作者: Giuliani, Francesco ; Lippolis, Anna Laura ; Messina, Raffaella ; Signorelli, Francesco ; Melaccio, Assunta ; Vitale, Pasquale ; Internò, Valeria ; Addeo, Raffaele ; Buonfantino, Massimo ; Spedaliere, Roberta

BACKGROUND AND OBJECTIVE:

The identification of mutation hot spots in the isocitrate dehydrogenase (IDH) genes is one of the most important cancer genome-wide sequencing discoveries with relevant impact in the treatment of some orphan tumors. These genes were mostly found mutated in lower-grade gliomas (LGGs), acute myeloid leukaemia (AML), myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPNs) and in cholangiocarcinoma. This aberrant genomic condition represents a therapeutic target of great interest in cancer research, especially in AML, given the limitations of currently approved therapies in this field. In this review, we investigate the role of IDH mutation and the mutant IDH (mIDH)- targeted therapies for cholangiocarcinoma and glioma.

METHODS:

Here, we provide an overview of the IDH mutation role and discuss its role in tumorigenesis and progression of some solid cancers, in which the therapeutic strategy can be completely changed thanks to these brand-new therapeutic options.

KEY CONTENT AND FINDINGS:

The encouraging early clinical data demonstrated to be a proof of concept for investigational mIDH1/2 inhibitors in tumors with a paucity of therapeutic possibilities.

CONCLUSIONS:

Moreover, we list the most important randomised clinical trials still active with their preliminary results.

2020-02-01·Molecular cancer therapeutics2区 · 医学

Dual mTORC1/2 Inhibition Sensitizes Testicular Cancer Models to Cisplatin Treatment

2区 · 医学

Article

作者: de Vries, Gerda ; Suurmeijer, Albert J.H. ; Gietema, Jourik A. ; de Jong, Steven ; Meersma, Gert Jan ; van Vugt, Marcel A.T.M. ; Rosas-Plaza, Ximena

Abstract:

Testicular cancer is the most common cancer type among young men. Despite highly effective cisplatin-based chemotherapy, around 20% of patients with metastatic disease will still die from the disease. The aim of this study was to explore the use of kinase inhibitors to sensitize testicular cancer cells to cisplatin treatment. Activation of kinases, including receptor tyrosine kinases and downstream substrates, was studied in five cisplatin-sensitive or -resistant testicular cancer cell lines using phospho-kinase arrays and Western blotting. The phospho-kinase array showed AKT and S6 to be among the top phosphorylated proteins in testicular cancer cells, which are part of the PI3K/AKT/mTORC pathway. Inhibitors of most active kinases in the PI3K/AKT/mTORC pathway were tested using apoptosis assays and survival assays. Two mTORC1/2 inhibitors, AZD8055 and MLN0128, strongly enhanced cisplatin-induced apoptosis in all tested testicular cancer cell lines. Inhibition of mTORC1/2 blocked phosphorylation of the mTORC downstream proteins S6 and 4E-BP1. Combined treatment with AZD8055 and cisplatin led to reduced clonogenic survival of testicular cancer cells. Two testicular cancer patient-derived xenografts (PDX), either from a chemosensitive or -resistant patient, were treated with cisplatin in the absence or presence of kinase inhibitor. Combined AZD8055 and cisplatin treatment resulted in effective mTORC1/2 inhibition, increased caspase-3 activity, and enhanced tumor growth inhibition. In conclusion, we identified mTORC1/2 inhibition as an effective strategy to sensitize testicular cancer cell lines and PDX models to cisplatin treatment. Our results warrant further investigation of this combination therapy in the treatment of patients with testicular cancer with high-risk relapsed or refractory disease.

2019-08-01·Molecular & cellular proteomics : MCP1区 · 生物学

Phosphoproteome Analysis Reveals Estrogen-ER Pathway as a Modulator of mTOR Activity Via DEPTOR

1区 · 生物学

Article

作者: Holz, Marina K ; Gritsenko, Marina A ; Liu, Tao ; Cuesta, Rafael ; Tsai, Chia-Feng ; McDermott, Jason E ; Shukla, Anil K ; Petyuk, Vladislav A

ER-positive breast tumors represent ∼70% of all breast cancer cases. Although their treatment with endocrine therapies is effective in the adjuvant or recurrent settings, the development of resistance compromises their effectiveness. The binding of estrogen to ERα, a transcription factor, triggers the regulation of the target genes (genomic pathway). Additionally, a cytoplasmic fraction of estrogen-bound ERα activates oncogenic signaling pathways such as PI3K/AKT/mTOR (nongenomic pathway). The upregulation of the estrogenic and the PI3K/AKT/mTOR signaling pathways are frequently associated with a poor outcome. To better characterize the connection between these two pathways, we performed a phosphoproteome analysis of ER-positive MCF7 breast cancer cells treated with estrogen or estrogen and the mTORC1 inhibitor rapamycin. Many proteins were identified as estrogen-regulated mTORC1 targets and among them, DEPTOR was selected for further characterization. DEPTOR binds to mTOR and inhibits the kinase activity of both mTOR complexes mTORC1 and mTORC2, but mitogen-activated mTOR promotes phosphorylation-mediated DEPTOR degradation. Although estrogen enhances the phosphorylation of DEPTOR by mTORC1, DEPTOR levels increase in estrogen-stimulated cells. We demonstrated that DEPTOR accumulation is the result of estrogen-ERα-mediated transcriptional upregulation of DEPTOR expression. Consequently, the elevated levels of DEPTOR partially counterbalance the estrogen-induced activation of mTORC1 and mTORC2. These results underscore the critical role of estrogen-ERα as a modulator of the PI3K/AKT/mTOR signaling pathway in ER-positive breast cancer cells. Additionally, these studies provide evidence supporting the use of dual PI3K/mTOR or dual mTORC1/2 inhibitors in combination with endocrine therapies as a first-line treatment option for the patients with ER-positive advanced breast cancer.

项与 CTPS1/2 inhibitors(Sygnature Discovery) 相关的新闻（医药）

2024-05-24

·PRNewswire

Antengene To Present One Oral and Four Abstracts at ASCO 2024

Oral Presentation：a Phase II study of ATG-008 (mTORC1/2 Inhibitor) combined with PD-1 antibody in patients with cervical cancer Three Poster presentations: Phase I/II studies of ATG-031 (anti-CD24 monoclonal antibody), ATG-022 (Claudin 18.2 antibody-drug conjugate), and selinexor (XPO1 Inhibitor) Journal Publication: the first-in-human Phase I dose-escalation study of ATG-017 (ERK1/2 inhibitor) in patients with advanced solid tumors SHANGHAI and HONG KONG, May 23, 2024 /PRNewswire/ -- Antengene Corporation Limited ( " Antengene ", SEHK: 6996.HK), a leading innovative, commercial-stage global biopharmaceutical company dedicated to discovering, developing and commercializing first-in-class and/or best-in-class medicines for cancer, today announced one oral presentation, three poster presentations and a journal publication at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, taking place from May 31st to June 4th at the McCormick Place Convention Center in Chicago, IL, the United States. Details of the Oral Presentation: ATG-008 (mTORC1/2 Inhibitor) Title: A phase I/II study of the TORC1/2 inhibitor onatasertib combined with toripalimab in patients with advanced solid tumors: Cervical cancer cohort Abstract: 5509 Session: Clinical Science Symposium – Stronger Together: Novel Combinations Across the Gynecologic Cancer Spectrum Date: June 1, 2024 Time: 1:15 PM - 2:45 PM (Central Daylight Time) 2:15 AM - 3:45 AM, June 2, 2024 (Beijing Time) 31 checkpoint inhibitor (CPI)-naïve cervical cancer patients who previously had at least one systemic line of chemotherapy were enrolled in the TORCH-2 study as of Oct 20th 2023. ATG-008 (Onatasertib; oral TORC1/2 inhibitor) combined with toripalimab (anti-PD-1 antibody) showed promising anti-tumor activity and acceptable tolerability in cervical cancer patients, achieving an overall response rate (ORR) of 53.3% and a disease control rate of 86.7%. In general, ATG-008 in combination with toripalimab are very well tolerated. The most common grade ≥ 3 treatment-related adverse events (TRAEs) included rash (12.9%), decreased lymphocyte count (9.7%), and decreased platelet count (6.5%). Encouraging response rates and disease stabilization were observed in patients, regardless of PD-L1 expression, with further data being collected in an ongoing expansion cohort for CPI-treated cervical cancer. Details of the Poster Presentations: ATG-031 (anti-CD24 monoclonal antibody) Title: A first-in-human phase I study of ATG-031, anti-CD24 antibody, in patients with advanced solid tumors or B-cell non-Hodgkin lymphomas (PERFORM) Abstract: TPS2691 Session: Developmental Therapeutics—Immunotherapy Date: June 1, 2024 Time: 9:00 AM - 12:00 PM (Central Daylight Time) 10:00 PM, June 1 - 1:00 AM, June 2, 2024 (Beijing Time) ATG-031 is a first-in-class CD24 antibody that promotes cancer cell phagocytosis and T cell activity by disrupting the CD24-Siglec-10 interaction on macrophages, while also triggering antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). The Phase I PERFORM study is designed to evaluate the safety and preliminary efficacy of ATG-031 in patients with advanced solid tumors or B-cell non-Hodgkin's lymphoma, employing a dose-escalation phase with a Bayesian Optimal Interval (BOIN) design and a dose-expansion phase with two or more dose levels to determine the recommended phase II dose (RP2D). As of April 2024, the study is underway in 4 U.S. sites, and the first dose level has been cleared. ATG-022 (Claudin 18.2 Antibody-drug Conjugate) Title: An open-label, multicenter, phase I study of ATG-022 in patients with advanced/metastatic solid tumors (CLINCH) Abstract: 3032 Session: Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology Date: June 1, 2024 Time: 9:00 AM - 12:00 PM (Central Daylight Time) 10:00 PM, June 1 - 1:00 AM, June 2, 2024 (Beijing Time) ATG-022 is a Claudin 18.2 (CLDN 18.2)-targeting antibody-drug conjugate (ADC) with sub-nM high affinity that showed promising tumor inhibition activity in vitro and in vivo. The CLINCH Phase I trial is assessing its safety, tolerability, and efficacy in patients with advanced/metastatic solid tumors. As of October 9th, 2023, 10 patients have been enrolled, receiving doses ranging from 0.3 to 2.4 mg/kg. The most common grade ≥ 3 TRAEs included nausea, vomiting, and decreased appetite, each occurring in 30% of patients. No dose-limiting toxicities (DLTs) were reported. Preliminary efficacy data among 7 gastric cancer patients across multiple doses in the Phase I dose escalation demonstrated one complete response (CR) in a patient with gastric cancer (2.4 mg/kg, CLDN 18.2-negative) and one partial response (PR) in another patient (1.8 mg/kg, CLDN 18.2 expression undetermined). ATG-022 demonstrated tolerability, safety, and potential anti-tumor activity. A Phase II trial is currently enrolling patients with gastric cancer and other solid tumors. Selinexor (XPO1 Inhibitor) Title: Selinexor combined with tislelizumab in patients with relapsed or refractory extranodal NK/T-cell lymphoma (R/R ENKTL): Results of dose-escalation of cohort C, from a multicenter, single-arm, phase I/II study (TOUCH) Abstract: 7065 Session: Hematologic Malignancies—Lymphoma and Chronic Lymphocytic Leukemia Date: June 3, 2024 Time: 9:00 AM - 12:00 PM (Central Daylight Time) 10:00 PM, June 3 - 1:00 AM, June 4, 2024 (Beijing Time) The Phase I/II TOUCH study is investigating selinexor combined with different drugs in relapsed/refractory extranodal NK/T-cell lymphoma (R/R ENKTL). Cohort C of the study aims to evaluate the safety, tolerability and preliminary efficacy of selinexor in combination with anti-PD-1 antibody tislelizumab. As of December 25th, 2023, 12 patients were enrolled, with no DLTs observed, and the maximum tolerated dose (MTD) was not reached. The most common adverse events included asthenia, neutropenia, and nausea/vomiting. Grade ≥ 3 adverse events occurred in 58.3% of patients. The ORR was 72.7% among 11 efficacy evaluable patients, including a CR rate of 36.4%. The combination showed a tolerable safety profile and promising efficacy. Details of the Journal Publication: ATG-017 (ERK1/2 Inhibitor) Title: Results of a first-in-human, dose-escalation phase I study of the ERK1/2 inhibitor ATG-017 in patients with advanced solid tumors Abstract: e15114 Session: Publication Only: Developmental Therapeutics – Molecularly Targeted Agents and Tumor Biology ATG-017, an oral and selective ERK1/2 inhibitor, was evaluated in a Phase I study to assess safety, pharmacokinetics, and MTD in patients with refractory advanced solid tumors. At the 20 mg BID level, no DLTs were observed, and pharmacokinetic analysis revealed effective ERK inhibition at this dose. Common treatment-emergent adverse events (TEAEs) were consistent with previously reported toxicities with other ERK pathway inhibitors (gastrointestinal, skin, and ocular adverse events). Efficacy data showed that one patient (4.8%) achieved a PR, while 8 patients (38%) achieved stable disease (SD). About Antengene Antengene Corporation Limited ( "Antengene", SEHK: 6996.HK) is a leading commercial-stage R&D-driven global biopharmaceutical company focused on the discovery, development, manufacturing and commercialization of innovative first-in-class/best-in-class therapeutics for the treatment of hematologic malignancies and solid tumors, in realizing its vision of "Treating Patients Beyond Borders". Since 2017, Antengene has built a pipeline of 9 oncology assets at various stages going from clinical to commercial, including 6 with global rights, and 3 with rights for the APAC region. To date, Antengene has obtained 29 investigational new drug (IND) approvals in the U.S. and Asia, and submitted 10 new drug applications (NDAs) in multiple Asia Pacific markets, with the NDA for XPOVIO® (selinexor) already approved in Mainland of China, Taiwan China, Hong Kong China, Macau China, South Korea, Singapore and Australia. Forward-looking statements The forward-looking statements made in this article relate only to the events or information as of the date on which the statements are made in this article. Except as required by law, we undertake no obligation to update or revise publicly any forward-looking statements, whether as a result of new information, future events or otherwise, after the date on which the statements are made or to reflect the occurrence of unanticipated events. You should read this article completely and with the understanding that our actual future results or performance may be materially different from what we expect. In this article, statements of, or references to, our intentions or those of any of our Directors or our Company are made as of the date of this article. Any of these intentions may alter in light of future development. For a further discussion of these and other factors that could cause future results to differ materially from any forward-looking statement, please see the other risks and uncertainties described in the Company's Annual Report for the year ended December 31, 2023, and the documents subsequently submitted to the Hong Kong Stock Exchange. For more information, please contact: Investor Contacts: Donald Lung E-mail: [email protected] Mobile: +86 18420672158 PR Contacts: Peter Qian E-mail: [email protected] Mobile: +86 13062747000 SOURCE Antengene Corporation Limited

临床1期临床结果ASCO会议免疫疗法临床2期

100 项与 CTPS1/2 inhibitors(Sygnature Discovery) 相关的药物交易

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