Peptide receptors are important for cancer therapies
Our understanding of estrogen signaling has increased significantly in recent decades. Research findings indicate that estrogen signaling is a balance between two opposing forces. The specific estrogen receptors (ERα and ERβ) and their splice variants were identified as the two major players in this receptor force-field. These receptors act as transcription factors and it was found that the two pathways involved can be selectively stimulated or inhibited using selective drugs. This opened up new promising therapeutic opportunities in clinical research areas as diverse as hormone replacement, autoimmune diseases, prostate and breast cancer, and depression. This invaluable information from molecular, biological, biochemical, and structural studies allows for the development of more selective and effective estrogen receptor (ER) ligands needed for the development of more effective drugs to modulate and regulate the action of these receptors. For example, anti-estrogens and aromatase inhibitors are now routinely used clinically to arrest the estrogen-dependent growth of breast cancer.
In addition, it is now also well known that ERs are over-expressed in approximately 70% of breast cancer cases. These types of cancers are referred to as "ER-positive" and a technique called immune-histochemistry can be used to reveal the over-expression of the receptors in tissue cells. Estrogen receptor proteins are found inside cells and are activated by the hormone estrogen or 17β-estradiol. In women the three major naturally occurring estrogens are estrone (E1), estradiol (E2), and estriol (E3). Estradiol is the predominant estrogen during the reproductive years. However, two classes of estrogen receptor have been found to exist; The first is ER which is a member of the nuclear hormone family of intracellular receptors. The other is GPR30, a member of the rhodopsin-like family of G protein-coupled receptors. It is now known that estrogens play key roles in the development and maintenance of normal sexual and reproductive functions.
Selective estrogen receptor modulators (SERMs) that act on the estrogen receptor, in addition to pure receptor agonists and antagonists are also investigated for their ability to selectively inhibit or stimulate estrogen-like action in various tissues. Also, enzyme inhibitors such as aromatase inhibitors which represent a newer drug type, are sometime, also used to treat breast cancer or to help keep breast cancer from reemerging after surgery.
The goal of these cancer drugs is to lower estrogen levels in the body so as to inhibit the growth of estrogen receptor-positive breast cancers. Another type of inhibitors called aromatase inhibitors, block estradiol synthesis and/or anti-estrogens that compete with hormone binding to the receptors. These drugs are now routinely prescribed. Unfortunately, the emergence of tumor resistance creates a need to develop new drug types. One promising approach is to design and synthesize peptides that can specifically inhibit intra- or inter-molecular interactions between proteins or peptide receptors and their target ligands or interfaces. Protein-protein interaction studies have allowed the identification of functional protein or peptide sequence motifs that are potentially suitable for the design of such antagonists. In addition, peptide and non-peptide mimics of these motifs are good candidates for this design or synthesis approach.
The following table shows a list of peptide receptors that are potential targets for new types of cancer therapies using peptide mimics.
Peptide receptors with a high potential in cancer therapy
| Peptide | Receptor subtypes | Expressing tumor type | Targeting agents |
| Somatostatin | sst1, sst2, sst3, sst4, and sst5 | GH-producing pituitary adenoma, paraganglioma, nonfunctioning pituitary adenoma, heochromocytomas | Radioisotopes, AN-201 (a potent cytotoxic radical 2-pyrrolino- doxorubicin), doxorubicin |
| Pituitary adenylate cyclase activating peptide (PACAP) | PAC1 | Pheochromocytomas and paragangliomas | Radioisotopes, doxorubicin |
| Vasoactive intestinal peptide (VIP/PACAP) | VPAC1, VPAC2 | Cancers of lung stomach, colon, rectum, breast, prostate, pancreatic ducts, liver, and urinary bladder | Radioisotopes, camptothecin |
| Cholecystokinin (CCK) | CCK1 (formerly CCK-A) and CCK2 | Small cell lung cancers, medullary thyroid carcinomas, astrocytomas, and ovarian cancers | Radioisotopes, cisplatin |
| Bombesin/gastrin- releasing peptide (GRP) | BB1, GRP receptor subtype (BB2), the BB3 and BB4 | Renal cell, breast, and prostate carcinomas | Doxorubicin, 2-pyrrolinodoxorubicin |
| Neurotensin | NTR1, NTR2, NTR3 | Small cell lung cancer, neuroblastoma, pancreatic and colonic cancer | Radioisotopes |
| Substance P | NK1 receptor | Glial tumors | Radioisotopes |
| Neuropeptide Y | Y1–Y6 | Breast carcinomas | Radioisotopes |
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Reference
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