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How can cancer be targeted without killing healthy cells?

Targeted Therapy: a tremendous solution

Abstract: Targeted therapy is a relatively new method of curing cancer that uses drugs to attack targets on which cancer cells’ growth closely depend. [1] By attacking the proteins or enzymes responsible for their abnormal growth, its effects are amplified. Targeted therapy is successful in curing many cancer patients, it has fewer effects on healthy cells and causes fewer long-term conditions or complications than other chemotherapy treatments [1]; although the side effects it can cause, such as hand-foot syndrome, are very complicated. [2]

Tracing Targeted Therapy

Targeted Therapy is a new way of curing cancer by using drugs that target specific proteins or enzymes in addition to blocking signals that help the cancer cells to grow and spread through the body’s systems. Targeted therapy has fewer side effects on the normal dividing cells and causes fewer long-term conditions than other chemotherapies. A significant factor in the functioning of other cancer treatments, like radiotherapy, is cytotoxicity, meaning they function to slow the spreading of or to kill the cancerous cells. This impacts the cells’ dividing routine: the cell cycle. [1]

Figure 2

The Cell Cycle

The cell cycle is the normal growth routine of cells. It has 5 phases [1] (as seen in Figure 2):

Cells in the G0 phase are not dividing nor preparing for dividing, and are in an inactive state. This stage can lasts for a few hours or for years depending on the cell type.

Specific signalling will allow progression to G1. In this stage normal metabolic processes occur (e.g. respiration and protein synthesis) and cells are preparing to progress to the next phase.

Next is stage S: now DNA is being replicated for the daughter cells that will form. There is then a second G phase (G2), before finally mitosis (the cell division) in stage M. [1]

Radiotherapy has been successful in targeting actively dividing cells (those not in G0) but has led to killing healthy cells as well. To avoid killing healthy cells, a new solution was needed: a cytostatic(meaning stopping tumor cells’ proliferation), targeted therapy. [3]

Targeted therapy differs from standard chemotherapy in several ways, including:

• Most standard chemotherapies act on all dividing cells, while targeted therapies act on specific molecular targets associated with cancer.

• Targeted therapies are designed to interact or change something involving the genes within cancer cells that causes further growth to be inhibited. Thus the tumour stays the same size and they are cytostatic. However many chemotherapies kill cells to decrease the size of tumours and therefore are cytotoxic. [1][2]

Targeted therapy can cause different reactions inside the cell such as:

• Preparing and developing immune systems to kill the cancer cells

• Carrying a toxin to the cancer cell to kill it without harming normal cells [4]

• Blocking or turning off the signals that tell cancer cells to grow and divide

• Keeping cells from living longer than normal [4.1]

• Changing proteins within the cancer cells so the cells die

• Stopping to make new blood vessels to feed the cancer cells [4.2]

Different cancers propagate through the body differently. Identifying the target of the targeted therapy is one of the most important factors in using this kind of method to cure cancer, as each type of cancer has its own target that needs to be identified to have a successful treatment.

Detailed Action of certain types of Targeted Therapy

Enzyme Inhibitors

One of the main goals of targeted therapy is the slowing down of the infected cells’ growth and spread, which can be targeted through enzyme inhibitors. In the human body, there are many enzymes that function to keep the body normal and some of these are enzymes give “spreading” and “growing” signals to infected cancer cells. Some targeted therapies block these signals, which results in the interruption of the infected cells’ cell cycles. However it does not distinguish cancerous cells from normal cells. [2]

In new research published on 21 March 2016 by Cornell researchers from Ithaca and Weil Cornell Medicine campuses, a promising new inhibitor which showed effectiveness most noticeably against several types of difficult and complicated cancer types, such as leukemia, breast and colorectal cancer was described. “This started from basic science, and the basic study led us to this path, which looks very promising. We have high hope that in a few years, we can develop an effective anti-cancer drug,” said co-lead author Hening Lin, professor of chemistry and chemical biology in the College of Arts and Sciences and a Howard Hughes Medical Institute investigator. [5] An important role in the survival of several types of cancer, and one of the major factors in this research was played by the oncoprotein c-Myc, which is found in almost half of all human tumors and on the enzyme SIRT2. Experimenting on a laboratory breast cancer mouse model, the tumor growth in the breast cancer was inhibited by the group of researchers in addition to inhibiting SIRT2 and decreasing the c-Myc protein level by using a compound known as TM, which is a thiomyristoyl lysine compound. [5]

Apoptosis-inducing drugs

Many cancer treatments, including radiotherapy, cause changes in cells which lead to apoptosis (programmed cell death). Targeted therapy drugs in this treatment, apoptosis-inducing drugs, cause the cancer cells to die. In some situations, the “signals” for cell death do not work properly and drugs such as Olaparib (Lynparza) try to restore them in addition to:

• Blocking poly ADP-ribose polymerase (PARP) enzymes so that the cancer cells’ DNA cannot be repaired, causing the cells to die [6]

• Making the cells more easily destroyed

• Blocking BCL2 which promotes cancer call survival resulting in more sensitivity to anti cancer drugs [1] [6]

Angiogenesis inhibitors

Tumors and cancer cells need blood and nutrients to grow and spread– if they get insufficient amounts of nutrients they will not be able to grow. Angiogenesis is the process of making new blood vessels, which is a healthy and normal process; it may not be much needed for healthy adults but is very useful and important in remaking blood vessels when injured for example. So, one way of stopping the growth of cancer tumors is stopping the supply of nutrients needed for their growth. Cancerous cells use VEGF, vascular endothelial growth factor, which is a family of protein growth factors made by some tumors: the VEGF proteins attach to their receptors in blood vessel cells and cause new blood vessels to form around the tumor, allowing it to become more massive. Some angiogenesis inhibitors work to block VEGF. [1]

Figure 3: Man-made targeted antibody drugs
Figure 4: Small-molecule drugs for inner cell treatments.

 

Types of Targeted Therapy Drugs:

Most targeted therapy drugs are divided into two main types:

Antibody drugs: Man-made versions of immune system proteins (as seen in Figure 3) called antibodies that have been designed to attack certain targets on cancer cells, mostly around the surface of infected cells as they are more massive than others drugs. Normally the body itself makes antibodies to fight harmful microbial attackers.

Small-molecule drugs: Such drugs are smaller and can easily go inside cells and therefore are assigned to do tasks inside cancer cells and that can be noticed in Figure 4. [2]

Some drugs that have noticeably great usage today:

Gleevec: There are many different kinds and types of targeted therapy drugs, one of the first to be used to cure cancer was Gleevec (imatinib mesylate) which is usually used to treat gastrointestinal  stromal tumor, a rare type of cancer in the gastrointestinal area known as GIST, and specific kinds of leukemia. This drug, imatinib, is a tyrosine kinase inhibitor meaning it targets tyrosine kinase proteins that are used for growth signaling of cells [7] and a type of small molecular drug that normally targets abnormal proteins or enzymes that form on and inside cancer cells and provide the key to the uncontrolled growth of dividing cells. Blocking these enzymes inhibit the growth of these cells, that is one of the main goals of targeted therapy. [2]

Iressa (gefitinib): One way to treat advanced non-small cell lung cancer is the targeting of epidermal growth factor receptors– (EGFR) which are found on the surface of many normal cells, but specific cancer cells have an abnormally high number of them on their surface which helps in giving more signals to the infected cells to grow and spread. Using gefitinib to stop the signals by blocking them  results in slowing or stopping of abnormal cell growth [2].

Sutent: One of the multi-functioning targeted therapy drugs available for treating both advanced kidney cancer and some gastrointestinal stromal tumors (GIST), which is very useful and impressive, is Sutent (sunnitinib). It is considered as a multi-targeted kinase inhibitor as it is a kind of vascular endothelial growth factor receptor inhibitor and an angiogenesis inhibitor. It stops the source of nutrients for cancer tumors, in addition to blocking the well-known tyrosine kinase enzyme. By succeeding in performing all these tasks, this useful drug not only slows cancer growth but it keeps tumors from making their own blood vessels to help the growth of them throughout the body. [2]

Velcade (bortezomib): This kind of drug, which is a small molecular drug, is necessary to treat multiple myeloma when other drugs have not responded to previous treatments. This proteasome inhibitor, bortezomib, stops the proteasome (which is a complex of enzymes that helps destroy proteins no longer necessary to the cell, including those regulating cell function and growth) from breaking down these proteins which in turn causes cancer cells to die. [2] Velcade has been used to treat an estimated number of 550000 atients worldwide which is very hopeful for a brighter future. [8]

Figure 5: Different kinds of side effects from targeted therapy, such as hand-foot syndrome (shown in the bottom-centre image)

Targeted Therapy Side Effects

One of the main benefits of targeted therapy is that it has fewer side effects on the body than other standard chemo treatments, although it can have side effects that are deeply dependent on the target that the drugs are used to attack. [2] Some drugs have more targets on cancer cells but also some on healthy cells that can cause negative impacts. The side effects increase in severity as the number of drug targets increase, especially drugs that play an important role in angiogenesis inhibition, as that affects new blood vessel formation all over the body, not just those near the infected cancer cells and tumors, meaning they can lead to complications, such as those seen in Figure 5.

Some people get few, if any side effects and it really depends on the person that uses the drugs; even the severity of the effects varies greatly from person to person and how long the drug was used. The side effects usually are not long-term as most side effects go slowly after treatment and the healthy cells recover however it really depends on the patient’s overall health conditions and the consumed drugs’ specifications. [2]  Some types of medicines may be given to the patient to control the side effects after or even before the medication. These are some of the most common side effects of targeted therapy:

Skin problems:

The most common skin problem after the treatment is rash: more than half of patients who chose this type of treatment are affected by it. Its severity depends on the type of cancer and the dose used to treat it, although it is mild for most people. It is often similar to acne but without blackheads as seen in Figure 6, and usually appears on the scalp, face, neck, chest and upper back by about the fourth week of the treatment, when the skin usually crusts and gets very dry and red (dryness of the skin which can even crack open is another side effect which is more difficult to handle than rash) and after that, flat or raised spots appear on the skin which can itch, burn, sting and may even be painful to touch (some patients may be needed to use drugs such as diphenhydramine to get relief); the rash usually should completely go away about after a month of the treatment [9].

Figure 6: Rash is the most common side effect of this therapy

These problems usually develop slowly over days to weeks and are not the signs of drugs allergy – which includes serious symptoms such as dizziness, trouble in breathing, tightness in the chest and throat, swelling of lips or tongue, intense itching or hives that usually becomes noticeable suddenly a few minutes to hours after taking the drug– but problems like lack of skin moisture, which is the result of some of the specialized drugs that target the epidermal growth factor receptor (EGFR) protein which sends growth and division signals to cancer cells, like Iressa (geftinib); as explained above, it affects the normal skin cells which do have a lot of EGFR on their surfaces making it harder to maintain skin moisture [10].

Figure 7: Hand-Foot syndrome can result in swelling of the soles and hands.

Other problems that are a result include the hand-foot syndrome –its cause is not known yet but is probably because of the damage to the tiny blood vessels in the hands and feet or the drugs themselves leaking out from the blood vessels and into tissues, leading to tissue damage that targets proteins such as the vascular endothelial growth factor (VEGF) which helps tumors build and maintain a blood supply. Some patients who reach severe levels of pain both in the hands and feet may be given medicine for relief as it can cause swelling in the palms of the hands and soles of the feet, which can be seen in Figure 7, redness which may even blister and open up and become painful sores and can even affect the ability to walk and doing normal activities. Scientists have reached the conclusion that patients getting radiotherapy, as well as targeted therapy, have more skin problems in the area where the radiotherapy treatment has been focused on as well. [2]

Another side effect caused by some targeted therapies is swollen, red, open and painful skin sores around fingernails and toenails which can superficially look like an infection or an ingrown nail as can be seen in Figure 5 (bottom right image). It happens mostly to the big toes and thumbs and may get infected, brittle and grow slowly.

Other types of side effect include changes in hair growth, affecting both men and women, can be noticed including the hair becoming thin, dry, curly and even brittle. Bold patches or complete loss of scalp hair may as well be observed when using targeted therapy for a long time. Some drugs may even affect the colour of the hair, in addition to a change of the skin colour; the skin usually tends to turn to a yellowish shade and in rare situations hair becomes darker. These effects usually fade away as the treatment ends.

Targeted therapy may even cause damage to the clear part of the eye, which can result in injury, pain, or infection as in few people the eyelids may turn inwards or outwards as seen in Figure 5, get tender, swollen or inflamed and crusts may be seen in the eyelashes. [2] The eye itself can become dry and red and burn painfully. Problems with wound healing like the opening up of old wounds and new ones not closing, perforations, which are holes opening up in the digestive system organs, can also be observed.

Complications with bleeding and clotting because of angiogenesis inhibitors’ interference in the formation of new blood vessels can occur and result in bruising. Throwing up blood may also be a sign that the patient is facing inner bleeding in the intestines and stomach, which is very severe. These drugs may even cause clots in the lungs and legs, heart attacks and strokes – of which  symptoms include sudden swelling, pain, or tenderness in the arm or leg. These symptoms should always be reported immediately to a doctor as they may lead to death. [2]

In conclusion, targeted therapy is a very useful treatment for many types of cancer, with fewer side effects on normal, healthy cells than other therapies. [1]  Specific drugs can attack their targets in many different ways to decrease the number of cancerous cells in the body, but inevitably do lead to complications (such as blood clots). The difficulties a patient may go through because of their treatments can include rare but possibly long-term diseases [3]; however, because these techniques are still young compared with other chemo treatments, there are still many more studies to be done and improvements to be made. The very best is wished to all victims of cancer, a deadly killer, in the hope of the best use of targeted therapy to cure them.

 

By Anne-Rosa Bilal

 

 

References:

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