PSMA-targeted polyinosine/polycytosine vector induces prostate tumor regression and invokes an antitumor immune response in mice

Langut, Yael; Talhami, Alaa; Samarasimhareddy, Mamidi; Shir, Alexei; Zigler, Maya; Joubran, Salim; Sagalov, Anna; Flashner-Abramson, Efrat; Edinger, Nufar; Klein, Shoshana; Levitzki, Alexander

doi:10.1073/pnas.1714587115

Cited by 11 publications

(8 citation statements)

References 49 publications

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“…Internalization of dsRNA induces the tumor to self-destruct by apoptosis, while activating immune modulatory pathways, leading to cytokine and chemokine induction. In addition to type I IFNs, we have detected RANTES, IP-10, GRO-α, IL-2, TNF-α, and IFN-γ (99,106,107). These molecules generate a "bystander effect" against the tumor: They are cytotoxic against tumor cells that do not themselves overexpress the receptor, boost tumor immunogenicity by increasing the expression of MHC-1 and tumor-specific antigens, and attract immune cells such as T cells and NK cells, which mount an attack against the tumor (100, 106, 108) (Fig.…”

Section: Targeting Polyinosinic/polycytidylic Acid To Tumorsmentioning

confidence: 91%

“…By changing the "homing head" of our vectors, we have targeted HER-2-overexpressing breast cancer and prostate-specific membrane antigen (PSMA)-overexpressing prostate cancer xenografts (106)(107)(108). The involvement of multiple pathways in the response to targeted polyIC, the induction of a direct apoptotic effect that leads to rapid cell death, and the recruitment of the innate and adaptive immune systems to attack heterogeneous tumors and hunt out even distant metastases have combined to produce very impressive preclinical results (100,106,107). We believe that this strategy will be a worthwhile addition to the anticancer arsenal.…”

Section: Targeting Polyinosinic/polycytidylic Acid To Tumorsmentioning

confidence: 99%

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My journey from tyrosine phosphorylation inhibitors to targeted immune therapy as strategies to combat cancer

Levitzki

Klein

2019

Proc. Natl. Acad. Sci. U.S.A.

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Since the 1980s there has been a drive toward personalized targeted therapy for cancer. “Targeted cancer therapy” originally focused on inhibiting essential tumor survival factors, primarily protein tyrosine kinases. The complexity and rapid mutability of tumors, however, enable them to develop resistance to tyrosine kinase inhibitors (TKIs), even when these are multitargeted or applied in combination. This has led to the development of targeted cancer immunotherapy, to enhance immune surveillance against the tumor. In this paper, we provide a personal view of the development of targeted therapy, from TKIs to targeted immunotherapy.

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Section: Targeting Polyinosinic/polycytidylic Acid To Tumorsmentioning

confidence: 91%

Section: Targeting Polyinosinic/polycytidylic Acid To Tumorsmentioning

confidence: 99%

My journey from tyrosine phosphorylation inhibitors to targeted immune therapy as strategies to combat cancer

Levitzki

Klein

2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Investigators were blinded to the group allocation. In this study, animal experiment was performed on mouse model with reconstituted immune system [ 22 ], in which, NOD/SCID mice were infused PBMCs (2 × 10 7 ) via tail veins at 1st and 14th day. One day after PBMCs infusion, 100 µL mixture of SGC-7901 or SW1990 (5 × 10 6 ) and Matrigel was inoculated subcutaneously.…”

Section: Methodsmentioning

confidence: 99%

Dexamethasone suppresses immune evasion by inducing GR/STAT3 mediated downregulation of PD-L1 and IDO1 pathways

et al. 2021

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T cell exhaustion plays critical roles in tumor immune evasion. Novel strategies to suppress immune evasion are in urgent need. We aimed to identify potential compounds to target T cell exhaustion and increase response to immune checkpoint inhibitors (ICIs). Differentially expressed genes (DEGs) were identified between tumors with different immune evasion potential by comparing the transcriptome data. DEGs were then analyzed in the Connectivity Map (CMap) platform to identify potential compounds to increase response to ICIs. Gene set enrichment analysis, LDH release assay, Chromatin immunoprecipitation (ChIP), and Co-IP were performed to explore the potential mechanisms in vitro. Patients derived organoids and humanized xenograft mouse model were utilized to validate the finding ex vivo and in vivo. We identified 25 potential compounds that may play critical roles in regulating tumor immune evasion. We further pinpointed a specific compound, dexamethasone, which shows potent anti-tumor effect in multiple cancer cell lines when cocultured with T cells. Dexamethasone can suppress T cell exhaustion by decreasing the activity of two immune checkpoints simultaneously, including PD-L1 and IDO1. Functional study shows dexamethasone can increase the sensitivity of ICIs in coculture system, 3D organoid model and humanized mouse model. Mechanism study shows dexamethasone mediated transcriptional suppression of PD-L1 and IDO1 depends on the nuclear translocation of GR/STAT3 complex. These findings demonstrate dexamethasone can suppress immune evasion by inducing GR/STAT3 mediated downregulation of PD-L1 and IDO1 pathways.

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“…The key benefits of nanotherapy can be disentangled into two major objectives, namely, maximized drug loading capacity due to their high surface-area-to-volume ratio, and increased tumor uptake through prolonged drug circulation and lessened risk of undesirable toxic effects to nearby healthy tissues [ 14 , 15 ]. Moreover, to overcome the mutability of cancer, it is critical to achieve an idealistic drug delivery vehicle that is characterized by long blood circulation time, and specific targeted therapy consists of clinically approved components to effectively combat the tumor within a short time frame [ 16 ]. This notion can be exemplified and put into perspective by the ample studies done on using nanomaterials in theranostics for different types of cancers [ 17 , 18 ].…”

Section: Nanotechnology and Its Importance In Theranosticsmentioning

confidence: 99%

Jumping on the Bandwagon: A Review on the Versatile Applications of Gold Nanostructures in Prostate Cancer

Sarkis

Ghanem

Rahme

2019

IJMS

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Prostate cancer (PCa) has remarkably emerged as a prominent disease in the face of the male population. Conventional treatments like prostatectomy or radiation can be curative only if PCa is diagnosed at an early stage. In the field of targeted therapy, a bevy of novel therapeutic approaches have left a landmark in PCa treatment and have proven to extend survival via distinct modes of actions. Nanotherapy has started to take root and has become the hype of the century by virtue of its abundant advantages. Scientists have invested a great deal of interest in the development of nanostructures such as gold nanoparticles (AuNPs), which hold particularly great hope for PCa theranostics. In this article, we present an overview of the studies published after 1998 that involve the use of different functionalized AuNPs to treat and diagnose PCa. Special reference is given to various in vitro and in vivo methods employed to shuttle AuNPs to PCa cells. Major studies show an enhancement of either detection or treatment of PCa when compared to their non-targeted counterparts, especially when AuNPs are tagged with specific ligands, such as antibodies, tea natural extracts, folate, anisamide, receptor inhibitors, and chitosan. Future approaches of treatment are dependent on those worthy multifunctional molecules, and are dictated by their ability to achieve a more versatile cancer therapeutic approach.

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PSMA-targeted polyinosine/polycytosine vector induces prostate tumor regression and invokes an antitumor immune response in mice

Cited by 11 publications

References 49 publications

My journey from tyrosine phosphorylation inhibitors to targeted immune therapy as strategies to combat cancer

My journey from tyrosine phosphorylation inhibitors to targeted immune therapy as strategies to combat cancer

Dexamethasone suppresses immune evasion by inducing GR/STAT3 mediated downregulation of PD-L1 and IDO1 pathways

Jumping on the Bandwagon: A Review on the Versatile Applications of Gold Nanostructures in Prostate Cancer

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