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May 11, 2011

Cancer Screening Approach Using HSV to Force Cells to Secrete Biomarker Developed

  • Scientists have developed a cancer screening approach that uses a tumor-selective engineered herpes simplex virus to force malignant cells to secrete a protein biomarker that can be detected in urine or blood serum. The scientists, at Cincinnati Children’s Hospital Medical Center and Cincinnati University, tested the approach in mice with different tumor types.

    They found that after systemic injection of the virus, the biomarker was detectable at high levels in the blood of cancer-bearing mice, but was virtually absent in control animals. The researchers suggest that modifying the approach further could enable the production of a screening system that not only results in biomarker secretion for early cancer diagnosis but also has stand-alone oncolytic activity.

    The research is published in PLoS One in a paper titled “Cancer Screening By Systemic Administration of a Gene Delivery Vector Encoding Tumor-Selective Secretable Biomarker Expression.”  

    Cancer-associated blood biomarkers such as prostate specific antigen (PSA) and alpha fetoprotein have been identified for a few tumor types, but not for most pediatric or adult cancers, report Timothy Cripe, M.D., senior author and a researcher at Cincinnati Children’s Hospital.

    In an attempt to develop a universal approach for minimally invasive cancer screening, the team developed a prototype virus-based screening strategy whereby genetic information encoding a universal serum biomarker for cancer could be injected into a patient systemically, delivered to and expressed within tumor cells selectively, and result in the ability to diagnose cancer in blood or urine.

    The team chose an HSV mutant known as rQ-M38G, which selectively replicates in cancer cells. They then engineered the mutant so that cancer cells replicating the virus would produce and secret the protein biomarker Gaussia luciferase (GLuc), which the researchers claim is 1,000 times brighter than other luciferases, more sensitive than secretable alkaline phosphatase, and detectable in blood and urine in vivo.  

    Having confirmed that the virus had the desired effect in cultured cells, the team then moved on to in vivo studies. They injected mice with tumor cells, and five weeks later both the tumor-implanted mice and tumor-free control animals were intravenously injected with the engineered rQ-M38G virus.

    Compared with control animals, all the mice that had developed a detectable tumor burden demonstrated 15- to 440-fold higher serum GLuc level within just days. Two of the animals injected with cancer cells didn’t develop tumors, and in these animals GLuc was also undetectable. Further examination of sacrificed animals confirmed that the virus had accumulated almost exclusively in tumors, which was confirmed by immunofluorescence and qPCR.

    Similar results were obtained when the researchers carried out a similar test using tumor models that were less susceptible to virus infection, including models of malignant peripheral nerve sheath tumors.

    A critical feature for cancer screening is the ability to detect small tumors, ultimately in people, the researchers point out, and one concern was that small tumors may be associated with less vascular surface area available for HSV entry. However, this issue did not appear to be a limitation in mice, they point out, because in some of the models it was possible to detect tumors as small as 4–5 mm in diameter. In another model the technique was capable of identifying microscopic tumor burden.

    They admit that scalability to humans, which have larger blood volumes, is difficult to predict. Dr. Cripe’s team were aware that small animal models used to detect minimal tumor burdens present theoretical challenges when translating findings to human scale. To try and determine the potential scalability of the approach, the researchers used a range of in vitro assays and in vivo tumor burden tests to evaluate the theoretical detection limits for the biomarker.

    They calculated that GLuc production could be detected if just 1,000 tumor cells were infected with the virus in a volume of cell culture media equal to a mouse blood volume. “Under these conditions infecting 10% of the cells in a tumor of diameter 400 μm (104 cells) would be detectable in a mouse,” they write.

    Using their calculations, the theoretical limit of detection when infecting 10% of tumor cells extrapolates to 1–4 mm tumor diameter in a human. Even if only 1% of tumor cells are transduced by the virus in humans, tumors as small as 8.5 mm might still be detectable, they note. “This sensitivity suggests strong potential for identifying minimal tumor burdens even when scaled to human proportions.”

    The Cincinnati team’s work provides proof-of-principle that the approach is at least feasible as a screening system for cancer. Moreover, Dr. Cripes and colleagues conclude, “it is possible our strategy could be further refined by the use of a more robust cancer-dependent promoter to drive biomarker expression. Improved vector delivery to the tumor may also be achieved using tumor targeting small molecule and nanoparticle uptake-enhancement strategies.”

    Ultimately, it may be possible to develop a biomarker secretion system as a universal cancer screening approach. “The impact of this approach would revolutionize the technology for cancer detection in industrialized nations and the developing world where imaging and biopsy-based diagnostics may not be as readily available.”


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