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Targeting Oncoproteins for Molecular Cancer Therapy

ABSTRACT: Cancer and efforts to treat cancer are described in Ancient Egyptian documents dating back to 1600B.C. The first successful cancer treatments were arsenic-based therapies for leukemias, with the first reported application to cancer in the nineteenth century. However, nitrogen mustards are often accredited as the first modern chemotherapy. Originally intended as a chemical warfare agent in World War I, nitrogen mustard was stockpiled by several countries. During World War II, Axis bombers sunk a ship containing large quantities of nitrogen mustard and killed numerous Allied sailors. This observation birthed the hypothesis that nitrogen mustards might prevent the rapid division of cancer cells, one of the few properties of cancer understood at that time. Today, the hallmarks of cancer as recently redefined by Hanahan and Weinberg include several complex and connected cellular properties that allow for this phenotype: resistance to cell death, sustained angiogenesis, limitless ability to replicate, self-sufficiency in growth factor signaling, unresponsiveness to anti-growth factor signaling, genomic instability and mutation, deregulating cellular energetics, evading immune-mediated destruction, oncogenic inflammation, and invasiveness and metastasis. The identification and understanding of these hallmarks is a direct result of our molecular understanding of cancer that has surfaced relatively recently. Each of these hallmarks is determined by a host of molecules that together represent distinct therapeutic opportunities to target molecules that give rise to these defining properties of cancer.

SUBMITTER: Coleman W

PROVIDER: S-EPMC7120969 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe oncogenic activity of the high risk human papillomavirus type 16 (HPV16) is fully dependent on the E6 and E7 viral oncoproteins produced during viral infection. The oncoproteins interfere with cellular homeostasis by promoting proliferation, inhibiting apoptosis and blocking epithelial differentiation, driving the infected cells towards neoplastic progression. The causal relationship between expression of E6/E7 and cellular transformation allows inhibiting the oncogenic process by hindering the activity of the two oncoproteins. We previously developed and characterized some antibodies in single-chain format (scFvs) against the HPV16 E6 and E7 proteins, and demonstrated both in vitro and in vivo their antitumor activity consisting of protective efficacy against tumor progression of HPV16-positive cells.MethodsEnvisioning clinical application of the best characterized anti-HPV16 E6 and -HPV16 E7 scFvs, we verified their activity in the therapeutic setting, on already implanted tumors. Recombinant plasmids expressing the anti-HPV16 E6 scFvI7 with nuclear targeting sequence, or the anti-HPV16 E7 scFv43M2 with endoplasmic reticulum targeting sequence were delivered by injection followed by electroporation to three different preclinical models using C57/BL6 mice, and their effect on tumor growth was investigated. In the first model, the HPV16+ TC-1 Luc cells were used to implant tumors in mice, and tumor growth was measured by luciferase activity; in the second model, a fourfold number of TC-1 cells was used to obtain more aggressively growing tumors; in the third model, the HPV16+ C3 cells where used to rise tumors in mice. To highlight the scFv possible mechanism of action, H&E and caspase-3 staining of tumor section were performed.ResultsWe showed that both the anti-HPV16 E6 and HPV16 E7 scFvs tested were efficacious in delaying tumor progression in the three experimental models and that their antitumor activity seems to rely on driving tumor cells towards the apoptotic pathway.ConclusionBased on our study, two scFvs have been identified that could represent a safe and effective treatment for the therapy of HPV16-associated lesions. The mechanism underlying the scFv effectiveness appears to be leading cells towards death by apoptosis. Furthermore, the validity of electroporation, a methodology allowed for human treatment, to deliver scFvs to tumors was confirmed.

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Targeting Oncoproteins for Molecular Cancer Therapy

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