Replicative oncolytic adenovirus for regulating lipid metabolism and use thereof

Abstract

Provided are embodiments of replicative oncolytic adenovirus AD5 ApoA1 for inhibiting tumor growth and metastasis and use thereof in preparation of anti-tumor drugs. The virus can rapidly replicate in tumor cells and exert an oncolytic effect. Tumor cells infected with the virus can highly express apolipoprotein ApoA1 which can be secreted extracellularly in large quantities, significantly inhibit the invasion and metastasis of tumor cells, inhibit tumor-promoting inflammation pathways, and significantly reduce a IDO-1 which is a key molecule that leads to tumor immune escape. The virus can significantly inhibit tumor growth, inhibit tumor invasion, delay progression of cachexia and prolong the survival time of tumor-bearing mice in mice with liver cancer, breast cancer, colon cancer, or lung cancer.

1 . A replicative oncolytic adenovirus vector comprising: a first promoter, an E1A early activation replication element, an insulator sequence, a second promoter, and a target gene sequence, wherein:
 the target gene is inserted into an E1 region of an oncolytic adenovirus;   the target gene sequence comprises a signal peptide recognition sequence or a degenerate sequence thereof, and an ApoA1 gene or a degenerate sequence thereof.   
     
     
         2 . The replicative oncolytic adenovirus vector according to  claim 1 , wherein:
 (1) the target gene sequence is SEQ ID NO:1;   (2) the first promoter is a constitutive promoter, a specific promoter, or an inducible promoter; and the second promoter is a constitutive promoter; and/or   (3) the adenovirus is of subtype C.   
     
     
         3 . The replicative oncolytic adenovirus vector according to  claim 2 , wherein the constitutive promoter is CMV, SV40, or EF1a promoter. 
     
     
         4 . The replicative oncolytic adenovirus vector according to  claim 3 , wherein the constitutive promoter is CMV having a nucleic acid sequence of SEQ ID NO:2. 
     
     
         5 . A replicative oncolytic adenovirus, comprising the replicative oncolytic adenovirus vector according to  claim 1 . 
     
     
         6 . The replicative oncolytic adenovirus according to  claim 5 , wherein the replicative oncolytic adenovirus expresses ApoA1 proteins in host cells and extracellularly secretes ApoA1 proteins. 
     
     
         7 . The replicative oncolytic adenovirus according to  claim 5 , wherein an amino acid sequence of the protein expressed by the target gene is SEQ ID NO:3. 
     
     
         8 . The replicative oncolytic adenovirus according to  claim 5 , wherein the virus is obtained by recombination of the replicative oncolytic adenovirus vector according to  claim 1  in 293T cells. 
     
     
         9 . A method for treating or preventing a tumor in a subject comprising administering to the subject a therapeutically effective amount of the replicative oncolytic adenovirus vector according to  claim 1 . 
     
     
         10 . A method for treating or preventing a tumor in a subject comprising administering to the subject a therapeutically effective amount of the replicative oncolytic adenovirus according to  claim 5 . 
     
     
         11 . The method according to  claim 9 , wherein the replicative oncolytic adenovirus vector is administered in a single-drug therapy, adjuvant therapy, or combination therapy. 
     
     
         12 . The method according to  claim 10 , wherein the replicative oncolytic adenovirus vector is administered in a single-drug therapy, adjuvant therapy, or combination therapy. 
     
     
         13 . The method according to  claim 9 , wherein the tumor is selected from the group consisting of liver cancer, breast cancer, lung cancer, colon cancer, stomach cancer, pancreatic cancer, cervical cancer, melanoma, prostate cancer, ovarian cancer, lymphoma, gallbladder cancer, esophageal cancer, kidney cancer, nasopharyngeal cancer, laryngeal cancer, thyroid tumor, mediastinal tumor, bladder cancer, and glioma. 
     
     
         14 . The method according to  claim 10 , wherein the tumor is selected from the group consisting of liver cancer, breast cancer, lung cancer, colon cancer, stomach cancer, pancreatic cancer, cervical cancer, melanoma, prostate cancer, ovarian cancer, lymphoma, gallbladder cancer, esophageal cancer, kidney cancer, nasopharyngeal cancer, laryngeal cancer, thyroid tumor, mediastinal tumor, bladder cancer, and glioma. 
     
     
         15 . The method according to  claim 9 , further comprising inhibiting tumor invasion and/or metastasis. 
     
     
         16 . The method according to  claim 10 , further comprising inhibiting tumor invasion and/or metastasis. 
     
     
         17 . The method according to  claim 9 , further comprising inhibiting tumor inflammation pathways, inhibiting IDO-1, and/or restoring anti-tumor immune surveillance. 
     
     
         18 . The method according to  claim 10 , further comprising inhibiting tumor inflammation pathways, inhibiting IDO-1, and/or restoring anti-tumor immune surveillance. 
     
     
         19 . The method according to  claim 9 , further comprising delaying a cachexia progress of a malignant tumor. 
     
     
         20 . (canceled) 
     
     
         21 . The method according to  claim 9 , further comprising up-regulating expression of an ApoA1 specific receptor ABCA1 in infected tumor cells. 
     
     
         22 . (canceled)