The main aims of this clinical study are to find out the maximum dose that can be given safely to patients, the potential side effects of the drug and how they can be managed and what happens to AZD3965 inside the body.
AZD3965 is a type of drug called a monocarboxylate transporter 1 inhibitor which is being used to stop the growth of cancer cells and kill cancer cells by blocking the action of one of the proteins involved in moving chemical compounds in and out of the cells of the body. This will be the first time that this type of drug has been given to patients.
The drug is a capsule and is taken daily. The study is in two parts. In Part 1 of the study, small groups of patients are treated at increasing doses to find the highest safe dose and best dose to give to patients in Part 2 of the study. It is planned that 40 patients will be entered into Part 1 of the trial.
In Part 2, the dose found to be safe in Part 1 is given to patients with diffuse large B-cell lymphoma (DLBCL) and Burkitt's lymphoma (BL). It is planned that 20 patients will be entered into Part 2 of the trial.
Patients will need to visit the hospital weekly for two months and then every fortnight. Patients will have regular blood and urine tests, scans, heart traces and eye tests amongst other clinical tests. Research blood samples will also be taken to look at what happens to the drug inside the body. Treatment is planned to be given for up to 6 months, but patients benefiting from treatment will be able to keep having it for as long as they continue to benefit. It is important to explain that this is the first study of this drug and patients will have advanced cancer so it is unlikely that patients will benefit directly from taking part but the study may help improve future treatment of cancer.

开始日期2013-04-23

申办/合作机构

Cancer Research UK

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100 项与 AZD-3965 相关的临床结果

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100 项与 AZD-3965 相关的转化医学

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100 项与 AZD-3965 相关的专利（医药）

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项与 AZD-3965 相关的文献（医药）

2024-10-01·The American Journal of Pathology

Lactate Contributes to Remote Ischemic Preconditioning–Mediated Protection Against Myocardial Ischemia Reperfusion Injury by Facilitating Autophagy via the AMP-Activated Protein Kinase–Mammalian Target of Rapamycin–Transcription Factor EB–Connexin 43 Axis

Article

作者: Zhang, Wei-Fang ; Shi, Hao ; Qu, Zhen-Sheng ; Du, Yun-Yan ; Wu, Zhi-Rong ; Yang, Zhang-Jian ; Jiang, Li-Ping ; Han, Xiao-Jian ; Jin, Qing-Qing

Remote ischemic preconditioning (RIPC) exerts a protective role on myocardial ischemia/reperfusion (I/R) injury by the release of various humoral factors. Lactate is a common metabolite in ischemic tissues. Nevertheless, little is known about the role lactate plays in myocardial I/R injury and its underlying mechanism. This investigation revealed that RIPC elevated the level of lactate in blood and myocardium. Furthermore, AZD3965, a selective monocarboxylate transporter 1 inhibitor, and 2-deoxy-d-glucose, a glycolysis inhibitor, mitigated the effects of RIPC-induced elevated lactate in the myocardium and prevented RIPC against myocardial I/R injury. In an in vitro hypoxia/reoxygenation model, lactate markedly mitigated hypoxia/reoxygenation-induced cell damage in H9c2 cells. Further studies suggested that lactate contributed to RIPC, rescuing I/R-induced autophagy deficiency by promoting transcription factor EB (TFEB) translocation to the nucleus through activating the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway without influencing the phosphatidylinositol 3-kinase-Akt pathway, thus reducing cardiomyocyte damage. Interestingly, lactate up-regulated the mRNA and protein expression of connexin 43 (CX43) by facilitating the binding of TFEB to CX43 promoter in the myocardium. Functionally, silencing of TFEB attenuated the protective effect of lactate on cell damage, which was reversed by overexpression of CX43. Further mechanistic studies suggested that lactate facilitated CX43-regulated autophagy via the AMPK-mTOR-TFEB signaling pathway. Collectively, this research demonstrates that RIPC protects against myocardial I/R injury through lactate-mediated myocardial autophagy via the AMPK-mTOR-TFEB-CX43 axis.

2024-10-01·American Journal of Physiology-Lung Cellular and Molecular Physiology

Enhanced glycolysis causes extracellular acidification and activates acid-sensing ion channel 1a in hypoxic pulmonary hypertension

Article

作者: Garcia, Selina M. ; Herbert, Lindsay M. ; Resta, Thomas C. ; Tuineau, Megan N. ; Jernigan, Nikki L.

In pulmonary hypertension, a metabolic shift to aerobic glycolysis drives a hyperproliferative, apoptosis-resistant phenotype in pulmonary arterial smooth muscle cells. We demonstrate that this enhanced glycolysis induces extracellular acidosis and activates the proton-gated ion channel, acid-sensing ion channel 1a (ASIC1a). Although multiple H+ transport/secretion mechanisms are upregulated in PHTN and likely contribute to extracellular acidosis, inhibiting glycolysis with 2-deoxy-d-glucose or syrosingopine effectively prevents extracellular acidification and ASIC1a activation, revealing a promising therapeutic avenue.

2024-08-01·Cell Biology International

7‐amino carboxycoumarin 2 inhibits lactate induced epithelial‐to‐mesenchymal transition via MPC1 in oral and breast cancer cells

Article

作者: Rathee, Meetu ; Umar, Sheikh Mohammad ; Kashyap, Akanksha ; Chauhan, Shyam S ; Dev, Arundhathi J R ; Prasad, Chandra Prakash ; Sharma, Atul

AbstractLactate is an oncometabolite that play important role in tumor aggressiveness. Lactate from the tumor microenvironment (TME) is taken up by cancer cells as an energy resource via mitochondrial oxidative phosphorylation (or OXPHOS). In the present study, by using an online meta‐analysis tool we demonstrated that in oral squamous cancer cells (OSCCs) glycolytic and OXPHOS governing genes are overexpressed, like in breast cancer. For experimental demonstration, we treated the OSCC cell line (SCC4) and breast cancer cells (MDA‐MB‐231) with sodium L‐lactate and analyzed its effects on changes in EMT and migration. For the therapeutic intervention of lactate metabolism, we used AZD3965 (an MCT1 inhibitor), and 7ACC2 (an MPC inhibitor). Like breast cancer, oral cancer tissues showed increased transcripts of 12 genes that were previously shown to be associated with glycolysis and OXPHOS. We experimentally demonstrated that L‐lactate treatment induced mesenchymal markers and migration of cancer cells, which was significantly neutralized by MPC inhibitor that is, 7ACC2. Such an effect on EMT status was not observed with AZD3965. Furthermore, we showed that lactate treatment increases the MPC1 expression in both cancer cells, and this might be the reason why cancer cells in the high lactate environment are more sensitive to 7ACC2. Overall, our present findings demonstrate that extracellular lactate positively regulates the MPC1 protein expression in cancer cells, thereby putting forward the notion of using 7ACC2 as a potential therapeutic alternative to inhibit malignant oxidative cancers. Future preclinical studies are warranted to validate the present findings.

项与 AZD-3965 相关的新闻（医药）

2023-03-28

·生物谷

高氧条件下通过抑制关键信号轴延缓肿瘤生长

为了帮助肿瘤生长和扩散，癌症细胞改变细胞外环境的化学成分，并通过释放代谢物、生长因子和趋化因子重新规划其微环境。反过来，微环境可以对癌症细胞施加各种非细胞自主压力，包括营养和缺氧以及细胞外空间酸化。为了帮助肿瘤生长和扩散，癌症细胞改变细胞外环境的化学成分，并通过释放代谢物、生长因子和趋化因子重新规划其微环境。反过来，微环境可以对癌症细胞施加各种非细胞自主压力，包括营养和缺氧以及细胞外空间酸化。癌症细胞对葡萄糖和谷氨酰胺的高需求和利用导致乳酸的过度生产和胞外转运，这被认为是导致肿瘤酸中毒的重要因素。正常细胞的细胞内pH（pHi）通常在~7.2左右，低于细胞外pH（pHe）~7.4。相比之下，癌症细胞通常表现出较高的pHi（>7.4）和较低的pHe（6.7-7.1）。这种特殊的pH平衡在肿瘤发展中的详细作用尚不清楚，但最新证据表明，它可能与癌症细胞增殖、避免凋亡、缺氧适应和细胞外基质重塑有关。图片来源：https://doi.org/10.1016/j.redox.2023.102647 近日，来自同济大学的研究者们在Redox Biol.杂志上发表了题为“Long-term exposure to house dust mites accelerates lung cancer development in mice”的文章，该研究显示，高氧可以抑制MYC/MCT1轴，并导致乳酸的积累和细胞内酸化，从而延缓肿瘤生长和转移。吸入性高氧（IH）在肿瘤学中的风险和前景仍有争议，尤其是对于癌症患者。越来越多的证据表明，高氧暴露与肿瘤微环境有关。然而，IH在癌症细胞酸碱平衡中的具体作用尚不清楚。本研究在H1299和A549细胞中系统地评估了60%氧气暴露对细胞内外pH值的影响。研究结果表明，高氧暴露会降低细胞内pH值，这可能会降低癌症细胞的增殖、侵袭和上皮-间充质转化。RNA测序、蛋白质印迹和PCR分析表明，单羧酸盐转运蛋白1（MCT1）在60%的氧气暴露下介导H1299和A549细胞的细胞内乳酸积累和细胞内酸化。体内研究进一步证明，MCT1基因敲除可显著降低癌症的生长、侵袭和转移。萤光素酶和ChIP-qPCR测定的结果进一步证实了MYC是MCT1的转录因子，并且PCR和Western印迹测定证实了在高氧条件下MYC被下调。 MCT1敲低可抑制体内肺肿瘤的生长和转移。图片来源：https://doi.org/10.1016/j.redox.2023.102647 综上所述，高氧暴露可以抑制MYC/MCT1轴，导致乳酸积累和细胞内酸化，这与癌症的生长和转移密切相关。本研究是对pHi直接靶向治疗癌症可行性的一次突破性尝试，为IH联合AZD3965治疗肺癌提供了理论依据。（生物谷 Bioon.com）参考文献 Xiucheng Liu et al. Hyperoxia induces glucose metabolism reprogramming and intracellular acidification by suppressing MYC/MCT1 axis in lung cancer. Redox Biol. 2023 ay;61:102647. doi: 10.1016/j.redox.2023.102647.

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01791595 (CTgov)	临床1期	实体瘤 \| 伯基特淋巴瘤 \| 弥漫性大B细胞淋巴瘤 \| 晚期癌症	53	AZD3965 (AZD3965 Cohort 1 (5 mg OD))	鬱範簾範築淵蓋鏇積醖(齋願淵願鑰鏇構積積餘) = 遞糧鬱艱顧簾鑰築壓憲鏇齋窪顧範廠獵壓遞製 (鹹鹹築簾鑰獵窪觸網糧, 艱夢壓觸齋醖衊餘鬱襯 ~ 選製獵鹽廠顧憲膚糧襯) 更多	-	2022-04-11
NCT01791595 (CTgov)	临床1期	实体瘤 \| 伯基特淋巴瘤 \| 弥漫性大B细胞淋巴瘤 \| 晚期癌症	53	AZD3965 (AZD3965 Cohort 2 (10 mg OD))	鬱範簾範築淵蓋鏇積醖(齋願淵願鑰鏇構積積餘) = 構網鬱齋網襯艱網選鏇鏇齋窪顧範廠獵壓遞製 (鹹鹹築簾鑰獵窪觸網糧, 觸鹹網醖餘夢憲鑰夢淵 ~ 夢獵繭製鏇簾網襯構網) 更多	-	2022-04-11
NCT01791595 (ASCO2021)	临床1期	伯基特淋巴瘤 \| 弥漫性大B细胞淋巴瘤	11	AZD3965 10mg bd	(憲艱鏇憲憲觸遞蓋衊獵) = no serious events of anaemia were seen, with one non-clinically significant episode of grade 3 anaemia reported 夢艱鑰鑰衊鏇獵鑰網壓 (簾醖築艱築夢餘齋餘窪 ) 更多	积极	2021-05-28
NCT01791595 (ASCO2017)	临床1期	晚期恶性实体瘤	35	AZD3965	(鏇鑰壓築蓋獵憲衊選衊) = 壓獵觸醖鬱製遞餘顧衊顧遞餘餘襯製蓋齋膚願 (夢遞淵艱鑰膚願餘艱遞 )	-	2017-05-30