Peptide Therapy

In recent years there has been significant scientific interest and growing excitement around the therapeutic potential of peptides. Peptides are short strings of amino acids (typically only ranging from 2 to 50). They act as signaling molecules for a wide range of physiological functions [1]. There are many different types of peptides each with different effects in the human body. As a therapeutic intervention, peptide drugs can closely mimic natural processes [1]. Peptides are easily obtained from the products of proteolysis (protein breakdown), direct synthesis in the body, or artificial synthesis [2].

Peptides have been shown to have therapeutic application in a wide range of conditions such as allergic diseases, infectious diseases, autoimmune diseases, asthma, and even cancer [2].** **Peptides have the capacity to kill bacteria, fungi, cancer cells, and can regulate the immune system [3]. Some types of peptides have been shown to help slow down the aging process, reduce inflammation, and destroy microbes [4]. Some of the most common peptides are collagen peptides for anti-aging and skin health, and creatine peptides for muscle growth and athletic performance [4].

Therapeutic peptides commonly function as hormones, growth factors, neurotransmitters, ion channel ligands (regulating cell membrane permeability), or anti-infective agents [5]. In cancer treatment there are three primary categories of peptide use: (1) peptide-alone therapy; (2) peptide vaccines; (3) and peptide conjugation (combination strategy) to enhance drug delivery and sensitivity [2]. Peptides that have direct anti-tumor effects are classified as anticancer peptides (ACPs) [3]. ACPs can inhibit tumor cell proliferation (rapid reproduction), migration (spread), and suppress tumor angiogenesis (growth of tumor blood vessels) [3].

Peptides that directly target cancer cells without harming healthy cells (targeted therapy) is a focus of ongoing research and development as a potential alternative to conventional chemotherapy drugs [6]. Peptide-based hormonal therapy has been widely studied and is commonly applied in the treatment of breast and prostate cancer [6]. There is considerable evidence supporting the efficacy of peptide based cancer vaccines [6]. Combination therapy is emerging as an important method to obtain synergistic effects and improve patient outcomes [6].

In recent years, the most frequent indication for peptides entering clinical trials has been for cancer treatment [6]. Peptides show great potential in cancer care. However, there are currently still major limitations with many ACPs regarding safety and efficacy [3]. Further research and development is still needed in this area.

History of Peptide Therapy and Cancer

The use of peptides as a medical therapy has evolved considerably over time and continues to progress with drug development and novel treatment paradigms [1]. Research into therapeutic peptides began with studies of natural human hormones such as insulin, oxytocin, vasopressin, and gonadotropin-releasing hormone (GnRH) during the first half of the 20th Century [5]. In this period several life-saving peptides were discovered, for example, insulin and adrenocorticotropic hormone (ACTH) [5].

The discovery of insulin is considered a landmark scientific achievement and one of the most important drug developments ever made [5]. Frederick Banting first isolated insulin in 1921 [5]. Banting then further developed insulin with the help of Charles Best to make it available for patients with diabetes just one year later [5]. The discovery and development of insulin marked the first commercial peptide drug to be brought to market [5].

Many more peptide hormones with therapeutic potential were identified and characterized between 1950 and 1990 [5]. During this time period there were major technological advancements in protein purification, synthesis, structure elucidation, and sequencing, which accelerated the development of numerous peptide drugs around the world [5].

One of the first peptides used in cancer treatment was LHRH (luteinizing hormone-releasing hormone). LHRH is a small peptide that regulates sex hormone production. It was discovered in the 1980s and analogues were developed for the treatment of prostate cancer [7]. These drugs work by overstimulating the LHRH receptor, which in turn lowers the amount of testosterone made by the testicles [8]. This type of therapy is also sometimes referred to as “medical castration” [8].

Another example of a peptide-based cancer treatment is the drug Herceptin, which is commonly used for breast cancer. Herceptin targets the HER2 protein (which is overexpressed in certain types of breast cancer) and blocks its activity thereby slowing or preventing the growth of cancer cells [9]. Peptides have also been developed to modulate the immune system for cancer treatment. Peptide vaccines have been created that stimulate the immune system to target cancer cells [10].

With the advent of the 21st century there have been major technological advances that have marked a new era of peptide drug development [5]. New peptide drugs have been used in a wide range of therapeutic areas including metabolic, cardiovascular, urology, respiratory, pain, antimicrobial, and oncology applications [5]. In the past two decades, many novel peptide-based cancer treatments have been developed such as peptide-drug conjugates, peptide inhibitors, and cell-penetrating peptides that can enhance the delivery and targeting of drugs to cancer cells.

Research on Peptide Therapy and Cancer

In recent years there has been a revival of interest and scientific momentum in peptide drug discovery [11]. The pharmaceutical industry has come to recognize the role that this class of therapeutics can play in medicine [11]. As of 2022 there are more than 170 peptides in active clinical development with many more in preclinical studies [5]. Since 2000 onwards close to ⅕ of peptides undergoing research and development have been for cancer related purposes [6].

There are currently thousands of clinical trials ongoing for anticancer peptides according to the US National Institutes of Health Clinical Trials database [3]. For example Bryostatin 1 has shown anti-tumor activity in Phase I clinicals for melanoma (skin cancer), lymphoma and ovarian cancer [3]. Aplidine is another peptide that has been studied for its action against thyroid cancer, melanoma, small cell lung cancer, and renal cell carcinoma (kidney cancer) [3].

Peptides have been shown in a 2013 study to significantly increase the survival of patients with advanced non-small cell lung cancer (NSCLC) [12]. Takahashi et al. reported that dendritic cell vaccines pulsed with Wilms’ tumor-1 peptide improved the survival period of patients with NSLCC. Furthermore, Kotsakis et al. also reported in a 2014 study that a peptide-based vaccine induced strong immune responses and improved clinical outcomes for the majority of patients with NSLCC [13].

There is also considerable preclinical research on the anticancer effects of peptides. Peptides derived from high oleic acid soybean have been shown to have an inhibitory effect in colon, liver, and lung cancer cells [14]. Furthermore, peptides from the venom of the green mamba have been shown to have toxic effects on non-small cell lung cancer cells [15]. Atrial natriuretic peptide (ANP), a cardiac and vascular derived peptide, has been shown to have anti-proliferative effects on colorectal cancer cells in laboratory studies [16].

Many ACPs have been approved by the FDA, but they also have some potential disadvantages such as risks of toxicity and poor targeting [3]. Nevertheless, anticancer peptides have become a major area of research focus as a possible alternative or addition to conventional cancer treatments [3]. Peptides show great promise and have a role to play in the future of cancer care. However, there is still further research and development required to better determine their safe and effective application for different cancer types.

Potential Applications of Peptide Therapy and Cancer

There are a great number of different peptides each with a specific physiological function in the human body. Research indicates that peptides can help to [4] [17]:

• Lower blood pressure
• Kill microbes
• Reduce inflammation
• Prevent blood clots
• Improve immune function
• Act as antioxidants

There is still more research needed to better understand the therapeutic potential of synthetic peptides. However, peptides are thought to have a wide range of possible applications and benefits for indications such as [4] [6] [17] [18]:

• Anti-aging: collagen peptides help to make collagen and elastin for healthy skin.
• Antimicrobial: antimicrobial peptides can help the body to fight infections.
• Muscle growth: creatine and collagen peptides can boost muscle growth and repair.
• Weight loss: certain peptides may have metabolic effects that help with weight loss
• Wound healing: antimicrobial, anti-inflammatory, and antioxidant properties of certain peptides can help with wound healing.
• Prevent age-related bone loss: collagen peptides may help to increase bone mass.

Therapeutic peptides can also be used for a range of different health conditions such as such as allergic diseases, infectious diseases, autoimmune diseases, fibrosis, and asthma [2]. Peptides also have a promising role to play in cancer care including early detection, prognosis predictors, and treatment of cancer patients with various cancer types [2].

In treating cancer peptide therapy can be divided into three primary categories: (1) peptide-alone therapy; (2) peptide vaccines; (3) and peptide conjugation to enhance drug delivery and sensitivity [2]. Peptides for cancer can be utilized in a number of different ways [6]:

• Anticancer drugs (for example ACPs and angiogenesis inhibitors)
• Targeted drug delivery: peptides can be used as carriers to deliver cytotoxic drugs directly to cancer cells (for example targeted chemotherapy)
• Immunotherapy: peptides can be used to stimulate an immune response against cancer cells (for example peptide vaccines and immune checkpoint inhibitors)
• Radiotherapy: peptides can be labeled with radioactive isotopes to target radiation directly to cancer cells and minimize side effects (for example peptide receptor radionuclide therapy).
• Combination therapy: peptides can be used in combination with chemotherapy and/or radiotherapy to enhance efficacy and reduce side effects.
• Peptide-based hormonal therapy: widely used for the treatment of breast and prostate cancer.
• Targeted imaging: peptides can be labeled with imaging agents to aid in diagnosis and treatment planning.

Given that peptides have the capacity to bind to different receptors and play a role in many biochemical pathways, they can also act as potential diagnostic tools and biomarkers in cancer development and progression [6].

Common peptides drugs that are currently used in the treatment of cancer include:

• Bortezomib (for myeloma and lymphoma)
• Mifamurtide (for osteosarcoma)
• PNC27 (selectively kills cancer cells)
• iRGD (controls cell permeability)
• Thymosin Alpha-1 (immune system and inflammation modulation)
• Met-enkephalin (opioid peptide for pain)
• Antimicrobial peptides (kill harmful bacteria)
• Cell-penetrating peptides (enhance drug delivery and sensitivity)

Since the FDA accepted the first peptide vaccine for the treatment of prostate tumors there have been an ever increasing number of peptides being developed for a wide range of cancer types [2]. There have been clinical trials and peptide drugs developed for many types of cancer such as melanoma, glioblastoma, breast cancer, gastric cancer and others[2].

However, the clinical response is currently considered to be limited and most of the trials show limited efficacy [2]. For this reason, many novel applications are under research and development such as combination strategies with nanomaterials and chemotherapy, individualized peptide vaccines, and improved drug delivery systems [2].

Risks and Side Effects of Peptide Therapy and Cancer

Peptides have shown that they have therapeutic value in conventional and integrative medicine. However, the physiological effect of each peptide is entirely different and highly specific to certain physiological functions and parts of the body. Therefore, it is not possible to outline all the potential side effects of peptide therapy.

Peptides generally have a short half-life and are quickly metabolized in the body. Therefore their side effect profile is normally very limited [19]._ _However, this does not mean that peptides are without side effects and careful considerations must be made by a medical professional prior to administration [19].

In light of the wide range of different peptides and their therapeutic effects, risks and side effects will vary greatly. Some potential risks and side effects of peptides in cancer treatment include:

• Allergic reactions: peptides can trigger allergic reactions in some people, which can range from mild (rash) to severe (anaphylactic shock).
• Immune related adverse events: peptides that modulate the immune system can potentially trigger inflammation or autoimmune conditions.
• Toxicity: some peptides can be toxic to healthy cells if not targeted to cancer cells.
• Cardiovascular effects: peptides that target receptors involved in cardiac function can lead to changes in blood pressure and heart rate.
• Other effects: depending on the peptide possible adverse effects include nausea, vomiting, hair-loss, diarrhea, reduced appetite, and fatigue.

Not all peptides used in cancer treatment will cause side effects. The severity and type of potential side effect will depend on the specific treatment and type of peptide used. Furthermore, it is important to be aware that many peptide-based therapies for cancer are still in experimental stages and have not yet been adequately studied to fully elucidate their safety profiles.