Oncotarget: Exploring the role of survivin in neuroendocrine neoplasms


Volume 11, Issue 23 of @Oncotarget reported that tissue microarrays of 132 patients were stained for survivin using immunohistochemistry and correlated with outcomes.

Using a genomic database, the authors then correlated survivin mRNA expression with the radiosensitivity index in 52 samples of Neuroendocrine tumors. Finally, they studied the effect of radiation on survivin expression in human cell lines and the impact of knock-down of BIRC5 on cell proliferation and radiation sensitivity.

The authors found that survivin positivity by IHC correlated with shorter survival.

Radiation exposure increased BIRC5 gene expression in a human carcinoid cell line.

Survivin expression in Neuroendocrine tumors correlates with an inferior survival and survivin expression in human carcinoid cell lines increases after exposure to ionizing radiation.

Dr. Renuka Iyer from The Department of Medicine at Roswell Park Comprehensive Cancer Center in Buffalo, New York said, "Neuroendocrine tumors (NET) are a heterogeneous group of neoplasms that arise from neuroendocrine cells or their precursors."

NET can occur throughout the body but is mostly associated with the digestive or bronchopulmonary systems.

Classification of NET ranges from well-differentiated neuroendocrine tumors to poorly differentiated neuroendocrine carcinomas based on their morphology and histological grade assessed by the Ki-67 proliferation index or a number of mitoses per 10 high-powered fields.

Figure 5: BIRC5 mRNA Expression in NET Cell Line.

Figure 5: BIRC5 mRNA Expression in NET Cell Line. (A). Radiation increases BIRC5 gene expression of NCI-H720 cells. Cells growing as clusters in suspension in triplicate wells were subjected to one dose of 15 Gy X ray radiation. Control cells (0 Gy) were not subjected to radiation. After 2 days, BIRC5 gene expression normalized to that of housekeeping ACTB gene was quantified by reverse transcription-PCR. Mean and range (n = 3) of relative BIRC5 expression are depicted. (B) siRNA-mediated BIRC5 knock-down in NCI-H720 cells. Single-cell suspensions of NCI-H720 were transfected with a non-specific siRNA (Neg. ctrl.) or with one of two siRNAs against BIRC5 (BIRC5#1 and #2) at a concentration of 8 nM. Whole cell lysates were prepared from the transfectants after 2 days and subjected to immunoblotting to detect BIRC5 and housekeeping calnexin proteins. Different portions of the same blot were used to detect the two proteins. Relative band intensities as measured by image densitometry are listed. (C) BIRC5 knock-down reduces NCI-H720 proliferation. Cells were transfected with siRNAs as described for panel B. Average cross-sectional area of cell clusters in cultures of transfectant cells 6 and 9 days after siRNA transfection was determined by quantitative analysis of light microscopy images. Mean and range (n = 3) of fold-change in the average cross-sectional area of cell clusters during the 3 days are depicted. (D) BIRC5 knock-down does not enhance radiation sensitivity of NCI-H720 cells. Cells were transfected with siRNAs as described for panel B and transfectants were dissociated a day later into single-cell suspensions (0.2 million cells/ml) and immediately treated with a single dose of radiation (1.5, 3, or 6 Gy). Average cross-sectional area of cell clusters in cultures of transfectant cells 6 days after radiation was determined by quantitative analysis of light microscopy images. Mean and range (n = 4) of average cell cluster radius relative to non-irradiated (0 Gy) cells are shown.

Tumors that progress on first-line therapies has limited systemic options that include cytotoxic chemotherapy, molecularly targeted therapy, interferon- and more recently, peptide receptor radioligand therapy.

To test the potential of survivin as a prognostic marker and therapeutic target the authors evaluated survivin expression in NET and correlated it with clinical outcomes using annotated tumor tissue microarrays from patients with NETs. To better understand the role if any survivin in NETs of lung origin, using a genomic database the authors correlated the survivin mRNA expression with sensitivity to radiation using the validated radio-sensitivity index.

Finally, to determine if survivin targeting may increase response to radiation, the authors assessed change in survivin expression in a pulmonary carcinoid cell line in response to radiation and effects of survivin knockdown using si RNA on cell proliferation and radiation sensitivity.

The Iyer Research Team concluded in their Oncotarget Research Paper that these observations led to attempts at creating a vaccine that can trigger a stronger immune response against survivin.

Several vaccine approaches targeting survivin have been evaluated in clinical or pre-clinical studies, including dendritic cell vaccines, DNA vaccines, and peptide vaccines, with variable responses.

More recently, researchers at Roswell Park developed a survivin long peptide-mimic vaccine, Sur Vax M, that was shown to generate survivin-specific immunological response through activation of CD8+ CTL as well as CD4+ helper T cells.

Based on the safety and efficacy signal of this vaccine in malignant gliomas that are survivin positive by IHC and our finding of survivin being a prognostic marker and present in NETs, the authors find survivin to be a potential target in NET and have begun a pilot trial of Sur Vax M in survivin expressing NETs. Its association with RSI makes it an attractive candidate to be targeted using combination strategies using PRRT upon completion of further preclinical studies testing Sur Vax M, survivin antibodies and CAR T-cell approaches to guide optimal therapy and sequencing schedule.

"The authors find survivin to be a potential target in NET and have begun a pilot trial of Sur Vax M in survivin expressing NETs"

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DOI - https://doi.org/10.18632/oncotarget.27631

Full text - https://www.oncotarget.com/article/27631/text/

Correspondence to - Renuka Iyer - Renuka.Iyer@RoswellPark.org

Keywords - neuroendocrine tumors, survivin, immunohistochemistry, biomarkers, radiosensitivity

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