Treating Cancer With Precision: Molecular Targets for Therapeutic Interaction in Cancer Cells

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Author: Jay Ann Kan

 

  1.  

Abstract:

Cancer, caused by spontaneous mutations, remains a lingering possibility in the lives of many. According to the National Cancer Institute, the risk of developing cancer in a lifetime is 42% and 38% for men and women respectively. However, as the options for cancer treatment progress, the treatments developed have improved in effectiveness and specificity, decreasing the rate of mortality. Some of the conventional cancer treatments today are surgery, radiation therapy, and chemotherapy. However, these treatments are often not individually tailored to each patient, could cause severe side effects, and lack the element of specificity required to treat cancer. Molecular Targeted Therapy is a new frontier in the field of cancer therapy and consists of using certain drugs to interfere with specific molecular targets which may be found in the cancer cell surfaces, proteins, genes, or tissue environments that are interlinked with the survival and proliferation of cancer cells. The major benefit of targeted therapy is that it is cytostatic compared to cytotoxic chemotherapy. Since targeted therapy is cytostatic, the drug administered only affects cancer cells in contrast to chemotherapy where both cancer cells and normal cells are affected. The “war on cancer”, as declared by President Nixon in 1971, is still ongoing. However, the path to victory is currently being paved with new research aimed at developing a further understanding of cancer biology and the creation of new cancer treatments. Despite the long road to victory, molecularly targeted therapy is a new hope.

1. Introduction

From a single cell making up the simplest organisms to trillions of cells constituting the complex human structure, cells are undeniably the basic building blocks of life; a fundamental component of humanity. While cells are the foundation of life, this foundation can quickly crumble with multiple gene mutations, a change characterised by damaged cells and uncontrollable cell proliferation, causing the highly fatal disease — Cancer.

As a present component in society for numerous millenniums, the earliest description of cancer was found in an Egyptian papyrus dating back to 1600 BC.[1] Despite its long-lasting history, the cure for cancer remains a lingering question as each passing generation continues to witness the substantial number of lives lost to cancer. Once deemed an incurable disease, the reputation of cancer as the equivalent of receiving the death sentence has gradually shifted with the rise in medical knowledge and the increasing role of technology in the medical field.[2] Although cancer remains one of the biggest challenges of the 21st century, with the aid of advanced technologies over the past decades, scientists can gain deeper insight into cancer, hence formulating a variety of cancer treatments and therapies. Currently, the primary focus in cancer research includes (1) cell signalling and regulation (2) cancer cell metabolism (3) early cancer detection (4) prevention of cancer development, and (5) developing drugs to treat cancer in progress (i.e., using specific molecular targets to kill cancer cells or to inhibit their growth) and (5) research into the tumour microenvironment.[3] Although the current therapies and treatments for cancer are increasing in precision and effectiveness, there has yet to be a treatment that can provide cancer patients with a complete restoration of health.

While conventional cancer treatments, such as chemotherapy, radiation therapy, and surgery are all viable cancer treatments, molecularly targeted therapy offers the prospect of more precise and personalised treatments. Due to its specificity and cytostatic nature, targeted therapy drugs are tailored to only act on specific molecular targets of cancer cells, therefore, yielding greater protection towards normal cells compared to chemotherapy, where both cancer cells and normal cells that divide rapidly are killed.[4]As acquired knowledge of cancer increases and somatic mathematical models can predict and explain the successes and failures of anti-cancer drugs, targeted therapy acts as a new frontier for cancer treatment, offering renewed hope for curing cancer. [5]

2. Cancer Biology

2.2 Characteristics of Cancer Cells and Normal Cells

Normal cells and cancer cells are different in numerous ways, as illustrated in Table 1, and understanding the differences is important to develop effective cancer treatments. As cancer cells rely heavily on some abnormal behaviours to survive, researchers can target these abnormal behaviours in their treatment. For instance, some tumours rely on blood vessels as their supply of oxygen and nutrients. However, by inhibiting the growth of blood vessels, the tumour is no longer supplied with the oxygen and nutrients it needs to survive, hence preventing further growth and spread. [6] As seen in Figure 1, cancer cells and normal cells also vary in terms of structure. While they both have a nucleus, nucleolus, chromatin, and cytoplasm, the size and quantity of these components are ultimately what differentiates the structure of a cancer cell from a normal cell. [7]

Normal Cells

Cancer Cells

Grow in the presence of growth signals

Grow in the absence of growth signals

Undergoes programmed cell death, or apoptosis

Ignore signals of programmed cell death or apoptosis

Stop growing when they encounter other

cells and mostly do not move around in the body

Invade into nearby areas and spread to other areas of the body

Does not utilise blood vessels as a means of survival

Signal blood vessels to grow towards tumours and act as a supplier of oxygen and nutrients to the tumour, while also removing waste products from the tumour

Does not need to avoid immune systems

Hide from the immune system as the immune system usually eliminates damaged or abnormal cells. However, the immune system

Table 1: Distinct traits of normal cells versus cancer cells could also be manipulated by cancer cells into protecting tumours instead of attacking it

Grows at a controlled rate relies on different nutrients to create energy, allowing cancer cells to grow at a more rapid rate

Contains 23 pairs of chromosomes per cell Accumulate multiple changes in their chromosomes, including duplications and deletions, making some cancer cells have nearly double the number of chromosomes compared to normal cells

Figure 1: The comparison between normal cells and cancer cells (National Cancer Institute, January 1st, 2001)[8]

2.3 Aetiology of Cancer

As shown in Figure 3, the causes of cancer are multifaceted, with some of the main causes being hereditary factors, exposure to excessive UV radiation, viruses, and chemicals, all of which can cause DNA damage.[9] Since cancer is a genetic disease, all these factors listed above can change the genes that control the way a cell should function and increase the probability of errors during cell division. Fortunately, the body has a way to eliminate cells with damaged DNA before they turn cancerous. However, as humans age, the body’s ability to eliminate damaged cells decreases, which is why the probability of developing cancer at older ages is significantly higher than developing cancer as a child or young adult.

Figure 3: Gene modifying factors that cause cancer by damaging the DNA (Cancer.gov, May 5, 2021)[10]

2.4 Cancer Classification

Cancer is not just one disease, rather it is a group of diseases in which cells in the body grow uncontrollably. Cancers are classified by their primary site of origin, tissue type, grade, or stage. Cancers that are named by their site of origin include breast cancer, lung cancer, etc. [11] For example, if cancer that originates from the kidney spreads to the lungs, it is still classified as kidney cancer and not lung cancer. [12] Moreover, due to the large variability in cancer types, cancers are also classified into five broad categories based on tissue types as illustrated in Table 1.

Tissue Types

  

Description

  

Examples

Carcinoma

 

Found in the epithelial tissue that covers or lines surfaces of glands, organs, or other structures.

Primarily affect organs or glands involved in secretion: breast, lungs, bladder, colon, and prostate.

Accounts for 80% – 90% of all cancer cases as epithelial tissues are the most abundantly found in the body, from being present in the skin to the covering and lining of organs and internal passageways.

 

Melanoma

Basal cell carcinoma

Squamous cell skin cancer

Merkel cell carcinoma

Sarcoma

  

A malignant tumour that grows from connective tissues, including cartilage, muscles, fat, bones, and tendons

 

Soft tissue sarcoma

Osteosarcoma
       

Ewing’s sarcoma
       

Chondrosarcoma

Myeloma

  

A type of blood cancer that grows in the plasma cells of bone marrow.

Myeloma cells usually collect in one bone and form a single tumour.

In other cases, myeloma cells can collect in many bones, forming multiple bond tumours.

 

Plasmacytoma

Table 2: The Five different tissue types in cancer, with key definitions, implications, and examples [13]

Leukaemia

  • Cancer of the bone marrow prevents the marrow from producing regular red and white blood cells and platelets.
  • Acute lymphocytic leukaemia
  • Acute myeloid leukaemia
  • Agnogenic myeloid leukaemia
  • Chronic lymphocytic leukaemia
  • Chronic myeloid Lymphoma
  • Originates in the glands or nodes of the lymphatic system, which has the function of producing white blood cells.
  • Classified into two further categories: Hodgkin’s lymphoma and non-Hodgkin’s lymphoma leakaemia
  • Essential thrombocythemia
  • Hairy cell leukaemia
  • Myelodysplastic syndrome
  • Cutaneous lymphoma
  • Hodgkin lymphoma
  • Non -Hodgkin’s

lymphoma

Another mode of cancer classification is based on grade, which works by assigning a grade based on the abnormality of cells with respect to the surrounding normal tissue. When a patient is suspected to have a malignant tumour, all or part of the tumour is removed to undergo a biopsy. During the biopsy, the pathologist can identify whether the tumour is benign or malignant as well as grade and determine other characteristics of the tumour.[14] The grading system differs based on the type of cancer, but generally, tumours tend to follow a grading scale from 1 to 4. A grade of 1 is the lowest grade and implies that tumour cells and tissues look like normal cells and tissues, meaning that they are well-differentiated tumours. Grade 2 is an intermediate grade, which implies that the cells and tissues are somewhat abnormal and are moderately differentiated from normal tumour cells and tissues. Grade 3, the second-highest grade, implies that the cells and tissues look very abnormal and are poorly differentiated since they no longer have an architectural structure and pattern. Grade 4 is the final and highest grade. At this level, the cancer cells look the most abnormal and have the appearance of non differentiable cells. Compared to lower-grade tumours, grade 4 tumours tend to grow and spread at the fastest rate. [15] Through the grading system for cancer, doctors can communicate the size and spread of cancer using a common language and can compare treatments between research studies.

3. Introduction to Targeted Therapy

Targeted Therapy is a type of cancer treatment using drugs and other substances that interfere with specific molecules in genes, proteins, or tissue environments that contribute to the growth and survival of cancer cells. [16]. As a form of precision medicine, targeted therapy consists of the use of drugs to inhibit specific sites on proteins that are involved in cell proliferation or interfere with certain aspects of cancer cells to promote cell cycle regulation and induce apoptosis. [17]

Although chemotherapy and targeted therapy both utilise drugs to treat cancer, they function differently in the human body. Chemotherapy was designed to kill all cells that are rapidly proliferating, adversely killing normal cells as well as cancer cells. [18] Additionally, chemotherapy is administered over a relatively short period, therefore causing more prominent side effects, such as anaemia, causing many patients to experience fatigue after their treatment. In contrast, treatment for targeted therapy is often given regularly over a long period, either through injection or swallowing pill capsules and since most targeted therapy drugs are taken regularly for a long period, the side effects are often less intense and occur much more gradually compared to chemotherapy. [19]

Targeted therapies are also cytostatic, meaning that the drugs used inhibit certain parts of a cell to stop cancer growth, without actually killing the cancer cell itself. Meanwhile, chemotherapy is cytotoxic, resulting in cell damage or death. [20]

Targeted therapy offers a wide range of benefits depending on which drugs are used and which sites are targeted. Some of the benefits of targeted therapy are that it could inhibit signals that promote cell proliferation, alter proteins in cancer cells that cause the cell to die, prevent the formation of blood vessels that provide oxygen and nutrients to tumour cells, manipulate the immune system to attack cancer cells specifically, and deliver toxins that kill cancer cells while sparing normal cells. Ultimately, the key benefit that targeted therapy offers, compared to other conventional cancer treatments, is its element of precision and specificity, which allows for targeting specific elements within cancer cells while causing minimal damage to other parts of the body.

4. Targeted Therapy Drug Development & Identification

The development of drugs used for cancer treatments must undergo an extensive process before being safe to be used on patients. The drug development scheme for cancer first begins with the identification of a molecular target.[21] As researchers begin to learn more about the cellular and molecular factors that promote cancer cell metastasis and proliferation, specific molecular targets have since been identified as potential areas of treatment.[22]

Common molecular targets used in targeted therapy are proteins found in cancer cells exclusively or proteins that are more abundant in cancer cells compared to normal cells. These cells are commonly associated with cancer cell growth or survival, which is why drugs tailored to inhibit proteins can be an effective way to treat cancer while causing minimal damage to normal cells.[23] For instance, overexpression of the Epidermal Growth Factor Receptor (EGFR) on many cell surfaces commonly results in a classification of cancer known as Carcinoma, a malignancy in the epithelial tissue which accounts for 80% to 90% of all cancer cases. [24]

Another molecular target used in targeted therapy is mutant proteins in cancer cells that drive cancer progression. The BRAF gene encodes a signalling protein for making a cell growth signalling protein that helps transmit chemical signals from the outside of the cell to the cell’s nucleus. [25] The BRAF gene is also characterised as an oncogene, meaning that it has the potential to transform normal cells into cancer cells.[26] In approximately 50% of all melanomas, which is a type of skin cancer, the BRAF protein is present in a mutant form known as BRAF V600E. Fortunately, Vemurafenib, a small molecule inhibitor of BRAF V600E kinase can selectively bind to the ATP-binding site

of BRAF V600E and inhibit its activity, resulting in the inhibition of an over-activated MAPK signalling pathway, which is the chain of proteins in the cell that communicates a signal from the receptor on the surface of the cell to the DNA inside the nucleus, ultimately resulting in a reduction in tumour cell proliferation. [27]

Furthermore, fusion proteins, a product of fusion genes, are caused by abnormalities in the chromosomes of cancer cells which drive cancer development, making it a potential target for molecularly targeted therapy.[28] In Leukaemia, there is a fusion protein called BCR-ABL which causes chronic myeloid leukaemia cells to grow and divide uncontrollably.[29] However, an orally taken medication known as Imatinib Mesylate can “switch off” the signalling pathways that promote leukemogenesis. The process of “switching off” the signalling pathways occurs by having Imatinib Mesylate bind to the amino acids of the BCR-ABL tyrosine kinase ATP binding site and stabilise the inactive and non-ATP binding form of BCR-ABL, thus preventing tyrosine autophosphorylation and phosphorylation of its substrates. [30] Overall, proteins are an essential component of targeted therapy, and inhibition of a certain type of protein can have a profound impact on aspects such as cellular proliferation and survival. On the contrary, proteins are not the only molecular targets. Instead of focusing on specific cellular targets, host mechanisms that facilitate nutrients and oxygen to cancer cells could also be inhibited. As such, DNA synthesis inhibitors or DNA damaging agents could be used to arrest cell growth as DNA synthesis is necessary for cancer expansion.

It is important to note, however, that cancer is heterogeneous, therefore molecular targets identified with one type of cancer may not work for another type. Additionally, it is of importance that the molecular targets identified should mostly most commonly be found in cancer cells and should rarely be present in normal cells. If not, there is a high risk of causing further damage by harming normal cells. After a molecular target has been identified, drug inhibitors or activators are designed to specifically bind with the molecular targets and undergo in vitro evaluations in cell culture studies as well as preclinical evaluation in small animals. Once the evaluation phase has been successful, clinical trials take place, and the drug will undergo a regulatory approval process. Only when the drug has been approved will patients be able to use the drug for treatment.

5. Types of Targeted Therapy

5.1 Monoclonal Antibodies — Block, Flag, and Deliver

Monoclonal Antibodies (MAbs) are an immunological tool commonly used in the field of clinical medicine today. MAbs currently account for one-third of all treatments for breast cancer, leukaemia, arthritis, and could potentially treat more illnesses. MAbs are small Y-shaped molecules that bind specifically to a target. In a laboratory, MAbs can be identically replicated and used to treat cancer by binding to specific proteins present on a cancer cell’s surface. There are three primary uses for MAbs in cancer treatment: Block, Flag, and Deliver. In simple terms, blocking constitutes the inhibition of molecules that stimulate cancer growth, flagging allows the body’s immune system to destroy cancer cells, and delivery is giving harmful substances to cancer cells itself. Due to the multifaceted approaches associated with MAbs, they act as a valuable approach to treating cancer and are often even interspersed with other cancer treatments such as chemotherapy.

An example of a blocking MAb is Trastuzumab, sold under the brand name Herceptin. Trastuzumab is used to treat cancers such as breast cancers and stomach cancers, but it could also treat cancers that have a positive HER2 receptor. Essentially, Traztuzumab attaches to the HER2 molecule found on some cancer cell surfaces, which blocks signals initiating cancer growth. Another common blocking MAb is Bevacizumab, which is used to block the VEGF molecule, preventing the growth of blood vessels. Blood vessels are essential to the growth and survival of tumours as it provides the necessary nutrients and oxygen required to sustain tumours.

Besides MAbs that block the growth of cancer cells, there are also MAbs that flag cancer cells for destruction. For instance, the MAb Rituximab, sold under the brand name Rituxan, is used to treat various types of non-Hodgkin’s lymphoma. Rituximab works by attaching to a molecule called CD20 on B-cells, acting as a flag for immune cells. By flagging CD20, the immune cells can recognize the B cell and destroy it.

Some MAbs deliver drugs, toxins, or radioactive particles to cancer cells. For instance, Brentuximab Vedotin is a MAb that works like chemotherapy, in which it delivers a chemotherapy drug to the cancer cell. However, the difference between drug delivery using MAbs is that the antibodies bind specifically to a protein or antigen on the cancer cell, which increases its precision and results in less harm to normal cells.

Figure 3: Function of Monoclonal Antibodies

5.2 Tyrosine Kinase Inhibitors

Tyrosine kinases are enzymes responsible for the activation of numerous proteins through signal transduction cascades. These signal transduction cascades occur by phosphorylation, the addition of a phosphate group to a protein as illustrated in Figure 4. Often, these signals regulate cell growth and division, hence the overexpression of Tyrosine kinases activated by gene amplification can lead to excessive cancer cell growth. Since Tyrosine Kinase Inhibitors (TKI) prevent phosphorylation, they can dysregulate numerous cellular functions present in both healthy and cancerous cells, including growth, transformation, and apoptosis.

There are several forms of antibodies that are developed for the treatment of cancer by targeting the extracellular domain of Receptor Tyrosine Kinases (RTK). These antibodies block ligands binding to the receptor or block receptor dimerization, both of which are essential for the functioning of the intracellular kinase domain. Cetuximab is a monoclonal antibody that has a high affinity for the extracellular domain of EGFR; it blocks ligand binding and activation of the intracellular kinase domain. But, there are other members of the RTKs such as ErbB-2 (HER2) which are ligand-independent and require dimerization with other members of the family (HER2) to be activated.

Figure 4: Addition and removal of protein phosphorylation with kinases and phosphatases [#]

5.3 Apoptosis-inducing drugs

Apoptosis is defined as programmed cell death, in which defective cells are detected and eliminated from the body’s system. Factors that are defined as cell defects include cell shrinkage, nuclear fragmentation, DNA fragmentation, chromatin condensation, mRNA decay, and more.

5.4 Angiogenesis Inhibitors

Table 3: The U.S. Food & Drug Administration (FDA) Approved Angiogenesis Inhibitors

Axitinib (Inlyta®)

Bevacizumab (Avastin®)

Carbozantinib (Cametriq®)

Everolimus (Afinitor®)

Lenalidomide (Revlimid®)

Lenvatinib Mesylate (Lenvima®)

Pazopanib (Votrient®)

Ramucircumab (Cyramza®)

Regorafenib (Stivarga®)

Sorafenib (Nexavar®)

Sunitinib (Sutent®)

Thalidomide (Synovir, Thalomid®)

Vandetanib (Caprelsa®)

Ziv-aflibercept (Zaltrap®)

6. Side Effects of Targeted Therapy

Although Targeted Therapy is cytostatic, there are still side effects present throughout the treatment. Side effects occur when treatments affect any healthy tissue or organ. Since targeted therapy strives to minimise damages to factors besides cancer cells, the side effects of targeted therapy are significantly reduced in contrast to chemotherapy. Hepatitis, liver problems, diarrhoea, and elevated liver enzymes are only some of the most common side effects of targeted therapy. Other side effects also include skin problems, blood clotting and wound healing, high blood pressure, gastrointestinal problems, and immunosuppression.

7. Limitations of Targeted Therapy

Despite its numerous benefits, there are certain limitations to targeted therapy that hinders its effectiveness. For instance, not all growth of tumours in cancer requires a specific target, thus no type of drug can prevent such growth. Mutations also cause shifts or differences in molecular targets. Since targeted therapy drugs are tailored to be specific, mutations that occur can cause resistance to the drug. A solution to this issue could be the combination of targeted therapy drugs with chemotherapy drugs. A common instance of the combination of the two treatments can be seen in the treatment of metastatic breast cancer where the targeted therapy drug, trastuzumab, and docetaxel, a traditional chemotherapy drug, were used in tandem to halt the overexpression of HER2/neu present in metastatic breast cancer. Additionally, targeted therapy drugs are difficult to develop due to the structure of the target along with how the target controls cellular functions and regulations in the cell. For instance, Ras, a common signalling protein mutated in over one-quarter of all cancers has yet to have a targeted therapy drug developed. Furthermore, there is also a significant limitation on “pathway-specific” targeted therapies as most tumours are the result of numerous mutations, thus inhibiting a single cellular pathway may not result in significant therapeutic outcomes.

8. Conclusion:

Targeted therapy proves to be an effective method for treating certain types of cancers. With its high level of specificity and precision, targeted therapy provides each patient with a treatment tailored to their own body. With a further examination of the complex cell interactions in cancer biology, new molecular targets are found, leading to the development of new drugs. Nevertheless, there is still a long way to developing the most effective cancer treatment, and to do so, there must be further developments in the field of molecular biology, imaging techniques, as well as the aid of artificial intelligence to achieve the most optimal treatment outcome. Future work should focus on further studying the specific protein-to-protein interactions on a molecular basis, which fuel the development, regulation, and growth of cancer cells. Though the road to finding a cure for cancer is long and at times daunting, the most important aspect of finding the most effective cancer treatment is to conduct further research and develop a greater understanding of molecular pathways and functions of cancer cells. A greater understanding of cancer will bridge together the current holes of knowledge in cancer biology, and hopefully, prove to be the guidelines for finally developing a cure for cancer.

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