Compositions and methods of treatment of cancers
Patent Number: US9546196

Executive Summary:
  • Invention Type: Therapeutic
  • Patent Status: US Grant
  • Patent Link: https://patents.google.com/patent/US9546196/
  • Research Institute: University of Toledo
  • Disease Focus: Prostate cancer
  • Basis of Invention: Peptide-based approach for blocking soluble guanylyl cyclase a1 (sGCa1) pro-cancer functions
  • How it works: The peptide A-8R mimics the sGCb1 heterodimerization domain that binds to sGCa1 to disrupt its function
  • Lead Challenge Inventor: Lirim Shemshedini
  • Inventors: Shao-Yong Chen, Changmeng Cai, Chen-Lin Hsieh, Lirim Shemshedini
  • Development Stage: Lead optimization
  • Novelty: Novel molecular target and peptide
  • Clinical Applications: Treatment of castration-resistant prostate cancer

General Description:
sGCa1 drives prostate cancer cell proliferation by blocking p53 activity. sGCa1 expression increases with advancing stages of cancer. The peptide A-8R was designed to target and inhibits this protein.

Scientific Progress:
Among the 4 peptides synthesized and tested, A-8R showed the strongest cytotoxic activity against several prostate cancer cells and castration-resistant prostate tumors in mouse xenograft studies.

Future Directions:
  • Tumor-targeting delivery system to enhance A-8R cytotoxic activity
  • In vivo PK/PD
  • Clinical proof-of-concept

Strengths:
  • Novel molecular target
  • First-in-class peptide

Weaknesses:
  • Competition with other antiandrogens in development for the treatment of advanced prostate cancer
  • Peptide
 
Patent Status:
Legal Status: Active
  • Priority date: 2009.05.30
  • Filing date: 2016.02.10
  • Publication date: 2017.01.17
  • Grant date: 2017.01.17

Publication PMID: 22174378, 23724033, 24236047, 24725084

Publications:
Cai C, Hsieh CL, Gao S, Kannan A, Bhansali M, Govardhan K, Dutta R, Shemshedini L. Soluble guanylyl cyclase α1 and p53 cytoplasmic sequestration and down-regulation in prostate cancer. Mol Endocrinol. 2012 Feb;26(2):292-307. doi: 10.1210/me.2010-0394. Epub 2011 Dec 15.

Gao S, Hsieh CL, Bhansali M, Kannan A, Shemshedini L. A peptide against soluble guanylyl cyclase α1: a new approach to treating prostate cancer. PLoS One. 2013 May 27;8(5):e64189. doi: 10.1371/journal.pone.0064189. Print 2013.

Gao S, Hsieh CL, Zhou J, Shemshedini L. Zinc Finger 280B regulates sGCα1 and p53 in prostate cancer cells. PLoS One. 2013 Nov 13;8(11):e78766. doi: 10.1371/journal.pone.0078766. eCollection 2013.

Bhansali M, Shemshedini L. COP9 subunits 4 and 5 target soluble guanylyl cyclase α1 and p53 in prostate cancer cells. Mol Endocrinol. 2014 Jun;28(6):834-45. doi: 10.1210/me.2014-1017. Epub 2014 Apr 11.

Inventor Bio: Lirim Shemshedini
http://www.utoledo.edu/nsm/bio/research/shemshedini.html