’s CDK4/6 inhibitor Ibrance (palbociclib) and AstraZeneca’s hormone therapy Faslodex (fulvestrant) in patient with PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, endocrine-resistant, locally advanced or metastatic breast cancer. Approximately 56,800 new breast cancer cases are diagnosed in the UK every year, and HR-positive disease is the most prevalent subtype. The PI3K signalling pathway is commonly dysregulated in HR-positive breast cancer, often due to activating PIK3CA mutations, which are considered to be a potential mechanism of resistance to standard-of-care hormone therapy in combination with CDK4/6 inhibitors. Results from INAVO120 previously reported by Roche showed that the Itovebi-based regimen reduced the risk of disease worsening or death by 57% compared with Ibrance and Faslodex alone in the first-line setting. The company has now announced that the trial met its secondary endpoint, with the triplet therapy demonstrating a statistically significant and clinically meaningful overall benefit versus Ibrance and Faslodex alone. Levi Garraway, Roche’s chief medical officer and head of global product development, said: “The INAVO120 overall survival results show that the Itovebi-based regimen not only delayed disease progression, but also helped people with advanced HR-positive, PIK3CA-mutated breast cancer live longer. “These findings underscore our ambition to improve survival rates for people with breast cancer. The Itovebi-based regimen has the potential to become the new standard of care for these patients.” The announcement comes just three months after the US Food and Drug Administration approved the Itovebi regimen based on results from INAVO120. Data from the trial is being reviewed by other global health authorities, including the European Medicines Agency. Garraway said at the time of the October authorisation: “Despite the high prevalence of PIK3CA mutations in this setting, treatment options have thus far remained limited, which makes [this] approval all the more significant.” Itovebi is also currently being evaluated in various combinations across three additional late-stage studies in PIK3CA-mutated locally advanced or metastatic breast cancer.

临床结果临床3期临床2期

2023-10-02

·BioPharmaDive

Adlai Nortye IPO gives old Novartis cancer drug new life

Brief: Cancer drug developer Adlai Nortye on Thursday raised $57.5 million in an initial public offering, becoming the 16th biotechnology company to debut on a U.S. stock exchange this year, according to BioPharma Dive data. The company sold 2.5 million shares at $23 apiece — a smaller offering than it had pitched in early August. Nippon Kayaku, a licensing partner and Japan-based pharmaceutical manufacturer, also agreed to acquire $40 million in additional shares in a concurrent private financing deal, according to a regulatory filing. The offering will fund the development of a targeted cancer drug once owned by Novartis. That medicine, formerly known as buparlisib and now AN2025, is in late-stage trials for a form of head and neck cancer and in earlier testing against other solid tumors. Insight: Near the end of the last decade, Novartis had two similar drugs advancing through clinical development. Known as PI3 kinase inhibitors because of the enzyme they target, the drugs steadily moved through human testing. One, Piqray, has since reached market, winning regulatory approval in 2019 for certain breast cancer patients. It’s been modestly successful, generating $373 million in worldwide sales last year. In 2018, Novartis offloaded the other, buparlisib, to Adlai Nortye, then a privately held China-based startup . Novartis did so despite having studied buparlisib in dozens of trials and over 4,200 patients. Among them was a Phase 3 study in a common form of breast cancer that met its main goal, but revealed safety issues that “[did] not support its further development” in that setting, wrote investigators in a paper published in Lancet Oncology in December 2017. Novartis licensed buparlisib to Adlai Nortye for only $9.5 million upfront in a heavily backloaded deal, according to the biotech’s IPO filing. Novartis still stands to receive additional milestone payments and, if the drug is approved, sales royalties. Adlai Nortye has focused on buparlisib’s potential in different settings and in combination with other drugs. The furthest along is a late-stage study testing the drug and chemotherapy in people whose head and neck cancers have progressed after a commonly used immunotherapy. The company, which operates in China and the U.S. through subsidiaries owned by a Cayman Islands holding company, will report findings next year. It claims it could file for an accelerated approval afterwards if results are positive. The biotech is also evaluating buparlisib’s use in solid tumors with so-called PIK3CA mutations, the group for which Piqray is approved for use in breast cancer. The Food and Drug Administration has recently stepped up scrutiny of PI3K inhibitors due to safety concerns that emerged during testing in certain blood cancers. A panel of experts earlier this year voted to raise the approval standards for the medicines, at least when considering broader use in lymphomas and leukemias. Adlai Nortye’s stock offering, which the company initially set plans for in late July, follows positive signs for what has otherwise been a moribund IPO market this year. Earlier this month, RayzeBio and Neumora Therapeutics successfully pulled off lucrative IPOs amid a flurry of activity that also saw chip designer ARM and the grocery delivery company Instacart price offerings. The content comes from the Internet. If there is any infringement, please contact us for deletion.