AUTHOR DETAILS: JATIN KUMAR, 4th YEAR B.TECH (BIOTECHNOLOGY), RPCAU, PUSA

ABSTRACT

Cancer is a nearly invincible disease that has plagued humankind for centuries, it arises from the uncontrolled and unregulated growth of malignant cells, having ability to invade new sites and spread over the other body parts. For the past half a century, non-surgical treatment has been dominated by two main types of traditional therapies – Chemotherapy and Radiation therapy. One of the major breakthrough in the treatment of cancer is Targeted therapy, came into existence in 1970s in the form of Tamoxifen, making it the 1st targeted drug for Cancer. Targeted cancer therapy uses drugs or other substances that blocks the growth and spread of cancer by interfering with molecules that are more specifically involved in growth of cancer cells and their progression. Targeted therapy requires the identification of ideal or good targets i.e., Cell markers (Biomarkers) and/or Cell pathways, which play a key role in cancer cell growth, development and survival. Once the target has been identified, the next step is to develop a therapy that alters its ability to promote cancer cell growth or survival. A therapy that could reduce the activity of the target or prevent it from binding to a receptor that it normally activates. The goal of targeted therapies is to get rid of cancerous cells while leaving the normal cells unharmed.

INTRODUCTION

Cancer is a nearly invincible disease that has plagued humankind for centuries, it arises from the uncontrolled and unregulated growth of malignant cells, having ability to invade new sites and spread over the other body parts. With about 14 million new cases of cancer each year, about 90.5 million cancer patients were in 2015 and caused about 8.8 million deaths. According to WHO, it is estimated that cancer related death is going to reach approx 13.1 million by the year 2030. However, mortality rate has decreased in last 5 years due to our better understanding about cancer biology & improved diagnostic tools and therapies. For the past half a century, non-surgical treatment has been dominated by two main types of traditional therapies – Chemotherapy and Radiation therapy. Chemotherapy uses drugs that have the potential to kill cancer cells while radiation therapy uses high energy radiations to kill cancer cells and shrink tumours. These traditional therapies kill the cancerous cells along with normal cells, which was a major drawback.

One of the major breakthrough in the treatment of cancer is Targeted therapy, came into existence in 1970s in the form of Tamoxifen, making it the 1st targeted drug for Cancer. In the last three decades, discovery of oncogenes and tumor suppressing genes & the completion of Human genome sequencing deciphered the molecular mechanism of cancer development and these genetic informations rapidly promoted the development of new targeted therapies. Targeted cancer therapy uses drugs or other substances that blocks the growth and spread of cancer by interfering with molecules that are more specifically involved in growth of cancer cells and their progression. The goal of targeted therapies is to get rid of cancerous cells while leaving the normal cells unharmed.

TRADITIONAL THERAPIES V/S TARGETED THERAPIES IN CANCER

Traditional cancer therapy includes surgery, hormonal therapy, chemotherapy and radiation therapy, of which chemotherapy and radiation therapy are widely popularized due to its effectiveness.

In Chemotherapy, drugs are used that have the potential to kill the cancerous cells by blocking their DNA replication.  DNA replication is a common process that is performed by all cells undergoing mitosis, and chemotherapy does not distinguish between cancerous cells and normal cells. Thus classic chemotherapy has many side effects as it also tends to kill normal cells that are undergoing replication. The fast growing normal cells that are more often affected by chemotherapy are blood cells in bone marrow, cells lining the digestive tract (such as mouth, oesophagus and stomach).

In radiation therapy, high energy radiations from X-rays, gamma rays, neutron, protons and other sources are used to kill cancer cells and shrink tumours. Radiation therapy damages the DNA, which prevents the cell from replicating. It is typically performed by directing a beam of high energy radiations at the site of cancer. At present, radiation therapy is highly accurate and does not typically cause the severe skin damage as seen in past years. However, like chemotherapy, radiation therapy targets both healthy and cancerous tissues.

Hormonal therapies for breast cancer have been used in clinical use for more than 30 years and have been called the first targeted therapies because they act on a specific protein that breast cancer cells used to grow.

Targeted cancer therapies are drugs or other substances that blocks the growth and spread of cancerous cell by interfering with molecules that are more specifically involved in cancer cell growth, than in normal cell activity. These drugs act on cell markers and/or pathways of cells to prevent them from replicating and proliferating. The aim of targeted therapy is to get rid of cancerous cells without harming normal cells. Hence, targeted therapy is more specific as compared to chemotherapy and radiotherapy. However we are not yet devised a targeted therapy which is completely specific for cancerous cells. Inevitably, some normal cells are still get affected by targeted therapies and also have some side effects.

IDENTIFICATION OF TARGETS FOR TARGETED CANCER THERAPIES

Targeted therapy requires the identification of ideal or good targets i.e., Cell markers (Biomarkers) and/or Cell pathways, which play a key role in cancer cell growth, development and survival.

Biomarkers are defined as anatomic, physiologic, biochemical or molecular parameters associated with the presence and severity of specific disease traits. However in the context of targeted therapy for cancer, it usually refers to biochemicals or molecules in or on the cancerous cells. These biomarkers are usually gene or proteins.

At the level of protein, one approach to identify the potential target of therapy is to compare the amount of individual proteins in both cancer cells and normal cells.  Proteins those are only present in cancerous cell and not in normal cells, or more abundant in cancerous cells than in normal cells, would be the potential target, especially if they are involved in cell growth or survival. An example of such target is the Human Epidermal Growth Factor Receptor-2 proteins (HER-2). HER-2 is expressed at high levels on the surface of some cancer cells, especially in the case of certain breast and stomach cancers. Trastuzumab (Herceptin) has been developed which targets HER-2 and is approved to treat certain breast and stomach cancers.

Another approach to identify the potential target is to determine whether the cell is producing a mutant or altered protein that drives the cancer progression. For example, the cell growth signalling protein BRAF is present in an altered form (called BRAF V600E) in many melanomas. Vemurafenib (Zelboraf) has been developed which targets this altered form of BRAF and is approved to treat the patients with metastatic melanoma.

Now at the level of genes, researchers have found some chromosomal abnormalities that are present only in cancer cells and not in normal cells. These abnormalities leads to the formation of fusion gene (a gene that incorporates parts of two different genes), whose product is a fusion protein, that may cause cancer development. Such fusion proteins are the potential targets of targeted therapies. For example, Imatinib mesylate (Gleevec) targets the BCR-ABL fusion protein, made from pieces of two genes that get joined together in some leukemic cells and promote its growth.

In Cell pathways, cells communicate with their environment and with one another in several different ways. One method of communication for a cell is to release chemicals that affect other cells. The chemicals that cells usually release are proteins, which include growth factors and hormones. These chemicals bind to receptors, which may be located outside of cells. This binding initiates a series of events that affects some aspect of the cell. These events occur via multiple pathways and involve many different proteins and chemicals inside the cell. The activation of these pathways usually results into altered gene expression or protein metabolism. The proteins involved in the pathways carry information to the cell nucleus where genes are either activated or suppressed (inhibited). Alternatively, pathways may affect key proteins that regulate important aspects of cellular behaviour such as survival and growth.

For example, a growth factor binding to its receptor is the signal that activates the pathway responsible for growth and replication. By blocking this receptor, targeted therapies such as Trastuzumab prevent activation of the growth pathway so that cancer cells become unable to grow and replicate. Trastuzumab belongs to a class of humanized monoclonal antibodies, used in targeted therapies.

DEVELOPMENT OF TARGETED THERAPIES

Once the target has been identified, the next step is to develop a therapy that alters its ability to promote cancer cell growth or survival. A therapy that could reduce the activity of the target or prevent it from binding to a receptor that it normally activates.

Most targeted therapies use either small molecules or monoclonal antibodies. Special small molecular compounds are developed that can easily cross the cell membrane and acts on the intracellular targets. Monoclonal antibodies are relatively bigger in size, so they are generally unable to get inside the cell. So they are used only for intercellular targets or the targets on the cell surface.

The activities of small molecules are usually identified in “high throughput screens,” in which the effects of thousands of them, on a target protein are examined. Compounds that act on the targets effectively, sometimes called “lead compounds” are then modified to produce numerous copies of related versions. These related versions are then tested on the same target protein to determine which one is more effective and cause no harm to non-targeted molecules.

Monoclonal antibodies are developed by hybridoma technology (by fusing myeloma cells with antibody producing B-cells of mice). These antibodies are then tested on the target proteins, and those that bind the target exactly, without binding with non-target proteins are selected.

Before being used in humans, these monoclonal antibodies has to “Humanized” by replacing the antibody portion of mice origin, with the corresponding portions of human antibodies, to prevent it from recognizing as a “foreign” element by our immune system and destroying before it get bind with the target proteins.

Humanization is not an issue in the case of small molecules, as they are typically not recognized by our body as foreign element.

AVAILABLE TARGETED THERAPIES

There are many different targeted therapies that have been approved for cancer treatment. These include the following therapies

Apoptosis inducers – These can be used to kill the cancerous cells by a process of controlled cell death called apoptosis. Unneeded or abnormal cells within the body have to be destroyed, but cancerous cells have strategies to avoid the process of apoptosis. So by using apoptosis inducers, the cell death can be induced efficiently in the cancerous cells.

Angiogenesis inhibitors – These are used to block the growth of new blood vessels to the tumors (a process called tumor angiogenesis), thus preventing the supply of nutrients and oxygen that a tumor need for continuous growth and development. Application of angiogenesis inhibitor may block the tumor growth. These inhibitors generally interfere with the action of vascular endothelial growth factor (VEGF), a substance that stimulates new blood vessel formation.

Gene expression modulators – These are used to modify the function of proteins that play a role in gene expression. This approach is also known as Transcription therapy. Transcription was traditionally considered as undruggable, but agents have been developed that targets various levels of transcriptional regulation, including DNA binding by transcription factors, protein-protein interactions, and epigenetic alterations.

Hormonal therapy – It stops or reduces the growth rate of hormone sensitive tumor, which requires hormone to grow. It has two approaches, either by preventing the body from producing the hormone or by interfering with the action of hormones. Hormone sensitive cancers are breast cancer, prostate cancer, ovarian cancer and womb cancer (endometrial cancer).

Surgical removal of endocrine organs such as testicles (Orchiectomy) and ovaries (Oophorectomy) can be performed to prevent the body from producing target hormones. Manipulation of endocrine glands by exogenous administration of specific hormones, particularly steroidal hormones or drugs (hormonal antagonists) which inhibit the production or activity of such hormones can also be performed, because steroidal hormone regulates the gene expression strongly, in certain cancer.

Immunotherapy – It is used to trigger the immune system to destroy abnormally growing cancerous cells. These are based on monoclonal antibody that recognizes specific epitopes, present on the surface of cancer cells, leading to their destruction. Monoclonal antibody may also bind to certain immune cells, triggering their immune response to kill the cancerous cells.

Monoclonal antibodies can also be used to deliver the toxic molecules that can cause the death of cancer cells specifically. Once the antibody bounds to its target cell, it releases the toxic molecule or chemical such as a radioactive substance or a poisonous chemical that is taken up by the cell, ultimately leading to their death. The toxin will not affect normal cells that lack the target for the antibody.

Signal transduction inhibitors – It blocks the activities of signalling molecules that help in signal transduction, the process by which a cell responds to signals from its environment. These signals are involved in various functions of cells including death, growth and division. Some cancerous cells are stimulated to divide continuously without being signalled to do so by external growth factors. So the signal transduction inhibitors are used to prevent these inappropriate signalling.

Many drugs have been developed to block particular signals, preventing the cancerous cells from uncontrolled growth and invading other tissues. Imatinib is an orally administered tyrosine kinase inhibitor used to treat CML (Chronic Myeloid Leukemia) in chronic phase.

Cancer vaccines and Gene therapy – A number of cancer vaccine and gene therapy approaches have been tested in lungs cancer patients. Cancer vaccine approach includes GM-CSF gene modified cancer cells, liposomal MUC1 peptide, anti-idiotype antibody targeting GD3, Mage-3 peptide, and mutant p53 pulsed dendritic cells. Gene therapy approach includes intratumoral gene replacement in lung cancer, predominantly with p53.

DETERMINING DOSES AND EFFECTIVENESS

Targeted therapy has introduced several new issues to the oncologists. Determining optimal dosing is one challenge. Clinical trials of chemotherapeutic drugs generally determine toxicity through the degree of myelosuppression. Targeted therapy, however don’t cause significant hematologic toxicity. Assessment of treatment effectiveness is also essential.

To determine the dosing and effectiveness of targeted therapies, cancer researchers are turning to pharmacodynamic end points, such as tumor metabolic activity on positron emission tomography scans, levels of circulating tumors and endothelial cells, and serial levels of target molecules in cancerous tissues. Although these studies may initially increase the time and expense of therapy, but may improve its long-term cost-effectiveness by identifying the subset of patients most likely to benefit from specific drugs.

LIMITATIONS OF TARGETED CANCER THERAPIES

Targeted therapies do have some limitations. First, cancer cells can become resistant to them. Resistance can occur in two ways: the target may change itself through mutation so that the targeted therapy no longer interacts with it, or the tumor may find a new pathway to achieve uncontrolled growth that does not depend on the target.

Thus, targeted therapies may work best in combination. For example, a recent study found that using two therapies that target different parts of the cell signalling pathway that is altered in melanoma by the BRAF V600E mutation slowed down the development of resistance and disease progression to a greater extent than using just one targeted therapy.

Another approach is to use a targeted therapy in combination with one or more chemotherapic drugs. For example, the targeted therapy Trastuzumab (Herceptin®) has been used in combination with Docetaxel, a traditional chemotherapy drug, to treat women with metastatic breast cancer that overexpresses the protein HER2/neu.

Another limitation of targeted therapy is that drugs for some identified targets are difficult to develop because of the target’s structure and/or the way its function is regulated in the cell. One example is Ras, a signalling protein that is mutated in as many as one-quarter of all cancers (and in the majority of certain cancer types, such as pancreatic cancer). To date, it has not been possible to develop inhibitors of Ras signalling with existing drug development technologies. However, new approaches are offering hope to overcome these limitations.

SIDE EFFECTS OF CANCER THERAPIES

Targeted cancer therapies are expected to be less toxic than traditional chemotherapy drugs because cancer cells are more dependent on the targets than are normal cells. However, targeted cancer therapies can have side effects.

The most common side effects that can be seen in targeted therapies are diarrhoea and liver problems, such as hepatitis and elevated liver enzymes. Other side effects include: Skin problems (acneiform rash, dry skin, nail changes, hair depigmentation), Problems with blood clotting and wound healing, High blood pressure, Gastrointestinal perforation (a rare side effect of some targeted therapies).

APPROVED TARGETED THERAPIES FOR SPECIFIC TYPES OF CANCER

The FDA has approved targeted therapies for the treatment of following types of cancer (some targeted therapies have been approved to treat more than one type of cancer):

Adenocarcinoma of the stomach or gastroesophageal junction: Ramucirumab (Cyramza®), Trastuzumab (Herceptin®).

Bladder cancer: Atezolizumab (Tecentriq™), Avelumab (Bavencio®), Durvalumab (Imfinzi™), Nivolumab (Opdivo®), Pembrolizumab (Keytruda®).

Brain cancer: Everolimus (Afinitor®), Bevacizumab (Avastin®).

Breast cancer: Abemaciclib (Verzenio™), Anastrozole (Arimidex®), Everolimus (Afinitor®), Tamoxifen (Nolvadex), Toremifene (Fareston®), Trastuzumab (Herceptin®), fulvestrant (Faslodex®), exemestane (Aromasin®), lapatinib (Tykerb®), letrozole (Femara®), pertuzumab (Perjeta®), ado Trastuzumab emtansine (Kadcyla®), Palbociclib (Ibrance®), Ribociclib (Kisqali®), Neratinib maleate (Nerlynx™), Plaparib (Lynparza™).

Cervical cancer: Pembrolizumab (Keytruda®), Bevacizumab (Avastin®).

Colorectal cancer: Avelumab (Bavencio®), Bevacizumab (Avastin®), Cetuximab (Erbitux®), panitumumab (Vectibix®), ziv-aflibercept (Zaltrap®), Regorafenib (Stivarga®), Ramucirumab (Cyramza®), Nivolumab (Opdivo®), Ipilimumab (Yervoy®)

Dermatofibrosarcoma protuberans: Imatinib mesylate (Gleevec®).

Endocrine/neuroendocrine tumors: Lanreotide acetate (Somatuline® Depot), lutetium Lu 177-dotatate (Lutathera®), iobenguane I 131 (Azedra®)

Head and neck cancer: Cetuximab (Erbitux®), Nivolumab (Opdivo®), Pembrolizumab (Keytruda®).

Gastrointestinal stromal tumor: Imatinib mesylate (Gleevec®), Regorafenib (Stivarga®), Sunitinib (Sutent®).

Giant cell tumor of the bone: Denosumab (Xgeva®)

Kidney cancer: Axitinib (Inlyta®), Bevacizumab (Avastin®), Cabozantinib (Cabometyx™), Everolimus (Afinitor®), Sorafenib (Nexavar®), Sunitinib (Sutent®), Pazopanib (Votrient®), Temsirolimus (Torisel®), Nivolumab (Opdivo®), lenvatinib mesylate (Lenvima®), ipilimumab (Yervoy®)
Leukemia: Alemtuzumab (Campath®), Blinatumomab (Blincyto®), Enasidenib mesylate (Idhifa®), Tretinoin (Vesanoid®), imatinib mesylate (Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), rituximab (Rituxan®), ofatumumab (Arzerra®), obinutuzumab (Gazyva®), ibrutinib (Imbruvica®), idelalisib (Zydelig®), venetoclax (Venclexta™), Ponatinib hydrochloride (Iclusig®), midostaurin (Rydapt®), inotuzumab ozogamicin (Besponsa®), tisagenlecleucel (Kymriah®), gemtuzumab ozogamicin (Mylotarg™), rituximab and hyaluronidase human (Rituxan Hycela™), ivosidenib (Tibsovo®).

Liver cancer: Lenvatinib mesylate (Lenvima®), Regorafenib (Stivarga®), Sorafenib (Nexavar®), Nivolumab (Opdivo®).

Lung cancer: Alectinib (Alecensa®), Atezolizumab (Tecentriq™), Bevacizumab (Avastin®), Ceritinib (LDK378/Zykadia™), crizotinib (Xalkori®), erlotinib (Tarceva®), gefitinib (Iressa®), afatinib dimaleate (Gilotrif®), ramucirumab (Cyramza®), nivolumab (Opdivo®), pembrolizumab (Keytruda®), osimertinib (Tagrisso™), necitumumab (Portrazza™), brigatinib (Alunbrig™), trametinib (Mekinist®), dabrafenib (Tafinlar®), durvalumab (Imfinzi™).

Lymphoma: Axicabtagene ciloleucel (Yescarta™), Belinostat (Beleodaq®), Copanlisib hydrochloride (Aliqopa™), Ibritumomab tiuxetan (Zevalin®), denileukin diftitox (Ontak®), brentuximab vedotin (Adcetris®), rituximab (Rituxan®), vorinostat (Zolinza®), romidepsin (Istodax®), bexarotene (Targretin®), bortezomib (Velcade®), pralatrexate (Folotyn®), ibrutinib (Imbruvica®), siltuximab (Sylvant®), idelalisib (Zydelig®), obinutuzumab (Gazyva®), nivolumab (Opdivo®), pembrolizumab (Keytruda®), rituximab and hyaluronidase human (Rituxan Hycela™), acalabrutinib (Calquence®), tisagenlecleucel (Kymriah®), venetoclax (Venclexta™), mogamulizumab-kpkc (Poteligeo®).

Microsatellite instability-high or mismatch repair-deficient solid tumors: Pembrolizumab (Keytruda®).

Multiple myeloma: Bortezomib (Velcade®), carfilzomib (Kyprolis®), Elotuzumab (Empliciti™) panobinostat (Farydak®), Daratumumab (Darzalex™), Ixazomib citrate (Ninlaro®).

Myelodysplastic/myeloproliferative disorders: Imatinib mesylate (Gleevec®), ruxolitinib phosphate (Jakafi®)

Neuroblastoma: Dinutuximab (Unituxin™)

Ovarian epithelial/fallopian tube/primary peritoneal cancers: Bevacizumab (Avastin®), olaparib (Lynparza™), Niraparib tosylate monohydrate (Zejula™), Rucaparib camsylate (Rubraca™).

Pancreatic cancer: Abiraterone acetate (Zytiga®), Erlotinib (Tarceva®), everolimus (Afinitor®), sunitinib (Sutent®)

Prostate cancer: Apalutamide (Erleada™), Cabazitaxel (Jevtana®), Enzalutamide (Xtandi®), Radium 223 dichloride (Xofigo®).

Skin cancer: Avelumab (Bavencio®), Alitretinoin (Panretin®), Vismodegib (Erivedge®), Sonidegib (Odomzo®), ipilimumab (Yervoy®), Vemurafenib (Zelboraf®), trametinib (Mekinist®), dabrafenib (Tafinlar®), Pembrolizumab (Keytruda®), Nivolumab (Opdivo®), cobimetinib (Cotellic™), Encorafenib (Braftovi™), Binimetinib (Mektovi®).

Soft tissue sarcoma: Alitretinoin (Panretin®), Pazopanib (Votrient®), Olaratumab (Lartruvo™).

Stomach cancer: Pembrolizumab (Keytruda®).

Systemic mastocytosis: Midostaurin (Rydapt®), Imatinib mesylate (Gleevec®).

Thyroid cancer: Cabozantinib (Cometriq®), Dabrafenib (Tafinlar®), vandetanib (Caprelsa®), sorafenib (Nexavar®), Lenvatinib mesylate (Lenvima®), Trametinib (Mekinist®).

References:” National Cancer Institute“(Source of monoclonal antibodies is taken from National Cancer Institute)

 

CONCLUSION

Targeted therapy has a promising future to cure the cancer more efficiently. However we are not yet devised a targeted therapy which is completely specific for cancerous cells. Inevitably, some normal cells are still get affected by targeted therapies and also have some side effects.

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