Experimental cancer therapy using restoration of NAD+ -linked 15-hydroxyprostaglandin dehydrogenase expression

Area of Science:

• Oncology
• Molecular Biology
• Gene Therapy

Background:

• Cyclooxygenase-2 (Cox-2) mediated prostaglandin E(2) (PGE(2)) overexpression promotes tumor growth, metastasis, and immunosuppression.
• NAD(+)-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH), crucial for PGE(2) inactivation, is suppressed in many cancers, including breast and colon carcinoma.

Purpose of the Study:

• To investigate the in vitro cytotoxicity and in vivo therapeutic efficacy of 15-PGDH-mediated cancer therapy.
• To explore the role of PGE(2) and VEGF expression in cancer cells and their correlation with receptor and promoter expression.

Main Methods:

• Development of adenoviral vectors (Ad) expressing 15-PGDH under control of VEGFR1/flt-1 and Cox-2 promoters.
• In vitro assessment of Ad-mediated 15-PGDH expression on cancer cell proliferation and migration.
• In vivo studies using animal models of breast and colon tumors to evaluate 15-PGDH gene therapy efficacy, alone and in combination with anti-VEGF antibody (bevacizumab).

Main Results:

• Ad-mediated 15-PGDH expression significantly reduced cancer cell proliferation and migration in vitro.
• 15-PGDH gene therapy significantly delayed tumor growth in preclinical models of breast and colon cancer.
• Combined therapy with 15-PGDH and bevacizumab demonstrated significantly enhanced inhibition of tumor xenograft growth compared to monotherapy.

Conclusions:

• 15-PGDH-mediated regulation of PGE(2) catabolism in the tumor microenvironment is a promising therapeutic strategy.
• Gene therapy targeting 15-PGDH offers a novel approach for treating human breast and colon cancers.
• Combination therapy with 15-PGDH and anti-VEGF agents may provide superior anti-cancer efficacy.