ANTI-METASTATIC AGENTS: NEW DRUG DEVELOPMENTS AND NATURAL PRODUCTS

The process by which cancer cells travel from the main tumor to other body parts, where they can form new tumors, is known as metastasis. Up until this day, metastasis remains one of the greatest challenges in oncology, known to be responsible for up to 90% of cancer-related deaths. Managing metastasis is an important goal of cancer research and treatment. Anti-metastatic agents are drugs or natural products that can interfere with metastatic processes and prevent or reduce the formation of secondary tumors.

In this blog, we will discuss some of the latest scientific breakthroughs for approved and novel anti-metastatic agents, which include common prescriptions and natural compounds that pose similar benefits. We will also explore how anti-metastatic agents work, what their underlying mechanisms are, and how the latest developments might improve chemotherapy in future.

What Do Anti-metastatic Agents Do?

Anti-metastatic agents prevent the spread of tumor cells by working on different aspects of the metastatic process.

Metastasis involves several steps: cancer cell transformation, detachment, invasion, migration, intravasation, circulation, extravasation, implantation, angiogenesis, and proliferation.

This essentially describes the process where cancer cells transform into cells capable of leaving the parent tumor, known as the epithelial-to-mesenchymal cell transition (EMT).^[1] These then detach and circulate the body before landing in suitable tissue, where they can develop into a second tumor.

Anti-metastatic drugs can target the particular molecules and pathways that control each of these processes. Some of the mechanisms that can initiate EMT are^[2]:

• Growth factors and cytokines which are soluble substances with the ability to bind to particular cell surface receptors and initiate intracellular signaling pathways that control the expression of genes and the actions of individual cells. 
• Hypoxia, which is a condition of low oxygen levels in the tumor microenvironment, caused by the rapid growth and poor vascularization of the tumor. Hypoxia can induce EMT by activating hypoxia-inducible factor-1 alpha (HIF-1α), a transcription factor that regulates the expression of genes related to angiogenesis, glycolysis, invasion, and metastasis. HIF-1α can also cooperate with other EMT-inducing factors, such as TGF-β, EGF, and Notch. Solid tumors have the highest risk for metastasis in a low-oxygen environment.
• Oncogenes and tumor suppressors^[3] are genes and factors that promote or inhibit tumorigenesis, respectively. These can be suppressed or activated with anti-metastatic agents to inhibit the growth and spread of tumors.
• Epigenetic modifications are changes in the DNA that affect the accessibility and expression of genes without altering the DNA sequence. These can be targeted by anti-metastatic agents to change the expression of genes, resulting in the inhibition of oncogenes or the expression of tumor suppressor genes.

Here is the table that summarizes some of the most common metastatic cell mechanisms, anti-metastatic tumor targets, and types of metastatic cancer:

Metastatic Mechanism	Tumor Target Examples	Metastatic Cancer Type
Growth factors, receptors and cytokines	HER2, TGF-β, EGF, HGF, FGF, and PDGF ER, MET, VEGFR, PDGFR, and FGFR IL-6 and TNF-α	Breast, prostate, lung, colorectal, pancreatic, gastric
Hypoxia	HIF-1α	Breast, lung, colorectal, cervical, renal, glioblastoma
Oncogenes and tumor suppressors	KIT, Lyn, Ras, Src, Akt and β-catenin p53, PTEN and E-cadherin	Colorectal, pancreatic, lung, breast, prostate, ovarian, bladder
Epigenetic modifications	DNA methylation Histone acetylation MicroRNAs	Breast, prostate, colorectal, gastric, esophageal, pancreatic

Novel Anti-Metastatic Agents

As we have seen, metastasis is a complex and dynamic process that involves multiple steps and interactions between cancer cells and their microenvironment. Each of these steps is regulated by specific molecules and pathways that can be targeted by anti-metastatic agents. Anti-metastatic agents are drugs or natural products that can inhibit or prevent the metastatic processes by interfering with the expression or activity of these molecules and pathways.

There are different types of anti-metastatic agents, depending on their mode of action, target, and source. Several of them are commonly used in chemotherapies. Some of the main types are discussed below.

Monoclonal antibodies are proteins that have the ability to attach to particular antigens, or foreign proteins, on the surface of cancer cells as well as other cells, like immune or endothelial cells, that are present in the tumor microenvironment.Like any antibody, this neutralizes the antigen in the tumor, causing it to become ineffective. The tumor antigens that are targeted are normally critical for the tumor’s survival, resulting in cell death when inhibited by a monoclonal antibody.

Some examples of anti-metastatic monoclonal antibodies include:

• Toripalimab-tpzi: Inhibits PD-1, which is a protein found on cancer cell membranes that prevent immune detection of the cancer cells. Blocking PD-1 allows the immune system to activate and attack the cancer cells. Toripalimab-tpzi is approved for the treatment of metastatic nasopharyngeal carcinoma^[4], which is a type of head and neck cancer. It may also be effective for other types of cancer that have high expression of PD-L1 or PD-L2, such as melanoma, lung, liver, gastric, and esophageal cancers.
• Retifanlimab-dlwr: Another PD-1 inhibitor, which works similarly to toripalimab-tpzi by blocking PD-1 and enhancing the immune system’s ability to fight cancer cells. Retifanlimab-dlwr is approved for the treatment of metastatic Merkel cell carcinoma, which is a rare and aggressive type of skin cancer.^[5] It may also be effective for other types of cancer that have high expression of PD-L1 or PD-L2, such as cervical, rectal, bladder, and head and neck cancers.
• Trastuzumab^[6]: Targets HER2 in some breast and gastric cancers, inhibiting cell growth, survival, and metastasis. It can also cause cancer cell death. May improve the survival and quality of life of patients with HER2-positive metastatic breast cancer and gastric cancer.
• Bevacizumab^[7]: Inhibits VEGF in some types of solid tumors, preventing them from growing new blood vessels and making it difficult for detached tumor cells to grow at other body sites. It has been demonstrated to enhance the overall and progression-free survival of patients with glioblastoma, renal cell carcinoma, metastatic colorectal cancer, non-small cell lung cancer, and ovarian cancer.
• Sipuleucel-T^[8]: An immunotherapy that stimulates the patient’s own immune cells to attack prostate cancer cells that express prostatic acid phosphatase (PAP), a marker of metastasis. It is known to improve the overall survival of patients with metastatic castration-resistant prostate cancer.

Tyrosine kinase inhibitors are small molecules that can inhibit the activity of tyrosine kinases. These are enzymes every cell uses to activate specific proteins involved in cell signaling and metabolism, which regulate cell growth and survival. Tyrosine kinases are often overexpressed or mutated in cancer cells, which contributes to their growth, spread, and invasion in other tissues (metastasis).

Anti-metastatic tyrosine kinase inhibitors include:

• Fruquintinib: Blocks VEGFR-1, 2, and 3 and inhibits tumor angiogenesis. Fruquintinib is approved for the treatment of metastatic colorectal cancer that has progressed after prior therapies.^[9] It may also be effective for other types of cancer that have high expression of VEGF, such as liver, lung, gastric, and ovarian cancers.
• Cabozantinib^[10]: Blocks the activity of MET (a protein that activates HGF) and VEGFR2, which are implicated in tumor growth, invasion, angiogenesis, and metastasis. Cabozantinib can prevent the metastasis of renal cell carcinoma and hepatocellular carcinoma, which have high expression of MET and VEGFR2. It is also known to improve survival rates in those with metastatic medullary thyroid cancer.
• Nintedanib^[11]: Targets several growth factor receptors, including FGFR, PDGFR, and VEGFR, that are involved in the development of new blood vessels. Nintedanib can prevent the metastasis of lung cancer, especially adenocarcinoma, which has high expression of VEGF, PDGF, and FGF. It may also improve the survival of patients with metastatic colorectal cancer, non-small cell lung cancer, ovarian cancer, and mesothelioma.
• Tivantinib: Inhibits MET, a key driver of tumor invasion, metastasis, and resistance to therapy. Tivantinib can prevent the metastasis of hepatocellular carcinoma and non-small cell lung cancer, which have high expression of MET.
• Masitinib: Targets KIT, PDGFR, and Lyn, which are involved in tumor growth, angiogenesis, and metastasis. Masitinib can prevent the metastasis of gastrointestinal stromal tumors and pancreatic cancer, which have high expression of KIT, PDGFR, and Lyn. It can also help to promote survival in patients with these tumors, as well as melanoma and mastocytosis.

Selective Estrogen Receptor Degraders (SERDs) are a type of antiestrogen therapy for breast cancer. SERDs function by attaching to the estrogen receptor (ER), a protein that is overexpressed in some types of breast cancer cells that stimulates their growth and survival. By binding to the ER, SERDs prevent estrogen from activating the ER and also cause ER degradation, reducing ER levels in tumor cells. They may also inhibit oncogenes and reduce inflammation. Unlike other anti-metastatic agents and chemo drugs, SERDs are a relatively new development.^[12]

SERDs with anti-metastatic properties include:

• Elacestrant: A SERD that binds to and degrades ERα, which reduces its expression and activity in tumor cells. Elacestrant was approved in 2023 for the treatment of breast cancer that is ER-positive, HER2-negative, and that also has an ESR1 mutation. ESR1 promotes the metastasis of resistant breast cancer. Elacestrant may also be effective for other types of cancer that have ERα expression or ESR1 mutations, such as ovarian, endometrial, and prostate cancers.^[13]

Microtubule inhibitors are small molecules that can disrupt the formation and function of microtubules. Microtubules are cytoskeletal structures that are essential for cell division, migration, and invasion. Microtubule inhibitors can induce cell cycle arrest, apoptosis, and inhibition of cell motility and invasiveness.

Microtubule inhibitors with anti-metastatic effects include:

• Eribulin: A synthetic analog of halichondrin B, a natural compound isolated from a marine sponge that binds to and inhibits tumor microtubules, promotes cell death, and disrupts cell division, migration and invasion.^[14] It has been demonstrated that Eribulin improves patients' overall and progression-free survival rates with liposarcoma and metastatic (triple-negative) breast cancer.
• Lurbinectedin: A synthetic analog of Ecteinascidin 743, a natural compound isolated from a marine organism, that binds to DNA and inhibits transcription, resulting in cell cycle arrest and cell death. Lurbinectedin^[15] can also lower levels of inflammatory cytokines that promote tumor growth, angiogenesis, and metastasis. It may improve survival rates of patients with metastatic small cell lung cancer, soft tissue sarcoma, and ovarian cancer.

Common Prescription Medications With Anti-Metastatic Properties

A few studies are starting to reveal that everyday prescription medications may exert anticancer and antimetastatic effects. This means that some people may be protected from metastasis against some types of cancer and not others due to the other prescription medications they are taking.

Commonly prescribed drugs with anti-metastatic properties include:

• Aspirin and other NSAIDs^[16]
• Warfarin and other anticoagulants^[17]
• Metformin^[18]
• Statins^[19]
• SSRIs and other antidepressants^[20]

More research is required to confirm how protective these prescriptions are and whether they may increase the risk of metastasis in untested tumor types.

Natural Products As Anti-Metastatic Agents

Besides synthetic drugs, there are also many natural products that have been reported to have anti-invasive and anti-metastatic activities. They can be found everywhere in nature and are extracted from plants, fungi, bacteria, marine organisms, and animals. They have diverse biological effects, capable of interfering with multiple signaling pathways involved in metastasis.^[21]

Some natural products that have shown promising results in preclinical and clinical studies are ginsenosides and cysteamine:

Ginsenosides

Natural components are found in panax ginseng, a herb used in traditional Chinese medicine. Studies continue to reveal that there are multiple anti-metastatic compounds in ginseng, several of which are ginsenosides. ^[22]

All of them have synergistic effects that work together to inhibit several aspects of metastasis, including migration, invasion, and proliferation. One mechanism of action involves inhibiting the expression of enzymes that allow metastatic cells to degrade membranes and penetrate into other tissues. Most ginsenosides suppress inflammation, induce cancer cell death, and inhibit tumor blood vessel growth.

Ginsenoside Rg3 and Rh2 have shown promising anti-metastatic effects in several clinical trials for various cancers, including lung, breast, colorectal, gastric, and liver cancers.

Cysteamine

A peptide produced in mammals from the breakdown of coenzyme A, or the decarboxylation of cysteine, that assists in various cellular processes. It has recently been shown to have anticancer and anti-metastatic properties, including inhibiting invasion and cancer cell growth.^[23] It also acts as a PD-1 inhibitor, which means it improves the immune system’s ability to detect and destroy the tumor.

In animal and human trials, cysteamine was able to improve survival, reduce tumor growth, and lower metastasis for various types of cancer, such as colorectal cancer, breast cancer, melanoma, and glioblastoma. To validate cysteamine's effectiveness and safety as an anti-metastatic medication in humans, more research is necessary.

Cysteamine is a medication and can be found in some natural sources, such as foods that contain cysteine, the amino acid that can be converted to cysteamine in the body. Some of the foods that are high in cysteine are eggs, dairy products, oats, broccoli, and sunflower seeds. However, the amount required for optimal efficacy is unknown and consuming foods or supplements containing cysteine or cysteamine may not be sufficient to achieve therapeutic effects. Long-term safety is also still under evaluation.

These compounds all show limitations, such as their low bioavailability, poor solubility, and rapid metabolism, which limit their therapeutic efficacy. More testing is required to assess adequate dosages for enhancing chemotherapy as well as their long-term safety. In the meantime, various strategies are being developed to improve their delivery and stability, such as nanoformulations, liposomes, and conjugates.

Other Natural Products and Their Sources

Other anti-metastatic compounds are currently being explored from many other natural sources, including:

• Genistein from soybeans and other legumes
• Artemisinins from artemisia
• Curcumin from turmeric
• Cucurbitacins from pumpkin
• Berberine from goldenseal, coptis, and several other botanicals
• Gingerols from ginger
• Resveratrol from grape seeds and other plants
• Citrus-derived flavonoids
• Peptides from shellfish, fish, and algae^[24]
• Compounds isolated from various bacteria

These agents have demonstrated significant clinical benefits for patients with metastatic cancers, but they also have some limitations and challenges, such as their high cost, limited availability, variable efficacy, adverse side effects, drug resistance, and toxicity.

Cutting-Edge Anti-Metastatic Agents of the Future

Some of the recent breakthroughs in anti-metastatic cancer treatment are still undergoing refinement in clinical trials. These include the use of viral proteins and anticancer vaccines with higher degrees of personalization and precision^[25].

Viral Proteins

While many viruses dramatically increase the risk of cancer, some viruses are now known to produce proteins that can combat the growth and spread of cancer. A few examples of some of the ones currently being studied include:

• The viral peptide vCPP2319: Derived from the capsid protein of the human papillomavirus (HPV). This peptide can inhibit the migration and invasion of cervical and breast cancer cells by blocking their ability to leave tumors or penetrate other tissues.^[26] This peptide can also cause cervical cancer cells to die off.
• The viral protein R (Vpr): A regulatory protein of the human immunodeficiency virus (HIV). This protein can inhibit the metastasis of prostate cancer cells by suppressing the expression and activity of enzymes involved in the degradation of cells and tissues, which would normally allow for metastatic cells to invade other tissues. This protein also promotes cell cancer death.
• The viral protein VP3: A structural protein of the chicken anemia virus (CAV). This protein can inhibit the metastasis of breast cancer cells by inhibiting a protease that plays a role in the invasion and migration of cancer cells. This protein can also cause breast cancer cell death.

These are some of the viral proteins that have been reported to have anti-metastatic effects in various studies. However, more research is needed to confirm their mechanisms of action, their safety, and their efficacy in human trials.

Patient-Derived Tumor Cell Vaccines

These are new types of vaccines currently being developed that work using the patient's own tumor cells to ensure a high degree of precision. There are several clinical trials testing the safety and efficacy of such vaccines for various types of cancer. Examples include:

• rWTC-MBTA: An autologous (self-derived) vaccine consisting of irradiated tumor cells from the patient that have been pulsed with a mixture of mannan-BAM, TLR agonists, and anti-CD40 antibodies. These compounds prevent metastases by activating the immune system to recognize and eliminate the tumor cells.^[27]
• AutoSynVax: A personalized vaccine that presents the antigens that match the patient’s own tumor, which might be used against many different types of solid tumors, such as brain, breast, ovarian, and colon cancer.
• TLPLDC: A vaccine that uses dendritic cells loaded with tumor lysate, which stimulates T-cells and may work synergistically with other immunotherapies.

These trials are still in the early stages and have not yet demonstrated the effectiveness of autologous whole-tumor cell vaccines. More research is needed to optimize the design, delivery, and safety of these vaccines before they can be approved for clinical use.

Other Active Developments

There are more therapies being developed to target metastasis, especially as many chemo drugs appear to enhance EMT and tumor spread. Further developments include:

• Agents that target cancer stem cells to prevent their growth and spread^[28]
• Gold nanoparticles which easily reach tumor cells and possess potent anti-metastatic effects^[29]
• Therapies that target tumor cell adhesion proteins^[30]
• Anti-metastatic drugs that target stress-related markers involved in metastasis in tumor cells, including adrenaline receptors and prostaglandins

Conclusion

Metastasis underpins the vast majority of cancer-related deaths and remains to be a challenge in the realm of chemotherapy. Developing suitable anti-metastatic agents capable of putting an end to metastasis has become an increasingly important area of investigation. The recent approval of several novel anti-metastatic agents is expected to improve the prognosis for late-stage cancer patients in the next few years.

Studies have also revealed that common prescription drugs, chemotherapeutics, and many natural products all pose several anti-metastatic effects, which may explain their improved efficacy and complementary benefits. Future anti-metastatic therapies are geared towards greatly enhanced personalization and precision with the use of specialized anticancer vaccines. Headway is also being made with respect to bettering delivery systems and optimizing treatment.

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