Utilizing adeno-associated virus as a vector in treating genetic disorders or human cancers.

Clinical data from over two decades, involving more than 3000 treated patients, demonstrate that adeno-associated virus (AAV) gene therapy is a safe, effective, and well-tolerated therapeutic method. Clinical trials using AAV-mediated gene delivery to accessible tissues have led to successful treatments for numerous monogenic disorders and advancements in tissue engineering. Although the US Food and Drug Administration (FDA) has approved AAV for clinical use, systemic administration remains a significant challenge. In this review, we delve into AAV biology, focusing on current manufacturing technologies and transgene engineering strategies. We examine the use of AAVs in ongoing clinical trials for ocular, neurological, and hematological disorders, as well as cancers. By discussing recent advancements and current challenges in the field, we aim to provide valuable insights for researchers and clinicians navigating the evolving landscape of AAV-based gene therapy.

DARPin-fused T cell engager for adenovirus-mediated cancer therapy.

Bispecific T cell engagers are a promising class of therapeutic proteins for cancer therapy. Their potency and small size often come with systemic toxicity and short half-life, making intravenous administration cumbersome. These limitations can be overcome by tumor-specific in situ expression, allowing high local accumulation while reducing systemic concentrations. However, encoding T cell engagers in viral or non-viral vectors and expressing them in situ ablates all forms of quality control performed during recombinant protein production. It is therefore vital to design constructs that feature minimal domain mispairing, and increased homogeneity of the therapeutic product. Here, we report a T cell engager architecture specifically designed for vector-mediated immunotherapy. It is based on a fusion of a designed ankyrin repeat protein (DARPin) to a CD3-targeting single-chain antibody fragment, termed DATE (DARPin-fused T cell Engager). The DATE induces potent T cell-mediated killing of HER2+ cancer cells, both as recombinantly produced therapeutic protein and as in situ expressed payload from a HER2+-retargeted high-capacity adenoviral vector (HC-AdV). We report remarkable tumor remission, DATE accumulation, and T cell infiltration through in situ expression mediated by a HER2+-retargeted HC-AdV in vivo. Our results support further investigations and developments of DATEs as payloads for vector-mediated immunotherapy.

Gene Therapy with Chitosan Nanoparticles: Modern Formulation Strategies for Enhancing Cancer Cell Transfection.

Gene therapy involves the introduction of exogenous genetic material into host tissues to modify gene expression or cellular properties for therapeutic purposes. Initially developed to address genetic disorders, gene therapy has expanded to encompass a wide range of conditions, notably cancer. Effective delivery of nucleic acids into target cells relies on carriers, with non-viral systems gaining prominence due to their enhanced safety profile compared to viral vectors. Chitosan, a biopolymer, is frequently utilized to fabricate nanoparticles for various biomedical applications, particularly nucleic acid delivery, with recent emphasis on targeting cancer cells. Chitosan's positively charged amino groups enable the formation of stable nanocomplexes with nucleic acids and facilitate interaction with cell membranes, thereby promoting cellular uptake. Despite these advantages, chitosan-based nanoparticles face challenges such as poor solubility at physiological pH, non-specificity for cancer cells, and inefficient endosomal escape, limiting their transfection efficiency. To address these limitations, researchers have focused on enhancing the functionality of chitosan nanoparticles. Strategies include improving stability, enhancing targeting specificity, increasing cellular uptake efficiency, and promoting endosomal escape. This review critically evaluates recent formulation approaches within these categories, aiming to provide insights into advancing chitosan-based gene delivery systems for improved efficacy, particularly in cancer therapy.

Structural Evaluation of a Nitroreductase Engineered for Improved Activation of the 5-Nitroimidazole PET Probe SN33623.

Bacterial nitroreductase enzymes capable of activating imaging probes and prodrugs are valuable tools for gene-directed enzyme prodrug therapies and targeted cell ablation models. We recently engineered a nitroreductase (E. coli NfsB F70A/F108Y) for the substantially enhanced reduction of the 5-nitroimidazole PET-capable probe, SN33623, which permits the theranostic imaging of vectors labeled with oxygen-insensitive bacterial nitroreductases. This mutant enzyme also shows improved activation of the DNA-alkylation prodrugs CB1954 and metronidazole. To elucidate the mechanism behind these enhancements, we resolved the crystal structure of the mutant enzyme to 1.98 Å and compared it to the wild-type enzyme. Structural analysis revealed an expanded substrate access channel and new hydrogen bonding interactions. Additionally, computational modeling of SN33623, CB1954, and metronidazole binding in the active sites of both the mutant and wild-type enzymes revealed key differences in substrate orientations and interactions, with improvements in activity being mirrored by reduced distances between the N5-H of isoalloxazine and the substrate nitro group oxygen in the mutant models. These findings deepen our understanding of nitroreductase substrate specificity and catalytic mechanisms and have potential implications for developing more effective theranostic imaging strategies in cancer treatment.

The investigation of the death-inducing potency of a recombinant Adenovector expressing Mda-7-tlyp-1 on different cancer cell lines.

Aim: The potency of Adenovector expressing Mda7-tLyp1 (Ad-Mda7-tLyp1) for death induction was evaluated on the breast (MCF7), liver (HepG2), and gastric (MKN45) cancer cell lines. Background: Mda-7 could be a possible complementary to traditional cancer therapy, and tethering to tumor-homing peptides (THPs) might improve its therapeutic efficacy. Methods: After the preparation of recombinant Ad-Mda7-tLyp1 and Ad-Mda7, the expression of recombinant proteins was analyzed by ELISA. Adenovectors were transduced (MOI=2-5) into Hep-G2, MCF7, MKN45, and normal skin fibroblast, then tumor-killing effect was measured by cytopathic effect (CPE) monitoring, MTT viability test, BAX gene expression analysis, and Caspase3/7 assay. Results: ELISA assay revealed a sustained level of recombinant protein secretion following Adenovector transduction. In CPE microscopy, all cancer cell lines showed a significant reduction (≥50%) in their normal phenotype after receiving Ad-Mda7-tLyp1 and Ad-Mda7. The viability was significantly lower compared to the control, indicating an anti-proliferating effect. In parallel, the viability test showed that Ad-Mda7 and Ad-Mda7-tLyp1 have a significant killing effect (≥50%) on MCF-7, Hep-G2, and MKN45 compared to normal fibroblast (P≤0.05). BAX gene expression analysis showed that both Ad-Mda7-tLyp1 and Ad-Mda7 vectors induced >2-fold increase of apoptosis (P<0.05), particularly in MCF7. Similarly, caspase3/7 activity showed a significant increase (P<0.05) following Ad-Mda7, and Ad-Mda7-tLyp1 transduction into cancer cell lines, but not in normal fibroblasts. Conclusion: The newly constructed Ad-Mda-tlyp1 showed a suitable tumor cell killing activity and enough specificity on studied cell lines.

Chromosomal 3q amplicon encodes essential regulators of secretory vesicles that drive secretory addiction in cancer.

Cancer cells exhibit heightened secretory states that drive tumor progression. Here, we identify a chromosome 3q amplicon that serves as a platform for secretory regulation in cancer. The 3q amplicon encodes multiple Golgi-resident proteins, including the scaffold Golgi integral membrane protein 4 (GOLIM4) and the ion channel ATPase Secretory Pathway Ca2+ Transporting 1 (ATP2C1). We show that GOLIM4 recruits ATP2C1 and Golgi phosphoprotein 3 (GOLPH3) to coordinate calcium-dependent cargo loading and Golgi membrane bending and vesicle scission. GOLIM4 depletion disrupts the protein complex, resulting in a secretory blockade that inhibits the progression of 3q-amplified malignancies. In addition to its role as a scaffold, GOLIM4 maintains intracellular manganese (Mn) homeostasis by binding excess Mn in the Golgi lumen, which initiates the routing of Mn-bound GOLIM4 to lysosomes for degradation. We show that Mn treatment inhibits the progression of multiple types of 3q-amplified malignancies by degrading GOLIM4, resulting in a secretory blockade that interrupts pro-survival autocrine loops and attenuates pro-metastatic processes in the tumor microenvironment. Potentially underlying the selective activity of Mn against 3q-amplified malignancies, ATP2C1 co-amplification increases Mn influx into the Golgi lumen, resulting in a more rapid degradation of GOLIM4. These findings show that functional cooperativity between co-amplified genes underlies heightened secretion and a targetable secretory addiction in 3q-amplified malignancies.

CRISPR editing to mimic porphyria combined with light: A new preclinical approach for prostate cancer.

Thanks to its very high genome-editing efficiency, CRISPR-Cas9 technology could be a promising anticancer weapon. Clinical trials using CRISPR-Cas9 nuclease to ex vivo edit and alter immune cells are ongoing. However, to date, this strategy still has not been applied in clinical practice to directly target cancer cells. Targeting a canonical metabolic pathway essential to good functioning of cells without potential escape would represent an attractive strategy. We propose to mimic a genetic metabolic disorder in cancer cells to weaken cancer cells, independent of their genomic abnormalities. Mutations affecting the heme biosynthesis pathway are responsible for porphyria, and most of them are characterized by an accumulation of toxic photoreactive porphyrins. This study aimed to mimic porphyria by using CRISPR-Cas9 to inactivate UROS, leading to porphyrin accumulation in a prostate cancer model. Prostate cancer is the leading cancer in men and has a high mortality rate despite therapeutic progress, with a primary tumor accessible to light. By combining light with gene therapy, we obtained high efficiency in vitro and in vivo, with considerable improvement in the survival of mice. Finally, we achieved the preclinical proof-of-principle of performing cancer CRISPR gene therapy.

Non-viral Gene Therapy for Melanoma Using Lysenin from Eisenia Foetida.

Earthworms, long utilized in traditional medicine, serve as a source of inspiration for modern therapeutics. Lysenin, a defensive factor in the coelom fluid of the earthworm Eisenia fetida, has multiple bioactivities. However, the inherent toxicity of Lysenin as a pore-forming protein (PFP) restricts its application in therapy. Here, a gene therapy strategy based on Lysenin for cancer treatment is presented. The formulation consists of polymeric nanoparticles complexed with the plasmid encoding Lysenin. After transfection in vitro, melanoma cells can express Lysenin, resulting in necrosis, autophagy, and immunogenic cell death. The secretory signal peptide alters the intracellular distribution of the expressed product of Lysenin, thereby potentiating its anticancer efficacy. The intratumor injection of Lysenin gene formulation can efficiently kill the transfected melanoma cells and activate the antitumor immune response. Notably, no obvious systemic toxicity is observed during the treatment. Non-viral gene therapy based on Lysenin derived from Eisenia foetida exhibits potential in cancer therapy, which can inspire future cancer therapeutics.

A Replication-Competent Retroviral Vector Expressing the HERV-W Envelope Glycoprotein is a Potential Tool for Cancer Gene Therapy.

The fusogenic membrane glycoprotein (FMG) derived from the human endogenous retrovirus-W (HERV-W) exhibits fusogenic properties, making it a promising candidate for cancer gene therapy. When cells are transfected with HERV-W FMG, they can fuse with neighboring cells expressing the receptor, resulting in the formation of syncytia. These syncytia eventually undergo cell death within a few days. In addition, it has been observed that an HERV-W env mutant, which is truncated after amino acid 483, displays increased fusogenicity compared to the wild-type HERV-W env. In this study, we observed syncytium formation upon transfection of HeLa and TE671 human cancer cells with plasmids containing the HERV-W 483 gene. To explore the potential of a semi-replication-competent retroviral (s-RCR) vector encoding HERV-W 483 for FMG-mediated cancer gene therapy, we developed two replication-defective retroviral vectors: a gag-pol vector encoding HERV-W 483 (MoMLV-HERV-W 483) and an env vector encoding VSV-G (pCLXSN-VSV-G-EGFP). When MoMLV-HERV-W 483 and pCLXSN-VSV-G-EGFP were co-transfected into HEK293T cells to produce the s-RCR vector, gradual syncytium formation was observed. However, the titers of the s-RCR virus remained consistently low. To enhance gene transfer efficiency, we constructed an RCR vector encoding HERV-W 483 (MoMLV-10A1-HERV-W 483), which demonstrated replication ability in HEK293T cells. Infection of A549 and HT1080 human cancer cell lines with this RCR vector induced syncytium formation and subsequent cell death. Consequently, both the s-RCR vector and RCR encoding HERV-W 483 hold promise as valuable tools for cancer gene therapy.

GSH/pH Dual Activatable Cross-linked and Fluorinated PEI for Cancer Gene Therapy Through Endogenous Iron De-Hijacking and in Situ ROS Amplification.

Ferroptosis-related cancer therapy is limited by insufficient Fe2+ /Fe3+ redox pair and hydrogen peroxide (H2 O2 ) for producing lethal hydroxyl radicals (·OH). Although exogenous iron or ROS-producing drugs can enhance ferroptosis, exploiting endogenous iron (labile iron pool, LIP) stored in ferritin and promoting ROS generation may be safer. Herein, a metal/drug-free nanomedicine is developed for responsive LIP release and H2 O2 generation on the mitochondria membranes, amplifying hydroxyl radical production to enhance ferroptosis-mediated antitumor effects. A glutathione(GSH)/pH dual activatable fluorinated and cross-linked polyethyleneimine (PEI) with dialdehyde polyethylene glycol layer nanocomplex loaded with MTS-KR-SOD (Mitochondria-targeting-sequence-KillerRed-Superoxide Dismutase) and CRISPR/Cas9-CA IX (Carbonic anhydrase IX (CA IX)) plasmids (FP@MC) are developed for enhanced ferroptosis through endogenous iron de-hijacking and in situ ROS amplification. Two plasmids are constructed to knockdown CA IX and translate KillerRed-SOD recombinant protein specifically on mitochondria membranes, respectively. The CA IX knockdown acidifies the intracellular environment, leading the release of LIP from ferritin as a "flare" to initiate endogenous chemodynamic therapy. Meanwhile, MTS-KR-SOD generates H2 O2 when irradiated by a 590 nm laser to assist chemodynamic therapy, leading to ROS amplification for mitochondria damage and lipid peroxide accumulation. The combined therapeutic effects aggravate cancer ferroptosis and suppress tumor growth, providing a new paradigm for amplifying ROS and iron ions to promote ferroptosis-related cancer therapy.

Anti-Gene IGF-I Vaccines in Cancer Gene Therapy: A Review of a Case of Glioblastoma.

OBJECTIVE: Vaccines for the deadliest brain tumor - glioblastoma (GBM) - are generally based on targeting growth factors or their receptors, often using antibodies. The vaccines described in the review were prepared to suppress the principal cancer growth factor - IGF-I, using anti-gene approaches either of antisense (AS) or of triple helix (TH) type. Our objective was to increase the median survival of patients treated with AS and TH cell vaccines. METHODOLOGY: The cells were transfected in vitro by both constructed IGF-I AS and IGF-I TH expression episomal vectors; part of these cells was co-cultured with plant phytochemicals, modulating IGF-I expression. Both AS and TH approaches completely suppressed IGF-I expression and induced MHC-1 / B7 immunogenicity related to the IGF-I receptor signal. RESULTS: This immunogenicity proved to be stronger in IGF-I TH than in IGF-I AS-prepared cell vaccines, especially in TH / phytochemical cells. The AS and TH vaccines generated an important TCD8+ and TCD8+CD11b- immune response in treated GBM patients and increased the median survival of patients up to 17-18 months, particularly using TH vaccines; in some cases, 2- and 3-year survival was reported. These clinical results were compared with those obtained in therapies targeting other growth factors. CONCLUSION: The anti-gene IGF-I vaccines continue to be applied in current GBM personalized medicine. Technical improvements in the preparation of AS and TH vaccines to increase MHC-1 and B7 immunogenicity have, in parallel, allowed to increase in the median survival of patients.

Magnetically-assisted viral transduction (magnetofection) medical applications: An update.

Gene therapy involves replacing a faulty gene or adding a new gene inside the body's cells to cure disease or improve the body's ability to fight disease. Its popularity is evident from emerging concepts such as CRISPR-based genome editing and epigenetic studies and has been moved to a clinical setting. The strategy for therapeutic gene design includes; suppressing the expression of pathogenic genes, enhancing necessary protein production, and stimulating the immune system, which can be incorporated into both viral and non-viral gene vectors. Although non-viral gene delivery provides a safer platform, it suffers from an inefficient rate of gene transfection, which means a few genes could be successfully transfected and expressed within the cells. Incorporating nucleic acids into the viruses and using these viral vectors to infect cells increases gene transfection efficiency. Consequently, more cells will respond, more genes will be expressed, and sustained and successful gene therapy can be achieved. Combining nanoparticles (NPs) and nucleic acids protects genetic materials from enzymatic degradation. Furthermore, the vectors can be transferred faster, facilitating cell attachment and cellular uptake. Magnetically assisted viral transduction (magnetofection) enhances gene therapy efficiency by mixing magnetic nanoparticles (MNPs) with gene vectors and exerting a magnetic field to guide a significant number of vectors directly onto the cells. This research critically reviews the MNPs and the physiochemical properties needed to assemble an appropriate magnetic viral vector, discussing cellular hurdles and attitudes toward overcoming these barriers to reach clinical gene therapy perspectives. We focus on the studies conducted on the various applications of magnetic viral vectors in cancer therapies, regenerative medicine, tissue engineering, cell sorting, and virus isolation.

FAP-retargeted Ad5 enables in vivo gene delivery to stromal cells in the tumor microenvironment.

Fibroblast activation protein (FAP) is a cell surface serine protease that is highly expressed on reactive stromal fibroblasts, such as cancer-associated fibroblasts (CAFs), and generally absent in healthy adult tissues. FAP expression in the tumor stroma has been detected in more than 90% of all carcinomas, rendering CAFs excellent target cells for a tumor site-specific adenoviral delivery of cancer therapeutics. Here, we present a tropism-modified human adenovirus 5 (Ad5) vector that targets FAP through trivalent, designed ankyrin repeat protein-based retargeting adapters. We describe the development and validation of these adapters via cell-based screening assays and demonstrate adapter-mediated Ad5 retargeting to FAP+ fibroblasts in vitro and in vivo. We further show efficient in vivo delivery and in situ production of a therapeutic payload by CAFs in the tumor microenvironment (TME), resulting in attenuated tumor growth. We thus propose using our FAP-Ad5 vector to convert CAFs into a "biofactory," secreting encoded cancer therapeutics into the TME to enable a safe and effective cancer treatment.

Visible Light-Guided Gene Delivery with Nonviral Supramolecular Block Copolymer Vectors.

To achieve efficient gene delivery in vitro or in vivo, nonviral vectors should have excellent biostability across cellular and tissue barriers and also smart stimuli responsiveness toward controlled release of therapeutic genes into the cell nucleus. However, it remains a key challenge to effectively combine the biostability of covalent polymers with the stimuli responsiveness of noncovalent polymers into one nonviral vehicle. In this work, we report the construction of a kind of cationic supramolecular block copolymers (SBCs) through noncovalent polymerization of ß-cyclodextrin/azobenzene-terminated pentaethylenehexamine (DMA-Azo-PEHA-ß-CD) in aqueous media using ß-CD-monosubstituted poly(ethylene glycol) (PEG-ß-CD) as a supramolecular initiator. The resultant SBC exhibits superior biostability, biocompatibility, and light/pH dual-responsive characteristics, and it also demonstrates efficient plasmid DNA condensation capacity and the ability to rapidly release plasmid DNA into cells driven by visible light (450 nm). Eventually, this SBC-based delivery system demonstrates visible light-induced enhancement of gene delivery in both COS-7 and HeLa cells. We anticipate that this work provides a facile and robust strategy to enhance gene delivery in vitro or in vivo via visible light-guided manipulation of genes, further achieving safe, highly efficient, targeting gene therapy for cancer.

Checkpoint blockade meets gene therapy: Opportunities to improve response and reduce toxicity.

Immune checkpoint inhibitors (ICIs) based on monoclonal antibodies represent a breakthrough for the treatment of cancer. However, their efficacy varies among tumor types and patients, and they can lead to adverse effects due to on-target/off-tumor activity, since they are administered systemically at high doses. An alternative and attractive approach for the delivery of ICIs is the use of gene therapy vectors able to express them in vivo. This review focuses on the most recent studies using viral vectors able to express ICIs locally or systemically in preclinical models of cancer. These vectors include non-replicating viruses, oncolytic viruses able to propagate specifically in tumor cells and destroy them, and self-amplifying RNA vectors, armed with different formats of antibodies against immune checkpoints. Non-replicating vectors usually lead to long-term ICI expression, potentially eliminating the need for repeated administration. Vectors with replication capacity, although they have a shorter window of expression, can induce inflammation which enhances the antitumor effect. Finally, these engineered vectors can be used in combination with other immunostimulatory molecules or with CAR-T cells, further boosting the antitumor immune responses.

Adenovirus VA RNAs impair maturation of primary microRNA.

BACKGROUND: Adenovirus expresses two non-coding virus-associated (VA) RNAs: VA I RNA and VA II RNA. Adenovirus-expressed VA RNAs interfere with the microRNA (miRNA) pathway by competing with precursor miRNAs. The processing pattern of primary miRNA (pri-miRNA) and factors to affect its processing are not exactly known when using adenovirus for the delivery of pri-miRNA. METHODS: To observe pri-miRNA processing, plasmid construct encoding pri-miRNA was co-transfected with VA I/II RNA expression plasmid, or recombinant adenovirus encoding pri-miRNA was generated and infected. Levels of miRNAs, VA I RNA and VA II RNA were analyzed by a quantitative real-time PCR (RT-PCR). VA I-II full-length RNA was analyzed by a RT-PCR. RNA immunoprecipitation analysis to pull-down the VA I-II full-length RNA binding with Drosha was conducted with Drosha antibody. RESULTS: pri-miRNA was normally processed into mature miRNA when it was expressed in cells using plasmid. However, miRNA maturation was impaired when pri-miRNA was delivered and expressed using adenovirus. Of note, pri-miRNA processing was observed to be blocked by VA RNA expression. Such blocked processing could be recovered by introducing antisense RNA of VA RNA, anti-3'VA RNA. In addition, VA RNAs were transcribed into VA I-II full-length RNA, which was found to bind and sequester Drosha. CONCLUSIONS: Adenovirus infection downregulated the processing of pri-miRNAs in cells, and such downregulation could be derived from VA I-II full-length RNAs in pri-miRNA-like form through competitively binding to Drosha protein. These results indicated that the expression of adenovirus VA RNAs should be inhibited for successful delivery and expression of pri-miRNA or shRNA in cells using adenovirus.

Gene therapy in cancer.

Gene therapy, recently frequently investigated, is an alternative treatment method that introduces therapeutic genes into a cancer cell or tissue to cause cell death or slow down the growth of the cancer. This treatment has various strategies such as therapeutic gene activation or silencing of unwanted or defective genes; therefore a wide variety of genes and viral or nonviral vectors are being used in studies. Gene therapy strategies in cancer can be classified as inhibition of oncogene activation, activation of tumor suppressor gene, immunotherapy, suicide gene therapy and antiangiogenic gene therapy. In this review, we explain gene therapy, gene therapy strategies in cancer, approved gene medicines for cancer treatment and future of gene therapy in cancer. Today gene therapy has not yet reached the level of replacing conventional therapies. However, with a better understanding of the mechanism of cancer to determine the right treatment and target, in the future gene therapy, used as monotherapy or in combination with another existing treatment options, is likely to be used as a new medical procedure that will make cancer a controllable disease.

Biological and therapeutic viewpoints towards role of miR-218 in human cancers: Revisiting molecular interactions and future clinical translations.

Understanding the exact pathogenesis of cancer is difficult due to heterogenous nature of tumor cells and multiple factors that cause its initiation and development. Treatment of cancer is mainly based on surgical resection, chemotherapy, radiotherapy and their combination, while gene therapy has been emerged as a new kind of therapy for cancer. Post-transcriptional regulation of genes has been of interest in recent years and among various types of epigenetic factors that can modulate gene expression, short non-coding RNAs known as microRNAs (miRNAs) have obtained much attention. The stability of mRNA decreases by miRNAs to repress gene expression. miRNAs can regulate tumor malignancy and biological behavior of cancer cells and understanding their function in tumorigenesis can pave the way towards developing new therapeutics in future. One of the new emerging miRNAs in cancer therapy is miR-218 that increasing evidence highlights its anti-cancer activity, while a few studies demonstrate its oncogenic function. The miR-218 transfection is promising in reducing progression of tumor cells. miR-218 shows interactions with molecular mechanisms including apoptosis, autophagy, glycolysis and EMT, and the interaction is different. miR-218 induces apoptosis, while it suppresses glycolysis, cytoprotective autophagy and EMT. Low expression of miR-218 can result in development of chemoresistance and radio-resistance in tumor cells and direct targeting of miR-218 as a key player is promising in cancer therapy. LncRNAs and circRNAs are nonprotein coding transcripts that can regulate miR-218 expression in human cancers. Moreover, low expression level of miR-218 can be observed in human cancers such as brain, gastrointestinal and urological cancers that mediate poor prognosis and low survival rate.

RNF112-mediated FOXM1 ubiquitination suppresses the proliferation and invasion of gastric cancer.

Forkhead box M1 (FOXM1) plays a critical role in development physiologically and tumorigenesis pathologically. However, insufficient efforts have been dedicated to exploring the regulation, in particular the degradation of FOXM1. Here, the ON-TARGETplus siRNA library targeting E3 ligases was used to screen potential candidates to repress FOXM1. Of note, mechanism study revealed that RNF112 directly ubiquitinates FOXM1 in gastric cancer, resulting in a decreased FOXM1 transcriptional network and suppressing the proliferation and invasion of gastric cancer. Interestingly, the well-established small-molecule compound RCM-1 significantly enhanced the interaction between RNF112 and FOXM1, which further promoted FOXM1 ubiquitination and subsequently exerted promising anticancer effects in vitro and in vivo. Altogether, we demonstrate that RNF112 suppresses gastric cancer progression by ubiquitinating FOXM1 and highlight the RNF112/FOXM1 axis serves as both prognosis biomarker and therapeutic target in gastric cancer.

Oncolytic virus-based suicide gene therapy for cancer treatment: a perspective of the clinical trials conducted at Henry Ford Health.

Gene therapy manipulates or modifies a gene that provides a new cellular function to treat or correct a pathological condition, such as cancer. The approach of using gene manipulation to modify patient's cells to improve cancer therapy and potentially find a cure is gaining popularity. Currently, there are 12 gene therapy products approved by US-FDA, EMA and CFDA for cancer management, these include Rexin-G, Gendicine, Oncorine, Provange among other. The Radiation Biology Research group at Henry Ford Health has been actively developing gene therapy approaches for improving clinical outcome in cancer patients. The team was the first to test a replication-competent oncolytic virus armed with a therapeutic gene in humans, to combine this approach with radiation in humans, and to image replication-competent adenoviral gene expression/activity in humans. The adenoviral gene therapy products developed at Henry Ford Health have been evaluated in more than 6 preclinical studies and evaluated in 9 investigator initiated clinical trials treating more than100 patients. Two phase I clinical trials are currently following patients long term and a phase I trial for recurrent glioma was initiated in November 2022. This systematic review provides an overview of gene therapy approaches and products employed for treating cancer patients including the products developed at Henry Ford Health.