Tumor Suppressing Properties of Rodent Parvovirus NS1 Proteins and Their Derivatives

Nüesch, Jürg P. F.; Rommelaere, Jean

doi:10.1007/978-1-4471-6458-6_5

Cited by 13 publications

(15 citation statements)

References 101 publications

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“…Furthermore, implants of tumor cells, including human neoplastic cells, were shown to be targets for parvoviral anti-cancer activity (oncolysis) in recipient animals [8–12]. Parvoviral cytotoxicity seems to be attributed to the viral nonstructural protein NS-1 [13]. …”

Section: Trial Rationale/justificationmentioning

confidence: 99%

A non-controlled, single arm, open label, phase II study of intravenous and intratumoral administration of ParvOryx in patients with metastatic, inoperable pancreatic cancer: ParvOryx02 protocol

et al. 2017

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BackgroundMetastatic pancreatic cancer has a dismal prognosis, with a mean six-month progression-free survival of approximately 50% and a median survival of about 11 months. Despite intensive research, only slight improvements of clinical outcome could be achieved over the last decades. Hence, new and innovative therapeutic strategies are urgently required. ParvOryx is a drug product containing native parvovirus H-1 (H-1PV). Since H-1PV was shown to exert pronounced anti-neoplastic effects in pre-clinical models of pancreatic cancer, the drug appears to be a promising candidate for treatment of this malignancy.MethodsParvOryx02 is a non-controlled, single arm, open label, dose-escalating, single center trial. In total seven patients with pancreatic cancer showing at least one hepatic metastasis are to be treated with escalating doses of ParvOryx according to the following schedule: i) 40% of the total dose infused intravenously in equal fractions on four consecutive days, ii) 60% of the total dose injected on a single occasion directly into the hepatic metastasis at varying intervals after intravenous infusions. The main eligibility criteria are: age ≥ 18 years, disease progression despite first-line chemotherapy, and at least one hepatic metastasis. Since it is the second trial within the drug development program, the study primarily explores safety and tolerability after further dose escalation of ParvOryx. The secondary objectives are related to the evaluation of certain aspects of anti-tumor activity and clinical efficacy of the drug.DiscussionThis trial strongly contributes to the clinical development program of ParvOryx. The individual hazards for patients included in the current study and the environmental risks are addressed and counteracted adequately. Besides information on safety and tolerability of the treatment after further dose escalation, thorough evaluations of pharmacokinetics and intratumoral spread as well as proof-of-concept (PoC) in pancreatic cancer will be gained in the course of the trial.Trial registrationClinicalTrials.gov-ID: NCT02653313, Registration date: Dec. 4th, 2015.

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Section: Trial Rationale/justificationmentioning

confidence: 99%

A non-controlled, single arm, open label, phase II study of intravenous and intratumoral administration of ParvOryx in patients with metastatic, inoperable pancreatic cancer: ParvOryx02 protocol

et al. 2017

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“…Besides enhanced production, the activity of the NS1 viral protein is also stimulated in transformed cells. For reasons yet unknown, NS1 exerts its cytotoxic effects in oncogene-transformed cells, but not in normal ones [ 62 ]. This qualitative modulation contributes additionally to the oncoselectivity of RoPV replication and lytic activity.…”

Section: Introductionmentioning

confidence: 99%

Oncolytic parvoviruses: from basic virology to clinical applications

Marchini

Bonifati

Scott

et al. 2015

Virol J

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Accumulated evidence gathered over recent decades demonstrated that some members of the Parvoviridae family, in particular the rodent protoparvoviruses H-1PV, the minute virus of mice and LuIII have natural anticancer activity while being nonpathogenic to humans. These studies have laid the foundations for the launch of a first phase I/IIa clinical trial, in which the rat H-1 parvovirus is presently undergoing evaluation for its safety and first signs of efficacy in patients with glioblastoma multiforme. After a brief overview of the biology of parvoviruses, this review focuses on the studies which unraveled the antineoplastic properties of these agents and supported their clinical use as anticancer therapeutics. Furthermore, the development of novel parvovirus-based anticancer strategies with enhanced specificity and efficacy is discussed, in particular the development of second and third generation vectors and the combination of parvoviruses with other anticancer agents. Lastly, we address the key challenges that remain towards a more rational and efficient use of oncolytic parvoviruses in clinical settings, and discuss how a better understanding of the virus life-cycle and of the cellular factors involved in virus infection, replication and cytotoxicity may promote the further development of parvovirus-based anticancer therapies, open new prospects for treatment and hopefully improve clinical outcome.

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“…NS1, the major protoparvoviral regulatory protein, is required for multiple steps in the virus life cycle, ranging from viral DNA amplification and trans -regulation of viral and cellular transcription to the egress and spread of progeny particles [ 3 ]. Because it interferes with multiple cellular pathways, NS1 appears as the main cytotoxic agent responsible for the oncolytic activity of PVs [ 4 , 5 ]. NS1 functioning is tightly regulated by phosphorylation, catalyzed by two kinases: PKCλ and the short-lived PKCη [ 6 , 7 ], both of which require activation by the phosphoinositide-dependent kinase 1 (PDK1).…”

Section: Introductionmentioning

confidence: 99%

PKCη/Rdx-driven Phosphorylation of PDK1: A Novel Mechanism Promoting Cancer Cell Survival and Permissiveness for Parvovirus-induced Lysis

2015

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The intrinsic oncotropism and oncosuppressive activities of rodent protoparvoviruses (PVs) are opening new prospects for cancer virotherapy. Virus propagation, cytolytic activity, and spread are tightly connected to activation of the PDK1 signaling cascade, which delays stress-induced cell death and sustains functioning of the parvoviral protein NS1 through PKC(η)-driven modifications. Here we reveal a new PV-induced intracellular loop-back mechanism whereby PKCη/Rdx phosphorylates mouse PDK1:S138 and activates it independently of PI3-kinase signaling. The corresponding human PDK1phosphoS135 appears as a hallmark of highly aggressive brain tumors and may contribute to the very effective targeting of human gliomas by H-1PV. Strikingly, although H-1PV does not trigger PDK1 activation in normal human cells, such cells show enhanced viral DNA amplification and NS1-induced death upon expression of a constitutively active PDK1 mimicking PDK1phosphoS135. This modification thus appears as a marker of human glioma malignant progression and sensitivity to H-1PV-induced tumor cell killing.

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Tumor Suppressing Properties of Rodent Parvovirus NS1 Proteins and Their Derivatives

Cited by 13 publications

References 101 publications

A non-controlled, single arm, open label, phase II study of intravenous and intratumoral administration of ParvOryx in patients with metastatic, inoperable pancreatic cancer: ParvOryx02 protocol

A non-controlled, single arm, open label, phase II study of intravenous and intratumoral administration of ParvOryx in patients with metastatic, inoperable pancreatic cancer: ParvOryx02 protocol

Oncolytic parvoviruses: from basic virology to clinical applications

PKCη/Rdx-driven Phosphorylation of PDK1: A Novel Mechanism Promoting Cancer Cell Survival and Permissiveness for Parvovirus-induced Lysis

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