Anti-Angiogenic Peptides from an Endogenous Protein
Angiogenesis is critical in tumor progression and metastasis in most, if not all, solid tumors; especially since a functional vascular supply is required for the continued growth of solid tumors and the spread of cancer cells. Small non-growing tumors may remain dormant for years and the angiogenic switch to aggressive metastatic phenotype involves a change in the local equilibrium between factors inducing blood vessel formation and those inhibiting the process.
There is an ongoing and unmet need to develop compositions and methods for inhibiting angiogenesis as a therapeutic modality for treating solid tumors, and in particular, for prophylaxis and/or therapy of prostate tumors.
Prior research has shown that peptides derived from PSA (human prostate specific antigen) are anti- angiogenic, and that the loss of PSA expression in multiple human tumors including prostate, breast, endometrial, cervical, and parotid cancers is correlated with poorer prognosis. Peptides derived from PSA represent an ideal therapeutic agent if they maintain the anti-angiogenic activity of the intact parent molecule because they would be less expensive to synthesize than to purify and because PSA as an endogenously produced molecule should be non- immunogenic.
In this invention, researchers at Roswell Park Comprehensive Cancer Center have demonstrated that PSA in which the serine-protease enzymatic activity has been completely ablated by incubation with Zn2+ is equally anti-angiogenic as enzymatically intact PSA. Furthermore, two of the five synthetic peptides that were based upon hydrophilic regions of native human PSA demonstrated approximately 40% of the anti-angiogenic activity of native PSA. Thus, this invention also provides evidence that the transcriptional, regulatory, anti-tumorigenic, and anti-angiogenic activity of human PSA are independent of the enzymatic activity of PSA.