Description:
Project ID: D2009-27
Background:
Prostate cancer, the second leading cause of cancer deaths among men, largely depends upon androgens for its development and progression. The importance of the Androgen Receptor in the development of prostate cancer is demonstrated by the success of anti-androgen therapy at the early stages of prostate cancer. Hormone ablation therapies continue to dominate the market, as they have proven to be the most effective at treating the early stage prostate cancer, which is hormone-dependent. However, this therapy and others currently used are ineffective against late stage prostate cancer (castration-resistant prostate cancer), which is hormone-refractory and usually lethal.
Another important signaling pathway in prostate cancer is mediated by EZH2 (Enhancer of Zeste 2) in a complex with EED and SUZ12 to form Polycomb Repressor Complex 2 (PRC2). It has been shown that EZH2 and the PRC2 complex are over-expressed in metastatic prostate tumors and considered as an excellent biomarker for the same.
Invention Description:
Researchers at the University of Toledo have developed a family of short amino-acid peptides (up to five aa) that are strongly cytotoxic to both hormone-dependent and, significantly, hormone-refractory prostate cancer cells and could result in therapy against lethal castration-resistant prostate cancer.
This invention is based on the recent discovery of the α1-subunit gene of soluble guannylyl cyclase (sGC) as a novel androgen receptor (AR)-regulated gene whose expression correlates with the growth properties of prostate cancer cells and increases with increasing grade of prostate cancer. The researchers demonstrated that sGCα1 is significantly elevated in advanced prostate cancer and provides cancer cells a pro-survival function, via a novel mechanism for p53 inhibition. They also showed that disruption of sGCα1 expression severely compromises the growth of both androgen-dependent and androgen-independent AR-positive cancer cells. Further, these positive effects of sGCα1 on prostate cancer cells are seen to be independent of its enzymatic activity on cGMP synthesis and known mediators of nitric oxide (NO) signaling [1]. The results of these studies make sGCα1 an important novel target for prostate cancer therapy.
It was also found that the mechanism of cytotoxicity is generation of reactive oxygen species, which recently have been recognized as a major mode of action of important cancer drugs. Our scientists also showed the inhibition effect of peptide A-8R on growth of pancreatic cancer cells, thus opening the possibility of treating other cancers having over-expression of sGCα1 by these peptides.
In their continued work to study the cytotoxic and anti-cancer activities of peptide A-8R and derivatives, our researchers have identified, from collaborative work with another group, that some derivatives of peptide A-8R have potent activity against EZH2, a member of the PRC2 complex that is an important epigenetic regulator of genes, with particular significance in cancer. Indeed, it has been clearly demonstrated that EZH2 activity is over-expressed in multiple cancers, making this protein an important novel target for cancer therapy that many labs and pharmaceutical companies are working on. The collaborative work has enabled our researchers to identify important biochemical features of the novel peptides essential for their anti-EZH2 activity. A summary of the anti-EZH2 data is shown in the table below.
Thus, these novel peptides act on two different targets important for the survival and progression of cancer:
i. sGCα1, the original target of peptide A-8R that has significant pro-survival and pro-growth functions in prostate cancer and perhaps other cancers.
ii. EZH2.
Peptide | EZH2 Inhibition (IC50 in µM) | Alpha values for SAM Comp. | Alpha values for Peptide Comp. |
#1 | 2.236 | 1.52 (not competitive) | 1000 (competitive) |
#2 | 0.627 | | |
#3 | 0.548 | 3.07 (not competitive) | 14 (not declarable) |
#4 | 0.841 | 3.58 (not competitive) | 1000 (competitive) |
#5 | 2.33 | 2.50 (not competitive) | 244 (competitive) |
Table. EZH2 inhibitory activity of Peptide A-8R derivatives.
Applications:
In treatment of late-stage prostate cancer and cancer-related conditions.
This invention can also be used as an effective therapeutics for any EZH2 mediated cancer.
IP Status:
US issued patent – US 8,575,087B2
Other patents pending
Publications:
1. Androgen regulation of soluble guanylyl cyclasealpha1 mediates prostate cancer cell proliferation. Oncogene. 2007 Mar 8;26(11):1606-15 [Link]
2. A peptide against soluble guanylyl cyclase α1: a new approach to treating prostate cancer. PLoS One. 2013 May 27;8(5) [Link]
3. COP9 subunits 4 and 5 target soluble guanylyl cyclase α1 and p53 in prostate cancer cells. Mol Endocrinol. 2014 Jun;28(6):834-45 [Link]