Summary of bi-shRNA&lt;sup&gt;furin&lt;/sup&gt;/GM-CSF Augmented Autologous Tumor Cell Immunotherapy (FANG™) in Advanced Cancer of the Liver

Nemunaitis, John; Barve, Minal; Orr, Douglas W.; Kuhn, Joseph A.; Magee, Mitchell J.; Lamont, Jeffrey; Bedell, Cynthia; Wallraven, Gladice; Pappen, Beena O.; Roth, A; Horvath, Staci; Nemunaitis, Derek; Kumar, Padmasini; Maples, Phillip B.; Senzer, Neil

doi:10.1159/000360993

Cited by 47 publications

(30 citation statements)

References 54 publications

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“…Elevated levels of GMCSF also resulted in increased activation of bone marrow-derived dendritic cells, facilitating the elimination of tumor cells. In a phase I trial, Nemunaitis et al [84–86] produced vaccines from a wide variety of tumor sources, including, small cell lung cancer, breast cancer, colon cancer, liposarcoma, and ovarian cancer [84] This approach is still underway, but anticipates positive outcomes in decreasing the relapse in patients diagnosed with hepatocellular carcinoma [84], metastatic advanced Ewing’s sarcoma [87, 88], advanced stage ovarian cancer [89]. …”

Section: Furin Silencing: Strengthening the Immune Responsementioning

confidence: 99%

Proprotein convertase inhibition: Paralyzing the cell’s master switches

Klein‐Szanto

Bassi

2017

Biochemical Pharmacology

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Proprotein convertases are serine proteases responsible for the cleavage and subsequent activation of protein substrates, many of them relevant for the development of an ample variety of diseases. Seven of the PCs, including furin and PACE4, recognize and hydrolyze the C-terminal end of the general sequence RXRR/KXR, whereas PCSK-9 recognizes a series of non-basic amino acids. In some systems, PC-mediated substrate activation results in the development of pathological processes, such as cancer, endocrinopathies, and cardiovascular and infectious diseases. After establishing PCs as relevant contributors to disease processes, research efforts were directed towards the development of inhibition strategies, including small and large molecules, anti-sense therapies, and antibody-based therapies. Most of these inhibitors mimic the consensus sequence of PCs, blocking the active site in a competitive manner. The most promising inhibitors were designed as bioengineered proteins; however, some non-protein and peptidomimetic agents has also proved to be effective. These efforts led to the design of pre-clinical studies and clinical trials utilizing inhibitors to PCs. Although the initial studies were performed using non-selective PCs inhibitors, such as CMK, the search for more specific, and compartmentalized selective inhibitors resulted in specific activities ascribed to some, but not all of the PCs. For instance, PACE4 inhibitors were effective in decreasing prostate cancer cell proliferation, and neovascularization. Decreased metastatic ovarian cancer utilizing furin inhibitors represents one of the major endeavors, currently in a phase II trial stage. Antibodies targeting PCSK-9 decreased significantly the levels of HDL-cholesterol, in a phase III trial. The study of Proprotein convertases has reached a stage of maturity. New strategies based on the alteration of their activity at the cellular and clinical level represent a promising experimental pharmacology field. The development of allosteric inhibitors, or specific agents directed against individual PCs is one of the challenges to be unraveled in the future.

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Section: Furin Silencing: Strengthening the Immune Responsementioning

confidence: 99%

Proprotein convertase inhibition: Paralyzing the cell’s master switches

Klein‐Szanto

Bassi

2017

Biochemical Pharmacology

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“…[10] Injection of these cells was found to be beneficiali np atients with varioust ypes of advanced cancers, [11] including hepatocellular carcinoma. [12] Moreover,n ol ong-term toxicity has been observed with these vaccines. Taken together,t hese studies suggest that despite important roles of furin-like PCs in essential physiological processes, its inhibition could be as uitable strategy for the treatment of numerousdiseases.…”

Section: Introductionmentioning

confidence: 99%

Novel Furin Inhibitors with Potent Anti‐infectious Activity

et al. 2015

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New peptidomimetic furin inhibitors with unnatural amino acid residues in the P3 position were synthesized. The most potent compound 4-guanidinomethyl-phenylacteyl-Arg-Tle-Arg-4-amidinobenzylamide (MI-1148) inhibits furin with a Ki value of 5.5 pM. The derivatives also strongly inhibit PC1/3, whereas PC2 is less affected. Selected inhibitors were tested in cell culture for antibacterial and antiviral activity against infectious agents known to be dependent on furin activity. A significant protective effect against anthrax and diphtheria toxin was observed in the presence of the furin inhibitors. Furthermore, the spread of the highly pathogenic H5N1 and H7N1 avian influenza viruses and propagation of canine distemper virus was strongly inhibited. Inhibitor MI-1148 was crystallized in complex with human furin. Its N-terminal guanidinomethyl group in the para position of the P5 phenyl ring occupies the same position as that found previously for a structurally related inhibitor containing this substitution in the meta position, thereby maintaining all of the important P5 interactions. Our results confirm that the inhibition of furin is a promising strategy for a short-term treatment of acute infectious diseases.

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“…Nevertheless, disruption of furin activity has been used successfully to enhance an anti-tumor immune response in patients with advanced cancers. Safety and efficient immune response of an autologous tumor cell vaccine (FANG) that combines furin shRNA and expression of GM-CSF were confirmed and benefits of treatment were observed from phase I trials in Ewing sarcoma and hepatocellular carcinoma patients [46–48]. Additionally, increased presence of furin on the cell surface of tumor cells could be used for targeted delivery of chemotherapeutics, as we could show previously that furin is the target receptor for RMS-homing peptides [32].…”

Section: Discussionmentioning

confidence: 99%

The proprotein convertase furin is required to maintain viability of alveolar rhabdomyosarcoma cells

et al. 2016

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Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Success of current therapies is still limited and outcome is particularly poor for metastatic alveolar rhabdomyosarcoma (aRMS). We previously identified the proprotein convertase furin as potential target for specific drug delivery with RMS-homing peptides. Furin is a protease that converts inactive precursor proteins into bioactive proteins and peptides. In this study, we investigate the biological role of furin in aRMS progression in vitro and in vivo. Furin expression was confirmed in over 86% RMS biopsies in a tissue microarray (n=89). Inducible furin silencing in vitro led to significant impairment of cell viability and proliferation in all investigated aRMS cell lines, but not in MRC5 fibroblasts. Furthermore, the aRMS cell lines Rh3 and Rh4 revealed to be very sensitive to furin silencing, undergoing caspase-dependent cell death. Notably, furin silencing in vivo led to complete remission of established Rh4 tumors and to delayed growth in Rh30 tumors. Taken together, these findings identify furin as an important factor for aRMS progression and survival. Thus, we propose furin as a novel therapeutic target for treatment of aRMS.

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Summary of bi-shRNA<sup>furin</sup>/GM-CSF Augmented Autologous Tumor Cell Immunotherapy (FANG™) in Advanced Cancer of the Liver

Cited by 47 publications

References 54 publications

Proprotein convertase inhibition: Paralyzing the cell’s master switches

Proprotein convertase inhibition: Paralyzing the cell’s master switches

Novel Furin Inhibitors with Potent Anti‐infectious Activity

The proprotein convertase furin is required to maintain viability of alveolar rhabdomyosarcoma cells

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