Oncolytic viruses are opening new possibilities in cancer therapy with their unique mechanism of selective replication within tumor cells and triggering of anti-tumor immune responses. HF10 is an oncolytic herpes simplex virus-1 (HSV-1) with a unique genomic structure that has non-engineered deletions and insertions accompanied by frame shift mutations, in contrast to the majority of engineered oncolytic viruses. At the genetic level, HF10 naturally lacks the expression of UL43, UL49.5, UL55, UL56, and latency-associated transcripts, and overexpresses UL53 and UL54. In preclinical studies, HF10 replicated efficiently within tumor cells with extensive cytolytic effects and induced increased numbers of activated CD4+ and CD8+ T cells and natural killer cells within the tumor, leading to a significant reduction in tumor growth and prolonged survival rates. Investigator-initiated clinical studies of HF10 have been completed in recurrent breast carcinoma, head and neck cancer, and unresectable pancreatic cancer in Japan. Phase I trials were subsequently completed in refractory superficial cancers and melanoma in the United States. HF10 has been demonstrated to have a high safety margin with low frequency of adverse effects in all treated patients. Interestingly, HF10 antigens were detected in pancreatic carcinoma over 300 days after treatment with infiltration of CD4+ and CD8+ T cells, which enhanced the immune response. To date, preliminary results from a Phase II trial have indicated that HF10 in combination with ipilimumab (anti–CTLA-4) is safe and well tolerated, with high anti-tumor efficacy. Improvement of the effect of ipilimumab was observed in patients with stage IIIb, IIIc, or IV unresectable or metastatic melanoma. This review provides a concise description of the genomic functional organization of HF10 compared with talimogene laherparepvec. Furthermore, this review focuses on HF10 in cancer treatment as monotherapy as well as in combination therapy through a concise description of all preclinical and clinical data. In addition, we will address approaches for future directions in HF10 studies as cancer therapy.

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Genomic Signature of the Natural Oncolytic Herpes Simplex Virus HF10 and Its Therapeutic Role in Preclinical and Clinical Trials.

Survival of patients with muscle-invasive bladder cancer is poor and new therapies are needed. Currently, none of the targeted agents that are approved for cancer therapy have been approved for the treatment of bladder cancer and the few clinical trials that have been performed had limited success, often owing to a lack of efficacy and toxic effects. However, many other novel targeted agents have been investigated in animal models of bladder cancer. EGFR, FGFR-3, VEGF, mTOR, STAT3, the androgen receptor and CD24 are molecular targets that could be efficiently inhibited, resulting in reduced tumour growth, and that have been investigated in multiple independent studies. Several other targets, for example COX-2, IL-12, Bcl-xL, livin and choline kinase α, have also been observed to inhibit tumour growth, but these findings have not been replicated to date. Limitations of several studies include the use of cell lines with mutations downstream of the target, providing resistance to the tested therapy. Furthermore, certain technologies, such as interfering RNAs, although effective in vitro, are not yet ready for clinical applications. Further preclinical research is needed to discover and evaluate other possible targets, but several validated targets are now available to be studied in clinical trials.

Targeted therapies in bladder cancer: an overview of in vivo research

Altered networks of gene regulation underlie many pathologies, including cancer. There are several proteins in cancer cells that are turned either on or off, which dramatically alters the metabolism and the overall activity of the cell, with the complex machinery of enzymes involved in the metabolism of glycolipids not being an exception. The aberrant glycosylation of glycolipids on the surface of the majority of cancer cells, associated with increasing evidence about the functional role of these molecules in a number of cellular physiological pathways, has received considerable attention as a convenient immunotherapeutic target for cancer treatment. This has resulted in the development of a substantial number of passive and active immunotherapies, which have shown promising results in clinical trials. More recently, antibodies to glycolipids have also emerged as an attractive tool for the targeted delivery of cytotoxic agents, thereby providing a rationale for future therapeutic interventions in cancer. This review first summarizes the cellular and molecular bases involved in the metabolic pathway and expression of glycolipids, both in normal and tumor cells, paying particular attention to sialosylated glycolipids (gangliosides). The current strategies in the battle against cancer in which glycolipids are key players are then described.

/pdf/glycosylation-of-glycolipids-in-cancer-basis-for-development-3z1o9l8z39.pdf

Glycosylation of glycolipids in cancer: basis for development of novel therapeutic approaches.

Bladder cancer remains one of the most expensive cancers to treat in the United States due to the length of required treatment and degree of recurrence. In order to treat bladder cancer more effectively, targeted therapies are being investigated. In order to use targeted therapy in a patient, it is important to provide a genetic background of the patient. Recent advances in genome sequencing, as well as transcriptome analysis, have identified major pathway components altered in bladder cancer. The purpose of this review is to provide a broad background on bladder cancer, including its causes, diagnosis, stages, treatments, animal models, as well as signaling pathways in bladder cancer. The major focus is given to the PI3K/AKT pathway, p53/pRb signaling pathways, and the histone modification machinery. Because several promising immunological therapies are also emerging in the treatment of bladder cancer, focus is also given on general activation of the immune system for the treatment of bladder cancer.

/pdf/molecular-targets-in-urothelial-cancer-detection-treatment-2ieq9jqbio.pdf

Molecular targets in urothelial cancer: detection, treatment, and animal models of bladder cancer

Ganglioside GM3 is strongly related with human tumors, such as lung, brain cancers and melanomas, and more and more evidences have revealed that GM3 possesses powerful effects on cancer development and progression GM3 is over expressed on several types of cancers, and can be as a tumor-associated carbohydrate antigen, used for immunotherapy of cancers GM3 can also inhibit tumor cells growth by anti-angiogenesis or motility and so on Especially, GM3 has effects on the EGFR tyrosine kinase signaling, uPAR-related signaling and glycolipid-enriched microdomains, which are essential for cancer signaling conduction It is obvious that GM3 will be a promising target for cancer treatment

/pdf/ganglioside-gm3-and-its-role-in-cancer-27d5v6aviq.pdf

Ganglioside GM3 and Its Role in Cancer

Enhanced Antitumor Efficacy of Integrin-targeted Oncolytic Adenovirus AxdAdB3-F/RGD on Bladder Cancer

Background Our previous studies have demonstrated potent oncolysis efficacy of the E1A, E1B double-restricted replication-competent oncolytic adenovirus AxdAdB-3 for treatment of bladder cancer. Here, we reported the feasibility and efficacy of AxdAdB-3 alone, or in combination with gemcitabine for treating renal cell carcinoma. Methods Cytopathic effects of AxdAdB-3 were evaluated in human renal cell carcinoma cell lines TOS-1, TOS-2, TOS-3, TOS-3LN, SMKT-R3, SMKT-R4 and ACHN, and in normal human renal proximal tubule epithelial cells (RPTEC). AxdAdB-3 induced down-regulation of the cell cycle was determined by flow cytometry. Combination therapies of AxdAdB-3 with gemcitabine were evaluated in vitro and in vivo on subcutaneous TOS-3LN tumors in a severe combined immunodeficiency disease (SCID) mouse model. Results AxdAdB-3 was potently cytopathic against the tested most renal cell carcinoma cell lines including TOS-2, TOS-3, TOS-3LN, SMKT-R3 and SMKT-R4, while normal human RPTEC were not destroyed. AxdAdB-3 effectively induced cell cycle S-phase entry. Combined therapy of AxdAdB-3 with gemcitabine demonstrated stronger antitumor effects in vitro and in vivo compared with either AxdAdB-3 or gemcitabine alone. Conclusion AxdAdB-3 alone, or in combination with gemcitabine may be a promising strategy against renal cell carcinoma.

E1A, E1B double-restricted adenovirus enhances the cytotoxicity and antitumor activity of gemcitabine to renal cell carcinoma.

Antitumor effects of exogenous ganglioside GM3 on bladder cancer in an orthotopic cancer model.

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Enhanced Antitumor Efficacy of Integrin-targeted Oncolytic Adenovirus AxdAdB3-F/RGD on Bladder Cancer

E1A, E1B double-restricted adenovirus enhances the cytotoxicity and antitumor activity of gemcitabine to renal cell carcinoma.

Antitumor effects of exogenous ganglioside GM3 on bladder cancer in an orthotopic cancer model.