Protease activated receptors (PAR) mimetics for cancer treatment
Target-specific approaches are recognized as the basis for novel cancer therapeutics. Protease-Activated-Receptors (PARs), a G Protein-Coupled Receptor, play central roles in tumor progression. PARs are over-expressed in a wide range of epithelial malignancies relative to normal epithelium, thus offering the opportunity for a tumor-specific drug. The PAR C-terminal PH domain binds to other proteins that have a key role in tumorigenesis, suggesting that this domain might be effectively targeted by a novel therapeutic.
PAR1 or PAR2 overexpression enhances breast tumor growth in a mouse xenograft model of breast cancer. PAR1 and PAR2 act as a functional heterodimeric unit during tumor development. It was shown that inhibition of PAR2 expression or activity either by a non-functional PAR2 protein or by knocking-down of PAR2 expression attenuates the activity of both PAR1 and PAR2.
Researchers from Hadassah have developed peptides mimicking the primary binding site on the PAR2 C-terminal PH-domain as a potential therapeutic for epithelial cell tumors. A peptide from the PAR2 PH domain inhibits the growth of tumors driven by PAR1/PAR2overexpression.
Cancer indications include breast, ovary, prostate, colon & melanoma.
Breast cancer, as the leading indication, is treated with monoclonal antibodies (Herceptin for Her2+ tumors), hormone-blocking therapy & chemotherapy. The estimated market is ~$10B (mostly Herceptin) and growing with increased disease incidence. Given PAR expression in epithelial tumors, additional cancer indications include ovary, prostate, colon & melanoma – each a growing >$1B market and in some cases $10B in the future. Since the mechanism of action of the PAR peptide is orthogonal to that of other drugs, the new drug is expected to be used in combination with other available drugs.
US Patent granted (9,745,347)
Nag, Jeetendra Kumar et al. “PH-Binding Motif in PAR4 Oncogene: From Molecular Mechanism to Drug Design.” Molecular cancer therapeutics vol. 21,9 (2022): 1415-1429. doi:10.1158/1535-7163.MCT-21-0946