Delving into the Latest Updates on PR-104 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

PR 104, SN-29244

Target

DNA

Action

inhibitors

Mechanism

DNA inhibitors(DNA inhibitors), DNA alkylating agents

Therapeutic Areas

NeoplasmsImmune System DiseasesDigestive System Disorders+ [2]

Active Indication-

Inactive Indication

Acute Lymphoblastic LeukemiaAdvanced Hepatocellular CarcinomaAdvanced Lung Non-Small Cell Carcinoma+ [4]

Originator Organization

Proacta, Inc.

Active Organization-

Inactive Organization

Proacta, Inc.

License Organization-

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC14H20BrN4O12PS

InChIKeyGZSOKPMDWVRVMG-UHFFFAOYSA-N

CAS Registry851627-62-8

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

Start Date01 Jan 2010

Sponsor / Collaborator

Proacta, Inc.

NCT00862082

/ TerminatedPhase 1/2

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

Start Date01 Mar 2009

Sponsor / Collaborator

Proacta, Inc.

NCT00862134

/ TerminatedPhase 2

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

Start Date01 Mar 2009

Sponsor / Collaborator

Proacta, Inc.

100 Clinical Results associated with PR-104

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100 Translational Medicine associated with PR-104

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100 Patents (Medical) associated with PR-104

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41

Literatures (Medical) associated with PR-104

17 Jan 2025·MEDICINE

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

Article

Author: 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.

01 Jul 2022·Cancer gene therapyQ2 · MEDICINE

Bioreductive prodrug PR-104 improves the tumour distribution and titre of the nitroreductase-armed oncolytic adenovirus ONYX-411NTR leading to therapeutic benefit

Q2 · MEDICINE

Article

Author: William R. Wilson ; Dan Li ; Dean C. Singleton ; Alexandra M. Mowday ; Amir Ashoorzadeh ; Jeff B. Smaill ; Sally Y. Bai ; Chris P. Guise ; Adam V. Patterson ; Sophie P. Syddall

Advances in the field of cancer immunotherapy have stimulated renewed interest in adenoviruses as oncolytic agents. Clinical experience has shown that oncolytic adenoviruses are safe and well tolerated but possess modest single-agent activity. One approach to improve the potency of oncolytic viruses is to utilise their tumour selectivity to deliver genes encoding prodrug-activating enzymes. These enzymes can convert prodrugs into cytotoxic species within the tumour; however, these cytotoxins can interfere with viral replication and limit utility. In this work, we evaluated the activity of a nitroreductase (NTR)-armed oncolytic adenovirus ONYX-411^NTR in combination with the clinically tested bioreductive prodrug PR-104. Both NTR-expressing cells in vitro and xenografts containing a minor population of NTR-expressing cells were highly sensitive to PR-104. Pharmacologically relevant prodrug exposures did not interfere with ONYX-411^NTR replication in vitro. In vivo, prodrug administration increased virus titre and improved virus distribution within tumour xenografts. Colonisation of tumours with high ONYX-411^NTR titre resulted in NTR expression and prodrug activation. The combination of ONYX-411^NTR with PR-104 was efficacious against HCT116 xenografts, whilst neither prodrug nor virus were active as single agents. This work highlights the potential for future clinical development of NTR-armed oncolytic viruses in combination with bioreductive prodrugs.

01 Feb 2022·Cancer gene therapyQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: Smaill, Jeff B ; Kubiak, Aleksandra M ; 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.

100 Deals associated with PR-104

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External Link

KEGG	Wiki	ATC	Drug Bank
-	PR-104	-	DB05968

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Lymphoblastic Leukemia	Phase 2	United States	Proacta, Inc.	01 Jan 2010
Refractory Acute Leukemia	Phase 2	United States	Proacta, Inc.	01 Jan 2010
Refractory acute myeloid leukemia	Phase 2	United States	Proacta, Inc.	01 Jan 2010
Advanced Hepatocellular Carcinoma	Phase 2	United States	Proacta, Inc.	01 Mar 2009
Advanced Hepatocellular Carcinoma	Phase 2	Hong Kong	Proacta, Inc.	01 Mar 2009
Advanced Hepatocellular Carcinoma	Phase 2	Singapore	Proacta, Inc.	01 Mar 2009
Advanced Hepatocellular Carcinoma	Phase 2	Taiwan Province	Proacta, Inc.	01 Mar 2009
Advanced Lung Non-Small Cell Carcinoma	Phase 2	United States	Proacta, Inc.	01 Mar 2009
Advanced Lung Non-Small Cell Carcinoma	Phase 2	Canada	Proacta, Inc.	01 Mar 2009
Advanced Lung Non-Small Cell Carcinoma	Phase 2	New Zealand	Proacta, Inc.	01 Mar 2009

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01037556 (ASCO2013)	Phase 1/2	refractory acute lymphoid leukemia in relapse	50	PR104	mvjczjblgf(pceikkuivz) = hepatic failure (n=1), enterocolitis (n=1), pneumonia (n=1) amgqzbttov (fzweeixknd ) View more	-	20 May 2013
NCT00862134 (CTgov)	Phase 2	Advanced Lung Non-Small Cell Carcinoma	42	Docetaxel (Docetaxel)	zgqkzihpxe = oxjasobjsn qerhvenctj (qrikgyjvhv, hftvurbkqa - xnukcyxxmh) View more	-	10 Jan 2013
NCT00862134 (CTgov)	Phase 2	Advanced Lung Non-Small Cell Carcinoma	42	PR104+Docetaxel (PR104 + Docetaxel)	zgqkzihpxe = xzvgotimjf qerhvenctj (qrikgyjvhv, olnyssupwy - uuglxhhwnj) View more	-	10 Jan 2013
NCT00544674 (CTgov)	Phase 2	Recurrent Lung Small Cell Carcinoma	5	F-18-fluoromisonidazole+PR104	fyejflqjnv = uxwjokfwbv qzwzbeyvlv (uspyegytnk, scoggxipmn - nbxgpbimku) View more	-	07 Jul 2011
ASCO2010	Phase 1	Solid tumor	26	PR104	apxilzdljf(hxkdfxblkn) = tnlqlwlimb uegajnnaxu (mckvatuioh, 0.11)	-	20 May 2010
ASCO2008	Phase 1	Solid tumor	13	PR-104	yhrtfxyrai(qsdhpkxnfc) = afpuqprakg xteybydhbd (sacrtoraqk )	-	20 May 2008
ASCO2008	Phase 1	Solid tumor	-	PR-104	dtorxucmko(peiffkuotp) = bdieigxmqq jgrjihcjhi (wazgbxqpej )	-	20 May 2008
ASCO2008	Phase 1	Advanced cancer	23	PR-104 + Gemcitabine	zfxtykcqti(gfjtzhcccm) = yhvpvoyjbe lrhvwthmfd (bwmzzlwpje )	-	20 May 2008