The current understanding of PR104 justifies the evaluation of PR104 in subjects with relapsed/refractory AML and ALL. These include:
* Hypoxia. Leukemic bone marrow is likely to demonstrate a level of hypoxia sufficient to activate PR104 to its active metabolites PR104H and PR104M.
* Myelotoxicity as the primary toxicity at MTD. In prior clinical studies in subjects with solid tumors PR104 has demonstrated myelotoxicity as the primary toxicity. This observation suggests that PR104 will exert a similar effect on leukemic cells.
* AKR1C3. AML has been reported to exhibit high levels of AKR1C3 which should lead to selective activation of PR104 within both hypoxic and oxic leukemic cells.
* Preclinical data. PR104 has demonstrated impressive activity in an initial study using primary human ALL in a mouse model.
The initial dose finding phase of the study will provide estimates of the activity and toxicity of PR104 in subjects with refractory/relapsed AML, and determine the optimal individualized dose to give each subject based on his/her covariates (prior CR duration, prior number of salvage therapies, age). Once a potentially beneficial dose has been determined, an expanded cohort of subjects with AML or ALL will receive PR104 at a uniform dose. This information will prove valuable in defining the future clinical development of PR104, and in determining if PR104 has sufficient activity and acceptable safety in AML to warrant future phase II or phase III studies in this indication.
Primary objectives
* Determine the toxicities and recommended dose of PR104 when administered IV to subjects with relapsed/refractory AML and ALL.
Secondary objectives
* Evaluate the pharmacokinetics (PK) of PR104 and a series of PR104 metabolites
* Evaluate any anti-tumor effects of PR104
* Evaluate the expression of AKR1C3 in bone marrow and leukemic cells
* Evaluate potential biomarkers of hypoxia

开始日期2010-01-01

申办/合作机构

Proacta, Inc.

NCT00862082

/ Terminated临床1/2期

A Randomized Phase I/II, Multi-Center, Open-Label Trial of PR104 and Sorafenib in Patients With Advanced Hepatocellular Carcinoma

The current understanding of PR104 justifies the evaluation of PR104 with sorafenib in patients with hepatocellular carcinoma. These include:
* Hypoxia. Hepatocellular Carcinoma (HCC) is likely to demonstrate a level of hypoxia sufficient to activate PR104 to its active metabolites PR104H and PR104M. In addition, in preclinical models, sorafenib has been demonstrated to increase the degree of hypoxia in tumors following treatment.
* Non-overlapping toxicity. PR104 and sorafenib do not share major toxicities. It is anticipated that both drugs can be administered at their full single agent dose when used in combination.
* Aldo-keto reductase 1C3 (AKR1C3). HCC has been shown to express high levels of AKR1C3 which should lead to selective activation of PR104 within both hypoxic and oxic HCC cells.
* Preclinical data. The use of sorafenib and PR104 alone and in combination in a hepatocellular carcinoma model demonstrates activity of PR104 as a single agent and increased activity when PR104 and sorafenib are used in combination.
The current study will provide an estimate of the activity of PR104 in subjects with HCC. This information will prove valuable in defining the future clinical development of PR104, and in determining if PR104 has sufficient activity in HCC to warrant a larger phase III registration study in this indication.
Primary objectives
* Phase I: Determine the maximum tolerated dose (MTD) of PR104 when used in combination with standard dose sorafenib
* Phase II: Estimate the response rate (RR) of PR104/sorafenib [Note: Phase II was never initiated]
Secondary objectives
* Evaluate survival
* Evaluate Progression Free Survival (PFS)
* Evaluate time to progression (TTP)
* Evaluate safety
* Evaluate the pharmacokinetics (PK) of sorafenib, PR104 and PR104 metabolites
* Collect diagnostic biopsy samples for the determination of aldo-keto reductase 1C3
* Collect plasma samples for assessment of potential biomarkers of tumor hypoxia

开始日期2009-03-01

申办/合作机构

Proacta, Inc.

NCT00862134

/ Terminated临床2期

A Randomized Phase II, Multi-Center, Open-Label Trial of PR104 and Docetaxel in Patients With Advanced Non-Small Cell Lung Cancer

The current understanding of PR104 justifies the evaluation of PR104 with docetaxel in subjects with Non Small Cell Lung Cancer (NSCLC). These include:
* Aldo-keto reductase 1C3 (AKR1C3). NSCLC has been shown to express high levels of AKR1C3 in about one half of tumors tested. Subjects with high levels of AKR1C3 should have increased activation of PR104 within their tumor.
* Hypoxia. NSCLC has been demonstrated to be a tumor with hypoxia based on both direct tumor measurements (oxygen electrodes) and hypoxic positron emission tomography (PET) imaging. Tumor hypoxia in NSCLC should be sufficient to activate PR104 to its active metabolites PR104H and PR104M.
* Preclinical data. The use of docetaxel and PR104 alone and in combination in preclinical models demonstrates activity of PR104 as a single agent and supraadditive activity when PR104 and docetaxel are used in combination.
* Manageable toxicity. PR104 and docetaxel with Granulocyte Colony-stimulating Factor (G-CSF) have been combined in a prior phase I study. A Maximum Tolerated Dose (MTD) has been identified and the major toxicities of this combination are understood.
The current study will provide an estimate of the activity of PR104 in subjects with NSCLC. This information will prove valuable in defining the future clinical development of PR104, and in determining if PR104 has sufficient activity in NSCLC to warrant a larger phase III registration study in this indication.
Primary objectives
• Estimate the response rate (RR) of PR104/docetaxel
Secondary objectives
* Evaluate survival
* Evaluate progression free survival (PFS)
* Evaluate time to progression (TTP)
* Evaluate safety
* Evaluate the pharmacokinetics of PR104 and its metabolites
* Evaluate the pharmacokinetics of docetaxel
* Evaluate the tumor hypoxia using 18F-fluoromisonidazole (18F-MISO) PET imaging
* Collect diagnostic biopsy samples for the determination of AKR1C3
* Collect plasma samples for assessment of potential biomarkers of tumor hypoxia

开始日期2009-03-01

申办/合作机构

Proacta, Inc.

100 项与 PR-104 相关的临床结果

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100 项与 PR-104 相关的转化医学

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100 项与 PR-104 相关的专利（医药）

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项与 PR-104 相关的文献（医药）

2025-01-17·MEDICINE

Osteosarcoma biomarker analysis and drug targeting prediction based on pyroptosis-related genes

Article

作者: Yuxiang Zhuang ; Xiaofeng Li

Osteosarcoma is a malignant bone tumor originating from mesenchymal tissue. Recent studies have found that the tumor inflammatory microenvironment plays an important role in promoting the malignant characteristics and metastatic potential of malignant tumors. Pyroptosis, an inflammatory programmed cell death, elicits immune responses that exhibit anti-tumor effects through released factors and contents. Therefore, improving anti-tumor immunity by targeting osteosarcoma-related pyroptosis genes and pathways may be of great significance in delaying early metastasis of osteosarcoma and improving patient survival rate. The study aimed to identify pyroptosis-related genes and biomarkers in osteosarcoma, predicting therapeutic drugs targeting these genes. Gene expression profiles of osteosarcoma were retrieved from Gene Expression Omnibus and cross-referenced with GeneCards and Comparative Toxicogenomics Database to identify differentially expressed pyroptosis-related genes. We conducted enrichment analysis on intersecting genes to identify their biological processes and signaling pathways and assessed immune cell composition in the tumor microenvironment through immune infiltration analysis. In addition, we further utilized Cytoscape software to screen out the top 10 genes with Degree values among the intersected genes as hub genes and performed GSEA analysis and drug prediction based on the hub genes. A total of 22 differentially expressed pyroptosis-related genes were identified in osteosarcoma, with 10 of them (TP53, CYCS, IL-1A, IL-1B, IL-18, CASP-3, CASP-8, IL-6, TNF, CASP-1) pinpointed as hub genes. Enrichment analysis found that the 22 intersection genes are mainly associated with pyroptosis, apoptosis, immune regulation, and related biological processes. The results of data validation targeting hub genes suggest that IL-18, CASP-1, and CASP-8 may be key genes involved in the regulation of pyroptosis in osteosarcoma. Immune infiltration analysis shows statistical differences in the distribution of immune cells like naive B cells, monocytes, M2 macrophages, and dendritic/mast cells, suggesting they play a role in the osteosarcoma tumor microenvironment. Hub gene drug targets suggest Triethyl phosphate, Plinabulin, and Siltuximab as potential osteosarcoma treatments. Our findings suggest potential mechanisms of action for 22 pyroptosis-related genes in osteosarcoma and preliminarily predicted that the occurrence of osteosarcoma is closely related to pyroptosis, apoptosis, and immune regulation. Predicted Triethyl phosphate, Plinabulin, Siltuximab as potential osteosarcoma treatments.

2022-02-01·Cancer gene therapy2区 · 医学

Use of an optimised enzyme/prodrug combination for Clostridia directed enzyme prodrug therapy induces a significant growth delay in necrotic tumours

2区 · 医学

Article

作者: Kubiak, Aleksandra M ; Smaill, Jeff B ; Theys, Jan ; Ackerley, David F ; Lambin, Philippe ; Guise, Christopher P ; Chan-Hyams, Jasmine V E ; Dubois, Ludwig J ; Ashoorzadeh, Amir ; Mowday, Alexandra M ; Minton, Nigel P ; Patterson, Adam V

Necrosis is a typical histological feature of solid tumours that provides a selective environment for growth of the non-pathogenic anaerobic bacterium Clostridium sporogenes. Modest anti-tumour activity as a single agent encouraged the use of C. sporogenes as a vector to express therapeutic genes selectively in tumour tissue, a concept termed Clostridium Directed Enzyme Prodrug Therapy (CDEPT). Here, we examine the ability of a recently identified Neisseria meningitidis type I nitroreductase (NmeNTR) to metabolise the prodrug PR-104A in an in vivo model of CDEPT. Human HCT116 colon cancer cells stably over-expressing NmeNTR demonstrated significant sensitivity to PR-104A, the imaging agent EF5, and several nitro(hetero)cyclic anti-infective compounds. Chemical induction of necrosis in human H1299 xenografts by the vascular disrupting agent vadimezan promoted colonisation by NmeNTR-expressing C. sporogenes, and efficacy studies demonstrated moderate but significant anti-tumour activity of spores when compared to untreated controls. Inclusion of the pre-prodrug PR-104 into the treatment schedule provided significant additional activity, indicating proof-of-principle. Successful preclinical evaluation of a transferable gene that enables metabolism of both PET imaging agents (for vector visualisation) and prodrugs (for conditional enhancement of efficacy) is an important step towards the prospect of CDEPT entering clinical evaluation.

2020-01-01·Theranostics1区 · 医学

E. coli nitroreductase NfsA is a reporter gene for non-invasive PET imaging in cancer gene therapy applications

1区 · 医学

ArticleOA

作者: Wang, Jingli ; Biemans, Rianne ; Theys, Jan ; Lambin, Philippe ; Syddall, Sophie Philippa ; Ackerley, David Francis ; Smaill, Jeff Bruce ; Mowday, Alexandra Marie ; Abbattista, Maria Rosaria ; Patterson, Adam Vorn ; Lieuwes, Natasja Gabi ; Dubois, Ludwig Jerome ; Copp, Janine Naomi ; Ashoorzadeh, Amir ; Guise, Christopher Paul ; Williams, Elsie May

The use of reporter genes to non-invasively image molecular processes inside cells has significant translational potential, particularly in the context of systemically administered gene therapy vectors and adoptively administered cells such as immune or stem cell based therapies. Bacterial nitroreductase enzymes possess ideal properties for reporter gene imaging applications, being of non-human origin and possessing the ability to metabolize a range of clinically relevant nitro(hetero)cyclic substrates. Methods: A library of eleven Escherichia coli nitroreductase candidates were screened for the ability to efficiently metabolize 2-nitroimidazole based positron emission tomography (PET) probes originally developed as radiotracers for hypoxic cell imaging. Several complementary methods were utilized to detect formation of cell-entrapped metabolites, including various in vitro and in vivo models to establish the capacity of the 2-nitroimidazole PET agent EF5 to quantify expression of a nitroreductase candidate. Proof-of-principle PET imaging studies were successfully conducted using ¹⁸F-HX4. Results: Recombinant enzyme kinetics, bacterial SOS reporter assays, anti-proliferative assays and flow cytometry approaches collectively identified the major oxygen-insensitive nitroreductase NfsA from E. coli (NfsA_Ec) as the most promising nitroreductase reporter gene. Cells expressing NfsA_Ec were demonstrably labelled with the imaging agent EF5 in a manner that was quantitatively superior to hypoxia, in monolayers (2D), multicellular layers (3D), and in human tumor xenograft models. EF5 retention correlated with NfsA_Ec positive cell density over a range of EF5 concentrations in 3D in vitro models and in xenografts in vivo and was predictive of in vivo anti-tumor activity of the cytotoxic prodrug PR-104. Following PET imaging with ¹⁸F-HX4, a significantly higher tumor-to-blood ratio was observed in two xenograft models for NfsA_Ec expressing tumors compared to the parental tumors thereof, providing verification of this reporter gene imaging approach. Conclusion: This study establishes that the bacterial nitroreductase NfsA_Ec can be utilized as an imaging capable reporter gene, with the ability to metabolize and trap 2-nitroimidazole PET imaging agents for non-invasive imaging of gene expression.

项与 PR-104 相关的新闻（医药）

2026-08-15

·胰路新程

84%的胰腺癌自带一种酶，新药拿它当"引爆器"

上世纪40年代，人类第一个用来治癌症的化疗药叫氮芥，它和战场上的芥子气是亲戚。八十多年过去了，化疗药一批接着一批地更换着，可这个家族一直没离开舞台，现在胰腺癌治疗方案里，还有不少靠着烧断DNA来起作用的老药。问题也特别明显，好坏细胞一块儿被烧，科学家研究了几十年，给这类炸药装上引信，让它只在肿瘤里爆炸。最近这个老家族出现了一个新成员，炸药没改变，引信换成了一种叫做AKR1C3的酶，正在找最后治疗方案的胰腺癌患者，有必要了解一下。引信在哪儿找，肿瘤自身之上吸引来的是一种酶，肿瘤里面特别多、正常组织里面几乎没有。被盯上的这个叫AKR1C3，是一种醛酮还原酶，它平常帮着肿瘤细胞抗氧化、解毒，还和一大堆耐药有关系：对阿霉素耐药、对放疗抵抗、对PD-1药物不敏感的背后，都能找到它的踪迹。在胰腺癌里面它特别厉害，有研究检测了23例胰腺癌标本，每一例都是阳性。从另外一个角度来说，这正好是个机会，肿瘤靠着这个酶神气活现，那就让这个酶自己亲手把炸药点着。这颗定制炸弹是怎么运作的国内有一款走这个路子的小分子偶联前药。当药进到身体里的时候，处于保险状态，全身循环基本没有毒性，一旦钻进AKR1C3高表达的肿瘤细胞，就会被这个酶剪开外壳，释放出强效的DNA交联剂，把肿瘤细胞的DNA焊死。酶所在的地方，爆炸就在那儿。正常组织里AKR1C3很少，就像没被点燃似的，全身治疗的负担自然就小很多。 I期研究已经透露，经过跨越10多个瘤种、11个剂量组的试验，没碰到剂量限制性毒性，连最大耐受量都没达到，治疗相关的不良反应大多是1到2级，在靶点符合要求的患者当中，疾病控制率是66.7%，肿瘤明显变小的占33.3%。同门师兄摔过的跟头，是要讲清楚的这条路并非没人摔过。同一家族的OBI-3424，设计思路大体相同，晚期胰腺癌的II期研究早早地就停止了。前药的风险是实实在在存在的，酶表达是否足够均匀、释放的药力是否足够厉害，任何一个环节出问题，治疗效果都会受影响。末线治疗本来就是胰腺癌最为困难的一步，多一条设计严谨的路，就多一分主动权。也正因为这样，这类研究入组前一定要做一件事：用你的病理切片检测AKR1C3表达，阳性才能进入。现在有个II期研究正在招募针对三线及以上、AKR1C3阳性的晚期胰腺导管腺癌，全国20多家中心正在进行一项II期注册研究，南京、上海、杭州等地都有参与，采用的是随机对照设计，一组是用这款前药加上支持治疗，另一组是用5-FU/LV化疗加上支持治疗。入组的时候需要提供病理蜡块或者切片，由中心实验室进行免疫组化检测来确定AKR1C3阳性，年龄要求在18到75岁之间，而且至少两线标准治疗失败。对于那些走到晚期胰腺癌治疗最后阶段的患者，家里的那块病理蜡块可别放在箱子底，它现在就是进入治疗的通行证。写在最后八十年前的氮芥不会想到，自己会以这样的形式返聘，炸药还是原来的炸药，引信换成了肿瘤自身的酶。胰腺癌晚期的治疗选择向来没多少，能多一个设计得这么认真的选手，值得去问问自己的主治医生，看看自己是否符合条件。参考文献 A novel selective AKR1C3-activated prodrug AST-3424/OBI-3424 exhibits broad anti-tumor activity（含AKR1C3依赖激活与广谱抗肿瘤数据） OBI-3424, a novel AKR1C3-activated prodrug, exhibits potent efficacy against preclinical models of T-ALL. Clinical Cancer Research The third generation AKR1C3-activated prodrug ACHM-025 eradicates disease in preclinical models of aggressive T-ALL（含PR-104、OBI-3424前代药物始末）. Blood Cancer Journal, 2024 AKR1C3-activated prodrug AST-3424/OBI-3424（含AKR1C3与多药耐药、放疗抵抗、PD-1耐药关联综述） Safety, pharmacokinetics, and clinical activity of OBI-3424 in patients with solid tumors (ASCO摘要） AKR1C3酶活化平台小分子偶联药物I期临床研究完成（医药魔方，2024年11月） II期注册研究首家中心启动并入组首例受试者（企业官网新闻，2026年3月） AKR1C3阳性晚期胰腺导管腺癌II期研究启动（天印山医院官网，2026年3月）小分子偶联新药联合支持治疗胰腺癌研究招募详情（搜狐健康，2026年3月） AST-001药物研发档案（智慧芽新药情报库）

100 项与 PR-104 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	PR-104	-	DB05968

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
急性淋巴细胞白血病	临床2期	美国	Proacta, Inc.	2010-01-01
难治性急性白血病	临床2期	美国	Proacta, Inc.	2010-01-01
难治性急性髓细胞白血病	临床2期	美国	Proacta, Inc.	2010-01-01
晚期肝细胞癌	临床2期	美国	Proacta, Inc.	2009-03-01
晚期肝细胞癌	临床2期	中国香港	Proacta, Inc.	2009-03-01
晚期肝细胞癌	临床2期	新加坡	Proacta, Inc.	2009-03-01
晚期肝细胞癌	临床2期	中国台湾	Proacta, Inc.	2009-03-01
晚期非小细胞肺癌	临床2期	美国	Proacta, Inc.	2009-03-01
晚期非小细胞肺癌	临床2期	加拿大	Proacta, Inc.	2009-03-01
晚期非小细胞肺癌	临床2期	新西兰	Proacta, Inc.	2009-03-01

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临床结果

适应症

分期

评价

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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


NCT01037556 (ASCO2013)	临床1/2期	复发难治性急性淋巴细胞白血病	50	PR104	範淵鏇衊製窪繭願蓋網(淵選繭鹽蓋顧艱構蓋鑰) = hepatic failure (n=1), enterocolitis (n=1), pneumonia (n=1) 獵範遞顧鏇遞構鑰鏇衊 (膚齋夢鬱觸鬱壓築襯繭 ) 更多	-	2013-05-20
NCT00862134 (CTgov)	临床2期	晚期非小细胞肺癌	42	Docetaxel (Docetaxel)	觸淵鹹鏇膚簾壓憲築積 = 觸衊選網製觸蓋觸襯淵獵製齋夢蓋獵積簾繭鬱 (艱壓顧願鏇淵簾鑰積願, 鹹簾窪齋醖襯廠餘繭壓 ~ 壓築壓夢製糧窪艱顧願) 更多	-	2013-01-10
NCT00862134 (CTgov)	临床2期	晚期非小细胞肺癌	42	PR104+Docetaxel (PR104 + Docetaxel)	觸淵鹹鏇膚簾壓憲築積 = 鑰鏇淵製艱憲繭餘範壓獵製齋夢蓋獵積簾繭鬱 (艱壓顧願鏇淵簾鑰積願, 積築窪獵觸積鑰廠網餘 ~ 艱簾範遞淵夢醖築遞觸) 更多	-	2013-01-10
NCT00544674 (CTgov)	临床2期	复发性小细胞肺癌	5	F-18-fluoromisonidazole+PR104	鬱壓鹽顧餘醖艱選選艱 = 網簾繭襯鏇選糧範簾鹽膚憲製鬱廠遞憲齋構窪 (壓糧鹹壓願鏇築顧鹽鑰, 鬱製鹽襯廠憲憲膚淵鑰 ~ 積網夢夢襯遞糧襯獵壓) 更多	-	2011-07-07
ASCO2010	临床1期	实体瘤	26	PR104	蓋蓋衊衊築艱鹹遞壓襯(網夢選範蓋鹹觸鬱壓蓋) = 餘鏇獵鹹築廠餘簾鑰鏇憲鏇網網獵窪醖簾淵鬱 (鹽淵觸願艱網鬱膚範積, 0.11)	-	2010-05-20
ASCO2008	临床1期	实体瘤	-	PR-104	齋獵積願壓窪艱淵獵製(遞簾範廠積願願憲鹽製) = 鹽壓餘醖選觸積網廠壓鹹網衊簾壓餘窪選壓餘 (簾範築窪衊網製蓋壓廠 )	-	2008-05-20
ASCO2008	临床1期	晚期癌症	23	PR-104 + Gemcitabine	鹹網淵選鏇淵夢餘膚鏇(鹹餘顧遞窪製窪鏇醖積) = 遞襯製範艱鏇餘鏇淵範鑰顧構艱膚餘衊願選齋 (構艱廠顧鬱夢築憲廠衊 )	-	2008-05-20
ASCO2008	临床1期	实体瘤	13	PR-104	獵築夢醖窪壓膚鬱願鹹(積獵繭構願壓觸觸顧範) = 糧壓淵衊築鹽網鹽糧繭製製製築醖淵鹽鑰獵範 (鏇蓋網艱蓋簾觸艱鹹構 )	-	2008-05-20