Therapeutic potential of adenovirus-mediated TFF2-CTP-Flag peptide for treatment of colorectal cancer

Zinaida A. Dubeykovskaya, Phaneendra Kumar Duddempudi, Huan Deng, Giovanni Valenti, Krystle L. Cuti, Karan Nagar, Yagnesh Tailor, Chandan Guha, Jan Kitajewski, Timothy C. Wang

Research output: Contribution to journalArticle

Abstract

TFF2 is a small, secreted protein with anti-inflammatory properties. We previously have shown that TFF2 gene delivery via adenovirus (Ad-Tff2) suppresses colon tumor growth in colitis associated cancer. Therefore, systemic administration of TFF2 peptide could potentially provide a similar benefit. Because TFF2 shows a poor pharmacokinetic, we sought to modify the TFF2 peptide in a manner that would lower its clearance rate but retain bioactivity. Given the absence of a sequence-based prediction of TFF2 functionality, we chose to genetically fuse the C-terminus of TFF2 with the carboxyl-terminal peptide of human chorionic gonadotropin β subunit, and inserted into adenoviral vector that expresses Flag. The resulting Ad-Tff2-CTP-Flag construct translates into a TFF2 fused with two CTP and three Flag motifs. Administered Ad-Tff2-CTP-Flag decreased tumorigenesis and suppressed the expansion of myeloid cells in vivo. The fusion peptide TFF2-CTP-Flag delivered by adenovirus Ad-Tff2-CTP-Flag as well purified recombinant fusion TFF2-CTP-Flag was retained in the blood longer compared with wild-type TFF2 delivered by Ad-Tff2 or recombinant TFF2. Consistently, purified recombinant fusion TFF2-CTP-Flag suppressed expansion of myeloid cells by down-regulating cyclin D1 mRNA in vitro. Here, we demonstrate for the very first time the retained bioactivity and possible pharmacokinetic advantages of TFF2 with a modified C-terminus.

Original languageEnglish (US)
JournalCancer Gene Therapy
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Cytidine Triphosphate
Adenoviridae
Colorectal Neoplasms
Peptides
Myeloid Cells
Therapeutics
Pharmacokinetics
Cyclin D1
Chorionic Gonadotropin
Colitis
Neoplasms
Colon
Carcinogenesis
Anti-Inflammatory Agents
Messenger RNA
Growth
Genes

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Cancer Research

Cite this

Dubeykovskaya, Z. A., Duddempudi, P. K., Deng, H., Valenti, G., Cuti, K. L., Nagar, K., ... Wang, T. C. (Accepted/In press). Therapeutic potential of adenovirus-mediated TFF2-CTP-Flag peptide for treatment of colorectal cancer. Cancer Gene Therapy. https://doi.org/10.1038/s41417-018-0036-z

Therapeutic potential of adenovirus-mediated TFF2-CTP-Flag peptide for treatment of colorectal cancer. / Dubeykovskaya, Zinaida A.; Duddempudi, Phaneendra Kumar; Deng, Huan; Valenti, Giovanni; Cuti, Krystle L.; Nagar, Karan; Tailor, Yagnesh; Guha, Chandan; Kitajewski, Jan; Wang, Timothy C.

In: Cancer Gene Therapy, 01.01.2018.

Research output: Contribution to journalArticle

Dubeykovskaya, ZA, Duddempudi, PK, Deng, H, Valenti, G, Cuti, KL, Nagar, K, Tailor, Y, Guha, C, Kitajewski, J & Wang, TC 2018, 'Therapeutic potential of adenovirus-mediated TFF2-CTP-Flag peptide for treatment of colorectal cancer', Cancer Gene Therapy. https://doi.org/10.1038/s41417-018-0036-z
Dubeykovskaya, Zinaida A. ; Duddempudi, Phaneendra Kumar ; Deng, Huan ; Valenti, Giovanni ; Cuti, Krystle L. ; Nagar, Karan ; Tailor, Yagnesh ; Guha, Chandan ; Kitajewski, Jan ; Wang, Timothy C. / Therapeutic potential of adenovirus-mediated TFF2-CTP-Flag peptide for treatment of colorectal cancer. In: Cancer Gene Therapy. 2018.
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