Promising Targeted Therapies for Cancer

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Figure 1: Culturing cancer cells. Image courtesy of the Babraham Institute

Cancer is a leading cause of deaths in the world. The World Health Organisation estimated that 8.2 million people died from cancer in 2012. The most common cause of cancer deaths is from cancers of the lung – in 2012, lung cancer resulted to 1.59 million deaths worldwide and 35,371 deaths in the UK. Recently, a number of new targeted therapies for cancer have been approved by the Food and Drug Administration (FDA). Studies have also shown that these drugs have fewer side effects than current cancer treatments, due to their selectivity in targeting cancer cells. Hence, understanding more about the basic biology that lies behind these new drugs is key in finding a cure for cancer.

Cancer is the result of genetic mutations in a cell that cause uncontrolled cell division. Sometimes, DNA—a molecule which contains the genetic instructions for controlled cell growth—becomes damaged. Normally, in a healthy cell, specific proteins in the cell detect damaged DNA and signal other molecules to drive cell death. However, in a cancer cell, sections of the DNA contain key oncogenes and tumour suppressor genes which are mutated. This results in the genes coding for the wrong proteins that normally regulate cell growth and death. Hence, the signaling pathway is deregulated, and the cell containing the damaged DNA survives, grows, replicates, and divides uncontrollably. As the cancer enlarges, it develops its own blood supply, allowing it to enter the blood vessels and eventually invade other healthy organs which are crucial for sustaining life. The spread of cancer from its primary site is referred to as metastasis.

Currently available treatments 

Surgery removes most cancer cells. However, some cancers are inoperable due to their location being too close to vital organs, such that removing them could harm the patient. For example, pancreatic cancer is typically diagnosed at a late stage because symptoms do not show up readily. The patient will usually start experiencing symptoms when the cancer is large enough to block the pancreatic ducts, or has metastasised to neighbouring organs (such as the liver). Statistics show that less than 20% of patients diagnosed with pancreatic cancer are suitable for surgery.[8] Hence, they would usually undergo other treatments, such as chemotherapy and radiotherapy.

Radiotherapy involves using x-rays, gamma rays, or high-energy particles to ionise atoms that make up the DNA. Ionisation of these atoms causes extensive damage within the DNA molecule in the cell, thus causing cell death. Radiation can be delivered externally using a linear accelerator machine. It can also be delivered internally by temporarily placing a radioactive material near the cancer site. Neighbouring healthy tissues may become damaged in the process, but will usually repair themselves. This temporary damage to healthy cells typically cause side effects such as tiredness, sore skin, and hair loss. Some scanning machines used to identify the location of the cancer may also miss out very small groups of cancer cells that have metastasised. Hence, radiotherapy may not kill all cancer cells.

Chemotherapy is frequently combined with radiotherapy to increase the effectiveness of the cancer treatment. Chemotherapy drugs act in many ways to disrupt cell division. They are especially good at targeting actively dividing cells. Some chemotherapy drugs will bind to parts of the DNA molecule during DNA replication. This way, DNA replication is disrupted and cell division cannot proceed. Unfortunately, these drugs are not selective towards cancer cells. They also target healthy cells that are actively dividing, such as skin cells, hair cells, blood cells, and cells lining the stomach. Patients therefore often experience adverse effects such as hair loss, deficiency of red blood cell, nausea, vomiting and diarrhoea.

New targeted therapies

In the last two decades, advancements in the design of cancer drugs for targeted therapies have become increasingly significant in the medical field. The successes of these new treatments were made possible by a greater understanding of cancer-cell biology. These treatments are more selective towards killing cancer cells and therefore cause fewer side effects. In 2016, the FDA has approved a number of new anti-cancer treatments. These include four novel targeted drugs (venetoclax, crizotinib, everolimus, and palbociclib). Many others are still undergoing clinical trials.

Targeted therapies are drugs that work by interfering with specific protein molecules which are involved in the growth of cancer cells, thus interfering with cell signalling. Cell signalling is part of an extremely complex system that governs all cellular activities such as cell division, cell growth, cell repair, and cell death. It is crucial that each component along the cell signalling pathway receives the right information and responds properly to microenvironment stimuli. These pathways typically involve molecules called protein kinases, which attach phosphate groups to other molecules, thereby generating a signal.

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Figure 2: Mutations that lead to cancer. Image courtesy of the National Cancer Institute.

However, signalling pathways are often deregulated due to two concurrent types of mutations. The mutations are in two types of genes – oncogenes and tumour-suppressor genes. As a result, the protein kinase coded by the oncogene is permanently in its activated form, stimulating uncontrolled cell division. The combination of deregulated oncogenes and tumour suppressor genes leads to cancer. Many researchers have therefore been working on the development of protein kinase inhibitors to stop the improper signalling that causes the cell to divide uncontrollably.

 

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Figure 3: Cancer cells treated with the drug selumetinib. Image Courtesy of The Babraham Institute.

 

The ERK (extracellular signal-regulated kinases) signaling pathway, which promotes cell growth, is usually represented as a linear pathway: RAS → RAF → MEK → ERK. As of now, studies have shown that these protein kinases are sometimes mutated in cancer cells. The RAS protein alone is mutated in 20—25% of all human cancers.[4] One type of RAS protein, called KRAS, is mutated in 90% of pancreatic cancers, 20% of lung cancers, and up to 40% of colon cancers.[5]

Selumetinib is a MEK protein kinase inhibitor. Although MEK is rarely mutated, as a link in the ERK signalling pathway, it also plays a crucial role in cell growth. One of the advantages of targeting MEK lies in its structure. It has a suitable binding site for the inhibitor which locks MEK in its inactive form. In addition, the MEK inhibitor is selective enough to leave binding sites of other types of protein kinases unchanged, thus avoiding the side effects associated with the their inhibition.

 

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Figure 4: Picture 4. Possible mechanisms for drug resistance. MEK inhibitors (MEKi) are represented by the red crosses. Source: Caunt, Sale, Smith, & Cook, 2015.

However, from recent studies there are several mechanisms by which drug resistance can occur. [3],[6] Firstly, imagine that along the RAS → RAF → MEK → ERK signalling pathway, the initial mutation is in a RAF protein kinase called BRAF. MEK which is activated after BRAF can become mutated and change its shape thus preventing Selumetinib from binding to it. Secondly, mutant BRAF can become amplified therefore maintaining or increasing the pool of active MEK. Thirdly, amplification of KRAS not only increases the pool of active MEK, but also activates other signalling pathways. Other disadvantages when using a MEK inhibitor such as Selumetinib include side effects such as cardio and gastrointestinal toxicity, fatigue, blurred vision, and dry skin.[2]

“The challenge is to continue to understand more of the basic biology that underpins how cells, including cancer cells, adapt to selective kinase inhibitors so we can anticipate new mechanisms of resistance – trying to keep up with the constantly evolving cancer cell,” said Dr. Simon Cook, group leader and head of knowledge exchange and commercialisation at the Babraham Institute.

Currently, much research is dedicated to finding the right combination of drugs, and to optimise drug dose. For example, to tackle drug resistance as explained in the first case, both MEK and ERK inhibitors could be used. Babraham Institute is working with Astra Zeneca in developing Selumetinib, which is now in phase III clinical trials for lung cancer and thyroid cancer. The efficacy and safety of Selumetinib is being tested in combination with a chemotherapy drug called Docetaxel in patients with KRAS mutant lung cancer.[1] Another trial is being conducted to compare complete remission rate for differentiated thyroid cancer following a 5-week course of Selumetinib or Placebo and radioactive iodine therapy.[7]

When Dr Cook was asked what motivates him to do cell signaling research, he replied: “I am fascinated by biology, how cells work, how they respond to changes in their environment. This is vital for normal lifelong health but it is also important for any disease. If any of the basic biology we discover can help to maintain our health or fight disease, then that is great.”

Ultimately, cancer is a challenging disease to treat. There are many alternative signalling pathways available to a cancer cell, making them difficult to wipe out. Just like in a game of chess, the player who thinks many steps ahead and stays ahead of the opponent wins the game. Without doubt, a deeper understanding of fundamental biology—as well as advancements in drug design—have given some cancer patients more treatment options. Nevertheless, a lot of research still needs to be done before we can win the battle against cancer.

References

[1] Assess Efficacy & Safety of Selumetinib in Combination With Docetaxel in Patients Receiving 2nd Line Treatment for v-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Positive NSCLC, ClinicalTrials.gov. (2016). Retrieved 22 April 2016.

[2] A study looking at selumetinib for non small cell lung cancer. (2015). Cancer Research UK. Retrieved 21 April 2016.

[3] C. Caunt, M. Sale, P. Smith, S. Cook. MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road. (2015). Nat. Rev. Cancer, 15(10), 577—592.

[4] J. Downward. Targeting RAS signalling pathways in cancer therapy. (2003). Nat. Rev. Cancer, 3(1), 11—22.

[5] Exploring the Pathway: MEK Inhibition Fact Sheet. (2015). ASCO Annual Meeting. Retrieved 22 April 2016.

[6] A. Samatar and P. Poulikakos. Targeting RAS–ERK signalling in cancer: promises and challenges. (2014). Nat. Rev. Drug Discov., 13(12), 928—942.

[7] Study comparing complete remission after treatment with selumetinib/placebo in patient with differentiated thyroid cancer. ClinicalTrials.gov. (2016). gov. Retrieved 22 April 2016.

[8] Surgery for pancreatic cancer. (2016). Cancer.org. Retrieved 22 April 2016.

 

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