Broad-spectrum anti-tumor and anti-metastatic DNA vaccine based on p62-encoding vector

Abstract

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.

p62/SQSTM1 – steering the cell through health and disease

“…osteosarcoma, oral squamous cell carcinoma, cutaneous malignant melanoma, esophageal adenocarcinoma, ovarian, colon, breast and non-small cell lung cancers, and solid tumors Daniels et al, 2013;Ellis et al, 2014;Giatromanolaki et al, 2014;Inoue et al, 2012;Iwadate et al, 2014;Liu et al, 2014a;Luo et al, 2013;Ma et al, 2018;Niklaus et al, 2017;Park et al, 2013;Ruan et al, 2018;Schläfli et al, 2016), and has attracted attention as a potential therapeutic target (Yan et al, 2017;Zhang et al, 2016). An antitumor SQSTM1 DNA vaccine has already been developed and trialed in humans (Gabai et al, 2014;Ponomarenko et al, 2017;Sabbieti et al, 2015;Venanzi et al, 2013); however, SQSTM1 can have both beneficial and deleterious effects depending on the pathological context, as is the case for autophagy itself (Dikic and Elazar, 2018). Then, any hope to develop successful therapeutic strategies in pathologies with SQSTM1 alterations needs to keep in mind the complexity of the SQSTM1 signaling network and how it is affected in each particular disease situation: its tight posttranslational regulation, its role in autophagy, its function in the Keap1-Nrf2 axis and its role as a signaling hub.…”

p62/SQSTM1 expression in canine mammary tumours: Evolutionary notes

“…Of note p62 DNA treatment of patients partially restored their sensitivity to conventional chemotherapy which they previously failed . However, it remains to be revealed if the anti‐cancer activity of p62‐encoding plasmid in humans is due to a direct adaptive immune response it elicits against the over‐expressed p62 as it was originally hypothesized or if the anti‐cancer effect results from the fact that the plasmid reduces chronic inflammation as observed in animal models for osteoporosis, age‐related macular degeneration and diet‐induced obesity .…”

“…More than 30 clinical studies are reported already testing autophagy inhibitors instead of, or in combinations with other types of cancer therapy . Simultaneously, preclinical studies aim to develop drugs and vaccines targeting p62 to fight cancer …”

Expression and Clinical Implication of Autophagy-Associated Protein p62 in Osteosarcoma

“…p62 vaccination has been used to suppress tumor metastasis in mice with sarcoma and in dogs with mammary tumors. It also dramatically decreased the number and sizes of lung or lymphatic metastases [45-47]. For improving the treatment of osteosarcoma, p62 vaccine may also be used as a novel cancer therapy for osteosarcoma in the future.…”