Broad-spectrum anti-tumor and anti-metastatic DNA vaccine based on p62-encoding vector
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Franco Venanzi1,*, Victor Shifrin2,*, Michael Y. Sherman3, Vladimir Gabai2, Oleg Kiselev4, Andrey Komissarov4, Mikhail Grudinin4, Maria Shartukova4, Ekaterina A. Romanovskaya-Romanko4, Yuri Kudryavets5, Natalya Bezdenezhnykh5, Oleksandra Lykhova5, Nadiia Semesyuk5, Antonio Concetti1, Anatoly Tsyb6, Marina Filimonova6, Victoria Makarchuk6, Raisa Yakubovsky7, Andrey Chursov2, Vita Shcherbinina2 and Alexander Shneider2
1. Laboratory of Translational Biology, Department of Biology MCA, University of Camerino, 62032, Italy
2. CureLab Oncology, Inc, Needham, MA, 02492, USA
3. Dept Biochem, Boston University School of Medicine, Boston MA, 02118, USA
4. Research Institute of Influenza, St-Petersburg, 197376, Russia
5. R.E.Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology of NAS of Ukraine, Kiev, 03022, Ukraine
6. Medical Radiology Reseach Center, Obninsk, 249036, Russia
7. Gertzen Research Oncology Institute, Moscow, 125284, Russia
* These authors contributed equally
Alexander Shneider, email:
Keywords: cancer immunotherapy, DNA vaccine, autophagy, metastases
Received: September 10, 2013 Accepted: September 30, 2013 Published: October 2, 2013
Autophagy plays an important role in neoplastic transformation of cells and in resistance of cancer cells to radio- and chemotherapy. p62 (SQSTM1) is a key component of autophagic machinery which is also involved in signal transduction. Although recent empirical observations demonstrated that p62 is overexpressed in variety of human tumors, a mechanism of p62 overexpression is not known. Here we report that the transformation of normal human mammary epithelial cells with diverse oncogenes (RAS, PIK3CA and Her2) causes marked accumulation of p62. Based on this result, we hypothesized that p62 may be a feasible candidate to be an anti-cancer DNA vaccine. Here we performed a preclinical study of a novel DNA vaccine encoding p62. Intramuscularly administered p62-encoding plasmid induced anti-p62 antibodies and exhibited strong antitumor activity in four models of allogeneic mouse tumors – B16 melanoma, Lewis lung carcinoma (LLC), S37 sarcoma, and Ca755 breast carcinoma. In mice challenged with Ca755 cells, p62 treatment had dual effect: inhibited tumor growth in some mice and prolonged life in those mice which developed tumor size similar to control. P62-encoding plasmid has demonstrated its potency both as a preventive and therapeutic vaccine. Importantly, p62 vaccination drastically suppressed metastasis formation: in B16 melanoma where tumor cells where injected intravenously, and in LLC and S37 sarcoma with spontaneous metastasis. Overall, we conclude that a p62-encoding vector(s) constitute(s) a novel, effective broad-spectrum antitumor and anti-metastatic vaccine feasible for further development and clinical trials.
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