Cancer refers to the uncontrolled division of cells and the ability of those cells to attack cells in neighboring organs to form tumor masses before spreading to other parts of the body. Although angiogenesis, or the development of new blood vessels from existing blood vessels, is a vital process for growth and development, it is also one of the steps used by tumors in transitioning from a tumor-dormant state to a malignant state. Therefore, one of the processes that have been explored in suppressing the growth of tumor cells is the smart use of angiogenesis inhibitors.
Chemotherapy is one of the popular approaches currently used in the treatment of cancer. With this approach, a cytotoxic agent is usually delivered to the cancer cells, with the hope that the agent will kill the cancer cells and stop their further growth, development, and spread within the body.
However, one of the challenges that comes with the classic use of chemotherapy is the lack of the ability to administer the right amount of drugs directly to the cancer cells without any adverse effects on the normal, healthy cells. The other challenges faced with conventional chemotherapies include premature clearance, biotransformation, altered blood distribution, and drug resistance.
To overcome such challenges associated with chemotherapies, targeted chemotherapies, as well as targeted drug delivery systems, are currently being explored. If these approaches used to circumvent the adverse side-effects of chemotherapy are successful, then it will be possible to select and effectively localize the drugs at pre-defined sites, while at the same time reducing the chances of the drug affecting other healthy normal cells.
The discovery of additional receptors that are abnormally overexpressed in cancer cells as well as tumor-related peptides have led to the design and development of a new era of more effective and selective anti-cancer drugs.
Some of the biologics approaches to cancer therapies feature the use of proteins, peptides, and monoclonal antibodies. The use of monoclonal antibodies (mAb), as well as large protein ligands, come with two major challenges when compared to the use of peptides.
Firstly, monoclonal antibodies and large protein ligands are poorly delivered to the tumors because of their large sizes.
Secondly, they come with dose-limiting toxicity to the liver as well as the bone marrow because of their non-specific uptake into the reticuloendothelial system. Due to these limitations, their applications have thus been restricted to vascular targets found in the luminal side of the tumor vessel, and to hematological malignancies.
Peptides, on the other hand, boast many advantages, including ease of modification, ease of synthesis, and their small sizes. Also, peptides are biocompatible and have the ability to successfully penetrate tumor tissues.
It is also possible to prevent the proteolytic degradation of peptides through various chemical interventions such as the inclusion of D-amino acid or processes such as cyclization. It is also worth pointing out that bicyclic peptides come with even better properties when compared to those present in antibody drugs. Currently, there are two main classifications of the peptide drugs in the market: analogs and antagonists of peptides hormones or tumor-targeting agents carrying radionuclides.
Agonists and Antagonists
Luteinizing-hormone-releasing hormone analog, or LHRH, is one example of the peptide drugs that have been introduced into cancer therapies. The first GnRH agonist was developed by Schally et al., which was later to be used in the treatment of prostate and breast cancers.
Following these developments, a variety of peptides have been developed and approved for use as therapies against various forms of cancer.
Some of the notable examples of these peptides include goserelin, leuprolide, buserelin, and triptorelin, among others. The depot formulation of these peptides makes it possible for them to be more efficacious and to conveniently treat patients suffering from prostate cancer.
Through several studies, it has been observed that the use of these peptides has a way of affecting the down-regulation of GnRH receptors found in the pituitary. This down-regulation leads to the inhibition of the release of follicle-stimulating hormones – FSH and LH. This is in addition to the concomitant release of the production of testosterone.
With the introduction of LHRH antagonists, it was observed that there was a therapeutic improvement over agonists. This is because they have the ability to induce immediate and dose-related inhibition of FSH and LH through the competitive blockage of the LHRH receptors. Presently, most of the highly potent GnRH antagonists are available for therapeutic use for patients suffering from prostate cancer.
Somatostatin Analogs in Cancer Therapies
In addition to using peptidic LHRH agonists and antagonists in the treatment and the development of cancer therapies, somatostatin analogs are currently the only cancer-therapeutic peptides that have been approved on the market.
Very powerful and potent agonists of somatostatin such as Sandostatin were developed to be used specifically for the treatment of acromegaly, thyrotropinoma, and gigantism, which are usually associated with diarrhea, and with carcinoid in patients suffering from vasoactive intestinal tumors. Lanreotide is another long-acting analog of somatostatin that is currently being used in managing acromegaly as well as other symptoms associated with neuroendocrine tumors.
The bulk of neuroendocrine tumors, or NETs, are known to display very strong overexpression of somatostatin receptors. At the moment, five somatostatin receptor subtypes (SST) have been clearly identified. It has been observed that the density of these receptors is usually abnormally high on tumor tissues compared to those on healthy tissues. As such, SST is currently being considered as an attractive target for delivering radionuclides that use well-modified somatostatin analogs.
For instance, Sandoz was introduced in the late 1980s, and it has since become one of the best benchmarks for diagnosing SST-positive NETs. The past decades have also seen the development of numerous peptide-based tumor-imaging agents developed with the sole purpose of targeting SST.
Currently, there are only two radiopeptide tracers in the market that have been approved by the FDA; they include NeoTect and Octreoscan. These radiopeptides tracers employ the use of scintigraphic methods in the detection of carcinoids as well as other types of tumors and for localizing sarcoidosis. DTPA-Octreotide is usually injected into a vein after radio-labeling with Indium-111 to get transported into the bloodstream. This is so that it can easily attach to the tumor cell that has receptors for somatostatin.
Following the injection of the DTPA-Octreotide in the vein, a device that is used to detect the radioactive octreotide is then used to generate images indicating the actual location of the tumor in the body. It is possible to also apply this principle in cancer therapies, specifically peptide receptor radionuclide therapy – PRRT.
This therapy works by combining modified octreotide with a radionuclide that also has the ability to bind to carcinoid tumor cells where there is an overexpression of somatostatin receptors. Following the binding, it is possible for the targeted radiation to destroy the malignant cells that the peptides are bound to. For this to be successful, however, it is important that the complex being used between the peptide and the radionuclide be very stable, especially if it will be subjected to radiopeptide therapy.
One of the most promising approaches for the treatment of cancer seems to be the use of active immunization featuring the employment of immune cells or immune molecules. With these methods of killing cancer cells, there is great reliance on vaccines that have peptides derived from amino acid sequences associated with certain types of tumors or antigens.
Tumor-associated antigens (TAA) are the agents normally expressed by tumor cells, and it is possible to recognize their presence with the use of T cells found within the host’s immune system. Currently, it is possible to identify a considerable number of TAAs and to characterize them as well.
It is possible to inject TAAs into cancer patients as a method of inducing a systematic immune response with the hopes that the response may lead to the destruction of the cancer cells. Any protein or peptide that has been produced in the tumor cell and has a mal structure owing to some certain form of mutation has the ability to act as a tumor antigen.
The production of such abnormal proteins or peptides is usually a result of mutations that are occurring and correspond to certain genes. Consequently, there are several clinical studies that have been started with the main goal of assessing the therapeutic potential of active immunization or the potential of active vaccination using TAA peptides in patients that have already developed metastatic cancer.
Up to now, just a handful of TAA peptides, the bulk of them being ones that can be recognized by CD8 (+), have undergone clinical testing. There are a lot of melanoma TAAs that have also been identified and are currently being evaluated for their potential as peptide-based cancer vaccines in a myriad of clinical trials around the globe.
With the recent developments in the field of molecular biology, it has been possible to rapidly identify dozens of candidates of TAAs that may be used to target a wide variety of cancers troubling the human population.
Current and Future State of Peptide-Based Anti-Cancer Therapies
There has been tremendous growth in the use of peptides in target drug delivery, diagnostic tools, and as direct therapeutic agents in cancer biology. Among the developments in controlled and targeted delivery of peptide therapeutics, there has been a significant rise in the use of binding peptides as a non-immunogenic approach used for targeting cancer cells.
For instance, the RGD peptide comes with the ability to efficiently recognize and penetrate cancerous tumors without any effect on the adjacent cells. Following the development of these and other similar peptides that boast extraordinary tumor penetrating capabilities, a significant improvement has been witnessed in the design and development of cancer therapies for the future.
For example, chlorotoxin has received a lot of attention recently since it has a very high affinity for glioma cells compared to normal brain cells and non-neoplastic cells. This ability to preferentially bind has made possible the development of new treatments as well as a new diagnosis for brain cancer. It is also worth observing that antiangiogenesis has sparked new interests in cilengitide. This is an integrin inhibitor that is currently being studied and evaluated for its potential as a non-small cell lung cancer therapeutic agent in numerous clinical trials around the globe.
Gastrin/bombesin releasing peptide (BN/GRP) peptides have also demonstrated the ability to bind selectively on the G-protein-coupled receptors on the surface of the cells, leading to the stimulation of the growth of various malignancies in both murine and human cancer models. Consequently, there have been proposals that the secretion of BN/GRP by neuroendocrine cells may be the main reason for the development and the progression of prostate cancer.
It has been observed that GRP is present in great numbers in the lungs and the gastrointestinal tracts. It is normally produced in the small cell lung cancer – SCLC, prostatic, breast, and pancreatic cancers. It primarily functions as a growth factor. Since bombestin-like peptides are very active in the pathogenesis of a wide variety of human tumors, and also due to their paracrine tumoral growth factors and the high presence of BN/GRP receptors in a myriad of human cancers, researchers have opted to create a design and synthesis of BN/GRP receptor antagonists such as RC-3950 and RC-3095.
Presently, there are numerous researchers and studies that are solely focused on the development of GHRH (growth-hormone-releasing hormone) antagonists as one of the highly potent anti-cancer therapies. This is because the growth hormone-releasing hormone is usually produced by various human tumors and has the ability to exert paracrine stimulatory effects on the tumors.
There is still a lot of work underway to discover angiogenesis inhibitors. Numerous ongoing clinical trials in this area are focused on peptides derived from sources such as growth factors, growth factor receptors, and extracellular matrix proteins. It is hoped that the result of the studies will be a major breakthrough in developing more viable cancer treatments and therapies.
- L.K. Kvols and E.A. Woltering
Role of somatostatin analogs in the clinical management of non-neuroendocrine solid tumors.
Anticancer Drugs 17, 601-608 (2006)
- R.T. Dorsam and J.S. Gutkind
G-protein-coupled receptors and cancer.
Nat. Rev. Cancer 7, 79-94 (2007)
- S. Fister et al.
Gonadotropin-releasing hormone type II antagonists induce apoptotic cell death in human endometrial and ovarian cancer cells in vitro and in vivo.
Cancer Res. 67, 1750-1756 (2007)
- L. Vujanovic and L.H. Butterfield
Melanoma cancer vaccines and anti-tumor T cell responses.
J. Cell. Biochem. 102, 301-310 (2007)
- F.G. Rick et al.
Agonists of luteinizing hormone-releasing hormone in prostate cancer.
Expert Opin. Pharmacother. 14, 2237-2247 (2013)
- F. Goel et al.
LHRH agonists for adjuvant therapy of early breast cancer in premenopausal women.
Cochrane Database Syst. Rev. CD004562 (2009)
Luteinizing hormone-releasing hormone (LHRH) agonists in the treatment of breast cancer.
Expert Opin. Pharmacother. 10, 2633-2639 (2009)
- F. Klug et al.
Characterization of MHC ligands for peptide based tumor vaccination.
Curr. Pharm. Des. 15, 3221-3236 (2009)
- G. Mezö and M. Manea
Luteinizing hormone-releasing hormone antagonists.
Expert Opin. Ther. Pat. 19, 1771-1785 (2009)
R.M. Myers et al.
Cancer, chemistry, and the cell: molecules that interact with the neurotensin receptors.
ACS Chem. Biol. 4, 503-525 (2009)
- E.D. Deeks
Histrelin: in advanced prostate cancer.
Drugs 70, 623-630 (2010)
- F. Hohla and A.V. Schally
Targeting gastrin releasing peptide receptors: New options for the therapy and diagnosis of cancer.
Cell Cycle 9, 1738-1741 (2010)
- P.J. Pommerville and J.G. de Boer
GnRH antagonists in the treatment of advanced prostate cancer.
Can. J. Urol. 17, 5063-5070 (2010)
- P. Whelan
Triptorelin embonate: a 6-month formulation for prostate cancer.
Expert Opin. Pharmacother. 11, 2929-2932 (2010)
- D. Wild et al.
First clinical evidence that imaging with somatostatin receptor antagonists is feasible.
J. Nucl. Med. 52, 1412-1417 (2011)
- B.L.R. Kam et al.
Lutetium-labelled peptides for therapy of neuroendocrine tumours.
Eur. J. Nucl. Med. Mol. Imaging 39 Suppl. 1, S103-112 (2012)
- K.P. Koopmans and A.W. Glaudemans
Rationale for the use of radiolabelled peptides in diagnosis and therapy.
Eur. J. Nucl. Med. Mol. Imaging 39 Suppl 1, S4-10 (2012)
- P. Limonta et al.
GnRH receptors in cancer: from cell biology to novel targeted therapeutic strategies.
Endocr. Rev. 33, 784-811 (2012)
- P.W. Moody et al.
Pituitary adenylate cyclase-activating polypeptide causes tyrosine phosphorylation of the epidermal growth factor receptor in lung cancer cells.
J. Pharmacol. Exp. Ther. 341, 873-881 (2012)
- P.K. Nanda et al.
Bombesin analogues for gastrinreleasing peptide receptor imaging.
Nucl. Med. Biol. 39, 461-471 (2012)
- J. Thundimadathil
Cancer treatment using peptides: Current therapies and future prospects.
J. Amino Acids 2012, 13 (2012)
- F. Barbieri et al.
Peptide receptor targeting in cancer: the somatostatin paradigm.
Int. J. Pept. 2013, 926295 (2013)
- R.A. Feelders et al.
Pasireotide, a multi-somatostatin receptor ligand with potential efficacy for treatment of pituitary and neuroendocrine tumors.
Drugs Today (Barc.) 49, 89-103 (2013)
- E. Harford-Wright et al.
The potential for substance P antagonists as anti-cancer agents in brain tumours.
Recent Pat. CNS Drug. Discov. 8, 13- 23 (2013)
- O. Keskin and S. Yalcin
A review of the use of somatostatin analogs in oncology.
Onco Targets Ther. 6, 471-483 (2013)
- F.G. Rick et al.
Agonists of luteinizing hormone-releasing hormone in prostate cancer.
Expert Opin. Pharmacother. 14, 2237-2247 (2013)
- N.D. Shore et al.
New considerations for ADT in advanced prostate cancer and the emerging role of GnRH antagonists.
Prostate Cancer Prostatic. Dis. 16, 7-15 (2013)
- U.W. Tunn et al.
Six-month leuprorelin acetate depot formulations in advanced prostate cancer: a clinical evaluation.
Clin. Interv. Aging 8, 457-464 (2013)
R. Varshney et al.
(68)Ga-labeled bombesin analogs for receptor-mediated imaging.
Recent Results Cancer Res. 194, 221- 256 (2013)
- Z. Yu et al.
An update of radiolabeled bombesin analogs for gastrin-releasing peptide receptor targeting.
Curr. Pharm. Des. 19, 3329-3341 (2013)
- O. Abdel-Rahman et al.
Somatostatin receptor expression in hepatocellular carcinoma: prognostic and therapeutic considerations
Endocr. Relat. Cancer 21, R485-493 (2014)
- Accardo et al.
Receptor binding peptides for target-selective delivery of nanoparticles encapsulated drugs.
Int. J. Nanomedicine 9, 1537-1557 (2014)
- V. Ambrosini et al.
The use of gallium-68 labeled somatostatin receptors in PET/CT imaging.
PET Clin. 9, 323-329 (2014)
- R. Baldelli et al.
Somatostatin analogs therapy in gastroenteropancreatic neuroendocrine tumors: current aspects and new perspectives.
Front. Endocrinol. (Lausanne) 5, 7 (2014)
- N.J. Carter and S.J. Keam
Degarelix: a review of its use in patients with prostate cancer.
Drugs 74, 699-712 (2014)
- K. Mander et al.
Advancing drug therapy for braintumours: a current review of the proinflammatory peptide Substance P and its antagonists as anti-cancer agents.
Recent Pat. CNS Drug Discov. 9, 110-121 (2014)