Does Targeted Therapy for Lung Cancer effectual?

Contents

Table of Contents

Targeted therapy for Lung Cancer: Sword for the fight?

Targeted therapy for Lung Cancer has become a successful treatment for most of the Non-Small Cell Lung Cancer communities. As the main targets for Lung Cancer,

  • Epidermal Growth Factor Receptor (EGFR)
  • EML4- Anaplastic Lymphoma Kinase (AKL)

perform a great clinical success. Lung cancer or Bronchogenic Carcinoma is responsible for the highest deaths (1.59 million deaths per year) in Cancer worldwide. According to the estimates, in the year 2025, there will be 19.3 million new cases around the globe. Lung Cancer is especially popular in the low and middle-income community. Together with targeted therapy oncologists use conventional therapies, like radiation, chemotherapy, and surgery as current treatments.

Over the past decades, scientists are on the continuous journey of finding new therapies for Lung Cancer. It is a rapidly growing field. Along with the findings of the Human Genome Project, “Personalized Medicine” for Cancers started. During the past years, many scientists researched evaluating the success of targeted therapy. Coupled with, finding new effective drugs of targeted therapy for Lung Cancer.

In this article, we will mainly focus on Lung Cancer and its types, the types of targeted therapy used in lung cancer, and evaluating the clinical results of Targeted Therapy in Lung Cancer.

Why do oncologists recommend Targeted therapy for lung cancer?

Lung Cancer is an extremely heterogeneous disease. Due to its complexity, it is too aggressive. The treatments for Lung Cancer are one of the most challenging tasks in medicine. Conventional therapies like,

  • Surgery
  • Radiation
  • Chemotherapy

are currently using in clinical settings. They are highly successful in targeting cancerous cells. They attack the rapidly proliferating cells. Moreover, they harm the normal healthy cells including hair, skin, and cells of the digestive system. The requirement of novel treatments, in this case, is to specifically attack the cancer cells without damaging the healthy cells. Thus it reduces the side effects for the whole body.

Targeted therapy for Lung Cancer, especially safely fulfills this aim. That’s why this approach has had a huge success in improving patient safety. Since, genetic susceptibility plays a major role in all types of cancer, including Lung Cancer. Because of this individualized medication plans became the role model in current cancer treatments. Every cancer has its own genetic variations. Likewise, people show unique variations on their own. Targeted therapy is important in this situation, to clarify it based on the individual needs. It breaks the concept of “one for all needs” in Cancer treatment. In contrast, targeted therapy gave space to personalized medication therapy specially designed for particular patients.

Conversely, the traditional methods may regain cancer, which means those therapies eradicate the cancerous cells. But, it is temporary and the patient can get a tumor again later. This is due to acquired resistance to drugs or the development of cancer stem cells.

What is the speciality of targeted therapy for lung cancer?

Unlike the bad results of traditional therapies, targeted therapy for Lung Cancer can successfully destroy tumors but not harm healthy cells. Ultimately, this is for better management of the disease and improving patient’s quality of life. However, your oncologist has the right to select the best treatment method for you as always.

Lung Cancer types and causes for Lung Cancer

Figure 01; Lung cancer types

Lung Cancer is a very complex type among all cancers. Understanding how it is happening or the mechanism of progression is really essential for the treatments. According to the latest theories, repeated exposures to external threats that can cause cancer, in other words, carcinogens, lead to several abnormalities. Those exposures may be,

  • Smoking
  • For non-smokers – second-hand smoking
    •     Air pollution – (1%-2% of lung cancer)
    •     Exposure to Radon (10% of lung cancer)
    •     Exposure to asbestos
    •     Diesel exhaust
    •     Exposure to any other chemicals that can cause cancer.

Exposure to the above threats leads to the growth of abnormal cells in lung tissues. This is dysplasia in the lung epithelium or the lining of the lung tissues. If these exposures continue, it leads to genetic mutations. Mutations mean variations in the genes. Certain drugs of targeted therapy for lung cancer attack these mutations. Those variations can block the cells’ protein synthesis. Moreover, it damages the cell cycle and produces cancer cells.

The most common mutations cause lung cancer.

Small cell lung cancer (SCLC)Non small cell lung cancer (NSCLC)
MYCEGFR
BCL2KRAS
 p53p16
Table no.01: mutations cause lung cancer

Among the main types of Lung Cancers, Non-Small Cell Lung Cancer (NSCLC) is the most common. It affects about 80%-85% of the population while Small Cell Lung Cancer(SCLC) affects only 10%-15%. The NSCLC has three subtypes.

  • Adenocarcinoma,
  • squamous cell carcinoma,
  • large cell carcinoma.

Additionally, NSCLC has other subtypes which are not very common, adenosquamous carcinoma and sarcomatoid carcinoma.

Identified comparison of Small Cell Lung Cancer (SCLC) and Non-Small Cell Lung Cancer (NSCLC)

SCLCNSCLC
Often starts in the trachea and bronchi of the lungStarts at the epithelial tissues of the lung
spreads quickly to all over the body, to lymph nodes to other organs (rapid metastatic potential)Slow progression than SCLC and usually shows no symptoms
Smoking  is the main cause of SCLCSmoking linked to about 30% of squamous cell carcinomas
Sensitivity to chemotherapy is highRelatively low sensitivity
Sensitivity to radiotherapy is highShows variable sensitivity
Treatments are chemotherapy and radiotherapyTreatments are chemotherapy, radiotherapy, and surgery
Relatively small advances in treatmentsRapid advances in treatments
Table No.02: Indicated comparison between SCLC and NSCLC

Global disease populations for Lung Cancer

Overall, Lung Cancer is more common in males than females. Usually, it is more popular between 50 -70 years of age in both sexes. The risk of developing cancer remains low until 39 years for both sexes. Internationally, lung cancer is responsible for one of the highest rates of cancer deaths.

Economic differences between countries have no clue in developing lung cancer deaths in males. In contrast, it shows a higher rate of lung cancer deaths in women in industrialized countries than in developing countries.

Emerging economic countries like China, India, Brazil, and South Africa have rapidly increasing economical states. However, lung cancer cases continuously progress rapidly in these countries also. According to GLOBOCAN, Lung Cancer is the most common cancer and the reason for deaths in cancer in China in 2012. It represents 21% of all cancers and 27% of all cancer deaths. Similarly, Russia has a higher rate of lung cancer deaths in men among all European countries but for women, it remains low.

Surprisingly, India shows the lowest cancer death rate in the world, thanks to the high usage of smokeless tobacco. According to a study, in India bidi smoking or hand-rolled tobacco is the most commonly used (92%) tobacco. Cigarette smoking is around 57%.

Identically, in developing countries, Asia, South America, Africa shows highly different patterns of lung cancer deaths. Southeast Asia has slightly lower rates. South America shows a wide variety of lung cancer new patients. It presents high rates in men compared to women, to clarify men in Uruguay and women in Venezuela and Argentina show the highest rates of new lung cancer cases.

Types of Targeted Therapy for lung cancer?

Targeted therapy for lung cancer usage often goes up with the patients who have biomarkers in their tumors or cancers. Given that, if they have such biomarkers usually they can go through targeted therapy. These biomarkers are the changes of DNA of a tumor, for example, mutations, deletions, additions, or rearrangements. These are the “targets” for the drugs used in this therapy.

The drugs specifically attack those targets thus it causes less harm to other tissues. Hence, it leads to fewer side effects.

Currently, the FDA has approved targeted therapy for lung cancer. For instance,

  • EGFR inhibitors (epidermal growth factor receptor)
  • ALK (Anaplastic Lymphoma Kinase)
  • ROS-1
  • NTRK
  • MET
  • RET
  • BRAF V600E.

These drugs have approval for use in lung cancer patients.

Scientists have identified successful clinical results with these treatments compared to traditional treatments. Uniquely, some of the treatments replaced traditional treatments (chemotherapy) as the first-line therapy, for example, EGFR inhibitors erlotinib, gefitinib, P13/AKT/mTOR inhibitors everolimus, and NTRK/ROS1 inhibitors Entrectinib. The efficacy of the above drugs remains high in targeted therapy for lung cancer. However, these treatments in NSCLC have shown positive results, the tumor has gained resistance towards them.

What are EGFR and ALK? – molecular targets

EGFR – EGFR is a member of a family of cell surface receptor Tyrosine Kinase(RTK). The EGFR family has four subtypes,

  1. EGFR / ErbB-1
  2. HER-2 / ErbB-2
  3. HER-3 /ErbB-3
  4. HER-4 / ErbB-4

These proteins are really important in cancer development pathways. To put it differently, it promotes the growth of tumors by controlling signal transduction pathways. Signal transduction is a mechanism that regulates cell apoptosis and proliferation.

Binding to specific activating soluble ligands causes the activation of RTKs, but except HER-2. Therein, this leads to a reaction between the ligand and the receptor.

  1. The interaction between those two promotes the formation of functionally active,
  2. Homodimers (EGFR dimer)
  3. Heterodimers (HER-3 or HER-4 dimer)
  • Also, it activates the intracellular kinase domain and ATP- dependent cross-autophosphorylation of the C-terminal tail of the receptor.

Ultimately, the phosphorylated residues supply a different set of molecules inside cells. These molecules trigger signal pathways inside cells including the P13K/AKT prosurvival, STAT transcription, and RAS/RAF/MEK proliferation pathways. This leads to block the regulation of signaling pathways and stimulate apoptosis and consequently, it blocks the growth.

50%-80% of NSCLC patients have shown overstimulation of EGFR, which leads to the development of new blood vessels (angiogenesis), and poor prognosis. Equally, the association between EGFR alteration and cancer development makes this mechanism an essential member for targeted therapy for lung cancer.

EML4-ALK – ALK is a member of the insulin receptor family. This is important as a new treatment method and as a biomarker in targeted therapy for Lung Cancer. Commonly, the variation or the rearrangement that leads to the cancer state is EML4-ALK translocation. EML4-ALK rearrangements are more common in young non-smoking patients of NSCLC adenocarcinoma.

Non-Small Cell Lung Cancer -NSCLC targeted therapy

What is NSCLC?

The Non-Small Cell Lung Cancer is named as it is based on the appearance of the cells involved. It is the most common type of lung cancer which accounts for about 85% of all lung cancers. Usually, the patients do not show any early symptoms. Among patients at first diagnosis, 20% have localized cancer, 25% have regional metastasis and in 55% of patients cancer spreads to other organs. NSCLC targeted therapy is showing many positive results in those patients.

To put it in another way, exposure to external cancerous agents and individuals’ inheritance of certain genes are responsible for this NSCLC. Studies show most of the people who had previous exposures to asbestos at their workplaces, are more susceptible to lung cancers. In addition to external threats, if you have lung diseases like chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, and tuberculosis(TB) you may have an increased risk of lung cancer including NSCLC.

Do you know there are two special gene types responsible for Cancer? They are,

  • Oncogenes (Cancer-causing genes) and
  • Tumor suppressor genes.

Studies have shown in NSCLC patients, increased activity of oncogenes and inhibiting the activity of tumor suppressor genes are available. The most important is the mutations in the RAS family of oncogenes. Granted that the studies show the RAS activation leads to tumor growth progression in persons with lung cancer. The RAS mutations are popular in adenocarcinoma.

Other than those abnormalities, mutations in the oncogenes c-myc and c-raf and tumor suppressor genes retinoblastoma (RB) and p53, are also found in NSCLC patients.

Non-Small Cell lung cancer targeted therapy drug list

Tyrosine Kinase Inhibitors for NSCLC

Tyrosine Kinase Inhibitors(TKIs) belong to a family of enzymes. They are involved in many cellular processes inside cells. For example signal transduction and cell division. Oncologists recommend Tyrosine Kinase Inhibitors for NSCLC targeted therapy. Because it has a lot of positive results. Here are some of the most common agents.

  1. Imatinib, dasatinib, and nilotinib

Imatinib mesylate is a signal transduction inhibitor. At the same time, it is a small molecule inhibitor. This is specially used for suppressing tumor tyrosine kinase activity. Imatinib can show “kinase pocket” activity and prevents the phosphorylation of tyrosine on the substrate molecule. Thus it inhibits the later steps that lead to cell proliferation. That is how TKIs block cancer activity. The half-life of Imatinib is long, about 18 hours. Meanwhile, there are some side effects such as nausea, pain, diarrhea, headaches, and sometimes rashes. All of these agents are available as oral formulations. However, there are some possible side effects such as toxicities, such as fluid retention and QT prolongation.

  1. Erlotinib

Erlotinib belongs to the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) family. It is also an oral drug. Erlotinib is a treatment not only for NSCLC but also for pancreatic cancer. Erlotinib is absorbed and the liver CYP3A4 isoenzyme system metabolizes it. In the targeted therapy for lung cancer, Erlotinib has a main role. However, there are some side effects of Erlotinib. The most common side effects are diarrhea, nausea, acne-like skin rashes, and eye disorders. Important to realize, Erlotinib shows a rare but severe side effect that can be fatal. That is an interstitial lung disease. This presents as acute dyspnea (shortness of breathing) with cough.

  1. Sorafenib and Sunitinib

These two drugs are oral medicines. Again, these are serine/threonine and tyrosine kinase inhibitors. These drugs target cell surface kinases (proteins) that involve tumor signaling, angiogenesis, and apoptosis. Sorafenib inhibits all of these kinases. These drugs slow down tumor growth.

Common side effects are diarrhea, feeling tiredness(fatigue), hand-foot syndrome, and hypertension.

  1. Gefitinib

Gefitinib is also a tyrosine kinase inhibitor. This has the approval for the treatment of locally advanced or metastatic non-small cell lung cancer with activating mutations of the Epidermal Growth Factor receptor. This available as oral formulations and recommended adult dose is 250mg once daily as in British National Formulary (BNF).

In contrast, Gefitinib is not recommended for the treatment of locally advanced or metastatic NSCLC that has progressed after non-targeted chemotherapy. This applies to patients who have tumors that are EGFR-TK mutation-positive.

However, Gefitinib is a successful drug agent in targeted therapy for lung cancer.

Drugs in targeted therapy for Non-Small Cell Lung Cancer(NSCLC): based on the target

1.    Drugs that target KRAS gene changes

  • Sotorasib – this drug inhibits the KRAS (Ki-ras2 Kirsten rat sarcoma viral oncogene homolog). Sotorasib attaches to the KRAS G12C protein which helps cancer cell growth. Sotorasib is usually taken as a pill.

2.    Drugs that target cells with EGFR gene variations

  • Erlotinib – this is a tyrosine kinase inhibitor. Coupled with this is a treatment for locally advanced or metastatic NSCLC after the failure of previous chemotherapy. Similarly, these drugs are used for monotherapy for maintenance treatment of locally advanced or metastatic NSCLC with stable disease after four cycles of platinum-based chemotherapy like Cisplatin. This is an oral drug. An adult daily dose is 150mg as in BNF.
  • Afatinib – is a protein kinase inhibitor. This is effective to treat locally advanced or metastatic NSCLC with activating epidermal growth factor receptor (EGFR) mutations. This is for the patients who have not previously been treated with EGFR tyrosine kinase inhibitor. This is an oral drug and the adult daily dose is 40mg. It shall be increased according to the response. If tolerated the dose can be up to 50mg daily. Important to realize that this is a decision of the physician.
  • Gefitinib – is a tyrosine kinase inhibitor. This is for the treatment of locally advanced or metastatic NSCLC with activating mutations of EGFR. This is an oral drug and the usual adult daily dose is 250mg once a day. This is one of the first drugs in targeted therapy for lung cancer.

3.    Drugs that target the cells with T790M mutation

  • Osimertinib – this belongs to the family of tyrosine kinase inhibitors. Osimertinib treats locally advanced or metastatic EGFR T90M mutation-positive NSCLC (but for specialist use only – according to BNF). This is an oral adult daily dose of 80 mg once a day. Once again this is based on the physician.

Osimertinib is prohibited to take in patients with congenital long QT syndrome.

4.    EGFR inhibitors used for squamous cell NSCLC

  • Necitumumab – this is a monoclonal antibody that binds to EGFReceptor. This is the therapy for locally advanced or metastatic EGFR expressing squamous NSCLC, in patients who have not received previous chemotherapy. For instance, combination with gemcitabine and cisplatin. This treatment is for specialist advice only.

This is available as an intravenous infusion (IV infusion). As directed in BNF, the normal adult dose is 800mg once daily on days 1 and 8 of the 3-week cycle, for up to 6 cycles. Patients whose disease has not progressed after combination therapy may continue with necitumumab monotherapy.

On this condition, this drug is cautious for patients with cardiorespiratory disorders, history of thromboembolic events.

5.    Drugs target cells with ALK gene changes

  • Crizotinib – this is a tyrosine kinase inhibitor. Crizotinib is a medication for anaplastic lymphoma kinase(ALK)-positive advanced NSCLC, but the patient can get this under the advice of a specialist only. This is taken by mouth. According to BNF, the usual adult dose is 250mg two times a day. Physicians may change this dose based on the status of the patient.

Targeted therapy side effects: based on the target

Targeted therapy side effects: based on the target
Targeted therapy side effects: based on the target

Why Targeted Therapy for NSCLC is a success?

Targeted therapy for lung cancer is becoming one of the most effective treatments for the benefit of the patients. Although the higher cost and minimal clinical improvements in patients, it has shown there is another thing with it. It is the relative effectiveness of NSCLC. Since targeted therapy focuses on only the specific target but not the healthy cells, toxic effects and side effects are also minimal.

Certain clinical tests proved targeted therapy can improve the patients’ quality of life over the traditional therapies. Despite having certain blockages to be common usage in clinical settings, this has become first-line therapy for some conditions. Of Course, there is evidence to show the effectiveness.

  • EGFR TKIs – according to a study based on more than 1200 Asian people who had adenocarcinoma and light or never smoked, EGFR TKIs have shown positive results. Patients with active EGFR mutation have gained significant benefits. This was a comparison study with the chemotherapy drugs carboplatin/paclitaxel and gefitinib. According to the results, patients showed a cancer progression period of one year. In addition, survival rates level up to 28 months.
  • EGFR antibodies – Cetuximab is a drug that inhibits anti-EGFR antibodies. It showed improved response rate and survival rate when combined with cisplatin/vinorelbine in patients with advanced NSCLC. Likewise, the response rate increased from 10.1 to 11.3 months. Accordingly, the survival rate was quite small; this drug was not approved by the authorities.
  •  Bevacizumab – There are significant novel therapies available for NSCLC. For example, Bevacizumab. It is a monoclonal antibody. It targets the vascular endothelial growth factor (VEGF) (endothelium is the inner cell layer of blood vessels). This is now completely recognized as a first-line drug in patients with advanced and metastatic NSCLC which has EGFR mutations.
  • Crizotinib – a novel inhibitor drug of ALK. This has been approved as the second-line treatment for NSCLC.

Moreover, several new drugs have brought hope with their successful mechanisms in treating NSCLC patients. For example, entering the signal transduction pathway which is important in the development of new blood vessels (angiogenesis). Additionally, certain therapies involve mitogen-activated extracellular signal-regulated kinase pathways. Besides, having some disadvantages of targeted therapy, the benefits have overcome them. In summary, targeted therapy for lung cancer provides effective methods for the development of treatment plans for NSCLC.

Molecular Targeted Therapy for Small Cell Lung Cancer

What is SCLC?

Small Cell Lung Cancer contributes only 10%-15% of all lung cancer cases. The existing patients of SCLC (prevalence) remain low because of reduced smokers, but studies suggest the rates will only reduce from 23.7% to 22% in a really small value. Estimates say we will have 872 million smokers remaining in 2030.

SCLC first develops in the neuroendocrine cells of the bronchus of the respiratory tree. It has rapid growth and shows early metastasis. By all means, the common metastatic locations are the liver, brain, and bone. Furthermore, SCLC metastatic cancer can spread to other organs and causes the syndrome of inappropriate ADH secretion, and ectopic adrenocorticotropic hormone (ACTH).

Symptoms of Small Cell Lung Cancer

  1. Difficulty in breathing
  2. Chest discomfort
  3. Difficulty in swallowing
  4. Blood in sputum
  5. Wheezing
  6. Hoarseness
  7. Loss of appetite
  8. Feeling of tiredness
  9. Swelling in the face
  10. Chest pain etc.

 Diagnostic procedures for SCLC

  • Physical examinations
  • Laboratory testing
  • Chest X-ray examinations
  • CT scan (Computed Tomography)
  • Biopsy
  • Fine needle aspiration (FNA)
  • Bronchoscopy
  • Thoracoscopy
  • Thoracentesis
  • Light and electron microscopy examinations
  • Sputum cytology
  • Immunohistochemistry 

Goals of Targeted Therapy for Small Cell Lung Cancer

The main goal of targeted therapy for small cell lung cancer is to enhance the efficacy of current treatments. For example, chemotherapy and radiation by using it as additional therapy. Over the years, using the understanding of the molecular biology of SCLC, there has been an advancement of treatments for the disease. Scientists use their knowledge in the development of new drug entities more effectively than traditional therapies. That is why “targeted therapy” has been successful in many clinical approaches.

However, prognosis or the future hope of cure from SCLC has changed in past decades, and patients’ need for new effective treatments also does increase.

In SCLC, there are important regulatory processes that we can use in the treatments. For instance, proliferation, the cell cycle, apoptosis, and angiogenesis.

Types of targeted therapy best fit for Small Cell Lung Cancer

  • Inhibitors of cell signaling pathways controlling proliferation
  • Apoptosis promoters
  • Immune conjugates and vaccines
  • Inhibitors of angiogenesis
  • Multidrug resistance

Small Cell Lung Cancer Targeted therapy drug list

Here are some of the new drugs for SCLC targeted therapy.

Targeted therapy for Lung Cancer

Table No.03: New drugs list for SCLC targeted therapy

These drugs are currently in various phases of clinical trials and some of them are successfully used for treatments.

Why is targeted therapy in SCLC showing less success?

Unlike, NSCLC due to the lack of specific targets in SCLC targeted therapy has not improved its results yet. Meanwhile, First-line therapy for SCLC which is chemotherapy has not developed for the past three decades. According to the US FDA, Platinum-based agents (Cisplatin or Carboplatin) together with Etoposide is the first-line treatment. Second-line therapies for recurrent SCLC are topotecan combined with systemic chemotherapy agents including docetaxel, paclitaxel, or gemcitabine. But patients often gain resistance to those drug agents with time, so, the requirement of targeted therapy as a new treatment is really important.

However, usage of targeted therapy in SCLC is a challenge. This is because this variety is quite different from NSCLC. It consists of only fewer mutations that are significant as targets. Here are the examples.

Drugs target angiogenesis

SCLC has more blood vessels, in other words, SCLC is more vascularized than NSCLC. Patients with SCLC have more functional vascular growth factor receptors (VEGFR)-2 and VEGFR-3 on the tumor cells. Tested drugs on SCLC that target angiogenesis had not shown expected progress. As predicted, the main reasons for these poor results are the increased levels of EGFR from previous treatments and the basic fibroblast growth factor.

  • Matrix metalloproteinases (MMPs)

      These are a family of enzymes(proteins) that are found between the spaces of the cells. (extracellular matrix proteins). These can break down some proteins, for example, collagen. They need Zinc (Zn) or Calcium (Ca) to do their work properly. That is why they are called matrix metalloproteinases. These are important in tumor development and progression. MMPs are the first molecules used to evaluate the treatment results for SCLC. According to the databases published in the Journal of Thoracic Disease two agents were evaluated, namely marimastat and tanomasta. But the outcome was so poor. Neither survival rate nor side effects have improved.

  • Thalidomide – this causes the prevention of angiogenesis. According to the several phases of clinical trials thalidomide also did not show any good results on the improvement of targeted therapy. It is associated with higher rates of thrombosis, toxicities, and neuropathy.

Vascular endothelial growth factor combined with VEGF receptor (VEGFR)

  • Bevacizumab – Bevacizumab is a human monoclonal antibody. It targets VEGF-A receptors. Several clinical trials have been conducted to evaluate bevacizumab as maintenance therapy. Bevacizumab is used with concurrent chemotherapies in SCLC patients. Although it showed some side effects like neutropenia, thrombocytopenia, dehydration, diarrhea, fatigue, and pulmonary symptoms, bevacizumab had more effective results. Therefore physicians agreed to take this into clinical usage. In Addition, several other studies were conducted for this drug. The Hoosier Oncology group conducted a study with Bevacizumab and Paclitaxel. But this was also not a solution. By all means, patients’ outcomes were not satisfied. Overall bevacizumab is undergoing study material that needs to be evaluated. Maybe this can be a positive sign for the targeted therapy for lung cancer.

Rapamycin (m-TOR)

The m-TOR pathway is originally controlling cellular mechanisms. Conversely, it is responsible for various diseases including cancer. In targeted therapy for lung cancer, there are two drugs of m-TOR inhibitors evaluated for their results in SCLC.

  • Temsirolimus
  • Everolimus 

Regardless, these tests have not shown any significant positive results in improving the diseases. Similarly, other drug candidates like vaccines and immune conjugates, multidrug resistance inhibitors, and apoptosis promoters were tested for their efficacy in the targeted therapy. Unfortunately, they have not shown significant results.

In summary, targeted therapy for Small Cell Lung Cancer needs much more studies. At the moment, no targeted therapy for SCLC is approved to use. Continuous clinical studies are going on to find acceptable results. However, bevacizumab, gefitinib, and bcl-2 inhibitors can be considered as hopes for the treatment.

Signal transduction and Targeted Therapy as a new approach for lung cancer

Signal transduction and targeted therapy for lung cancer is a kind of evolution in cancer treatments. Scientists focus on signal transduction in the mechanism of lung cancer development. Moreover, they pay attention to the signaling pathway-targeted therapies. This includes biological agents and small molecular drugs.

What is signal transduction?

Signal transduction is a process that chemical or physical signals transmit through a cell. That is achieved by a series of molecular events. The drug is the signal and the receptor in the cell recognizes the drug molecule as the signal. This progresses into molecular events and ultimately causes a cellular response. In the discussion of targeted therapy for lung cancer, signal transduction is a match for a fine solution.

How does signal transduction relate to cancer?

Cell signaling pathways are essential to control normal cellular mechanisms. However, in this case, various genetic mutations in the cancer cells cause changes in signaling pathways. Cancer cells need those pathways to maintain tumor development.

Mutations of Cancer-causing genes (oncogenes) lead to

  • overexpression of those genes. For example, gene amplification, the activity of that gene raised.
  • Produce proteins whose activity is dysregulated and those proteins involved in the cell signaling pathways.

For example,

  • Growth factor receptor kinase (RTKS; e.g. EGFR(epidermal growth factor receptor)
  • Small GTPases (e.g,. Ras)
  • serine/threonine kinases(e.g., Raf and akt)
  • Cytoplasmic tyrosine kinases (e.g., Src and Abl)
  • Lipid kinases (e.g., phosphoinositide 3-kinases, P13Ks)
  • Nuclear receptors (e.g., the estrogen receptor, ER).

Changes in these proteins lead to the dysregulation of cell signaling pathways essential to normal cell functions. This promotes and helps cancer progression. In addition, mutations and inactivations can deactivate certain negative regulators such as tumor suppressor genes. This also causes cancer progression alternatively.

Important to realize that cancer cells show different unique features. Because of the dysregulation of cellular signal transduction pushes towards the growth of cancer. The dangerous fact is this does not affect only cancer cells. It also affects other tissues of the body. Moreover, it spreads to other large signaling networks of the body such as blood, extracellular matrix, immune system. Ultimately, this causes the person to die of cancer as having a systemic disease.

How signal transduction is involved in targeted therapy for lung cancer?

There are several targeting pathways of targeted therapy for lung cancer related to cell signaling pathways.

  • Targeting EGFR

Epidermal growth factor receptor(EGFR) has a known connection with 6 hallmarks in cancer. Its involvement allows cancer cells to develop freely in several ways including,

  • Bypass apoptosis
  • Promotes continuous angiogenesis
  • Cell growth
  • Reduce cancer cells’ response to normal cell control mechanisms
  • Tumor metastasis.

Likewise, if we find a target on this cellular pathway, it provides an effective method to treat cancer. According to the National Comprehensive Cancer Network (NCCN), over 80% of NSCLC patients have high levels of EGFR proteins in their tumors. That is the point to focus on to find drug molecules that can block the pathway. Several studies are conducting to find small molecules bound to EGFR in targeted therapy. For example, gefitinib and Erlotinib.

  • Targeting VEGF and angiogenesis

Angiogenesis is another hallmark of cancer. It is the development of new blood vessels from previous blood vessels. This is normally happening in wound healing. But in cancer, it promotes vascular growth towards the tumor and promotes the growth of the tumor.

First proteolytic enzymes damage the blood vessels endothelium basement membrane and extracellular matrix. Second, it releases the membrane-sequestered angiogenic factors such as VEGF, basic FGF, and TGF- β.

VEGFRs are located on the surfaces of the tumor cells in many cancers, including NSCLC. The binding of ligands or signaling molecules with those receptors promotes not only angiogenesis but also lymphangiogenesis, to clarify the growth of lymph vessels. Studies are conducted to find drug molecules to block the interaction between the ligands and the VEGFRs. Monoclonal antibodies and VEGFR tyrosine kinase inhibitors are under study. For example, bevacizumab. This is the first approved angiogenesis inhibitor.

  • Targeting IGF-1R

The IGF pathway is important for fetal development, growth, and metabolism. This system has two receptors,

  1. IGF receptor [IGF-1R]
  2. Insulin receptor [IR].

And three ligands,

  1. IGF-1
  2.  IGF-2
  3. Insulin

Above receptors are located on the cell surface. Upon binding with the ligands the receptors activate and start their activity. IGF-IR is a receptor tyrosine kinase. It helps tumor growth and survival. The receptor needs oncogenic signals to do this. Activation of the receptor promotes a series of events towards tumor development.

Patients with lung cancer have elevated blood IGF levels. In addition, it is the same in tumor tissues. Therefore, inhibition of the IGF pathway is an effective target in lung cancer.

There are two groups of IGF-IR inhibitors.

  1. Small molecule TKIs
  2. Monoclonal antibodies – Figitumumab
  • Targeting the PI3K–Akt pathway

The PI3Ks belong to a family of enzymes. It needs receptor tyrosine kinase for activation. PI3k-Akt is essential for the growth and survival of cancers. Together with that, it regulates the number of cellular pathways. For example, inhibition of pro-apoptotic proteins such as Bad, Bix, and Bid. This process is phosphorylation-dependent. Moreover, it activates anti-apoptotic proteins such as Bcl-xL. PI3K inhibitors enhance the sensitivity to apoptosis-promoting drugs in NSCLC.

For example – GDC-094, Everolimus

  • Targeting the TRAIL apoptosis pathway

TNF-Related Apoptosis-Inducing Ligand(TRAIL) increases apoptosis in tumour cells. They bind to certain transmembrane receptors. This results in trimerization of these receptors and it forms a signalling complex. It pushes the tumour cells to death.

For example, Mapatumumab – a fully humanized anti-TRAIL-R1 monoclonal antibody.

  • Targeting heat shock proteins

Heat shock proteins produce a response to temperature and anaerobic shock. They act like this under normal conditions as well as cellular chaperones. However, when they act as chaperones Hsps also can perform carcinogenic activities. Hsp90 is a protein of this family. It is essential for cellular functions including cell signalling, proliferation, and survival. Furthermore, Hsp90 also has a connection with cancer hallmarks. In targeted therapy, Hsp90 inhibitors are used.

For example, Geldanamycin

  • Targeting histone deacetylases

These drugs lead to stopping the cell cycle. And also, it promotes apoptosis by blocking the deacetylation of HDAC. Ultimately it facilitates the intrinsic apoptotic pathway.

Furthermore, hyperacetylation of histone tails stabilizes the p53 protein. It stops the cell cycle and induces pro-apoptotic factors. Collectively, these block tumor development. For example, CI-994 is an oral formulation.

  • Targeting stem cell pathways

“Cancer stem cells” (CSCs) therapy has entered into the targeted therapy for lung cancer. This has gained increased survival rates in cancer patients including NSCLC. Identically, Hedgehog (Hh) and Wingless (Wnt) pathways lead to lung organ development and cancer in the lung. Using these pathways in targeted therapy for lung cancer, show significant results.

Inhibition of the Wnt pathway using siRNA is a successful strategy for cancer. This reduces tumor growth and pushes cells towards apoptosis.

  • EML4-ALK

Echinoderm Microtubule-associated protein-like 4 (EML-4) and ALK fusion therapy were studied in Japan in 2007, using NSCLC patients. ALK tyrosine kinase activity is necessary for cancer development. In this study, they showed ALK inhibitors cause apoptosis and tumor shrinkage. After That, it was proved by several clinical studies. They conducted a phase 1 clinical trial of PF-02341066 (crizotinib, this was first designed as an inhibitor of MET). This trial showed a 53% response rate and a 79% disease control rate in EML4-ALK NSCLC patients.

Is targeted therapy better than immunotherapy for lung cancer?

It is not possible to say that targeted therapy is better than immunotherapy for lung cancer. This is because both of the treatments use different methods and both have shown positive results dependently. Besides, still, we cannot exactly say one of them provides the best cure for lung cancer. In most cases, combinations of these methods have given the best results. Your oncologist will choose the best treatment for you.

In targeted therapy for lung cancer, physicians use several drugs that target genes. For instance, EGFR, ALK, ROS1, BRAF, and MET. Those are the genes responsible for lung cancer.

If the physician identifies the gene in the patient, he specifically prescribes drugs to attack that gene. Therefore, it will damage only cancer cells but not normal cells.

In immunotherapy, drugs don’t attack cancer cells directly. Instead, it stimulates the immune system to attack the cancerous cells. In other words, it indirectly prevents cancer.

Patients may get both of these therapies according to their disease condition.

How long can you live with targeted therapy?

After undergoing different traditional methods of treatments in cancer, targeted therapy was just like a light to the darkness of cancer patients. Unlike traditional therapy due to the fewer side effects, it provides effective management of lung cancer.

After being treated with targeted therapy, patients with advanced and metastatic NSCLC could survive three to four years. Patients show more response to targeted therapies. From the very first approved drug “Gefitinib”, several new molecules in targeted therapy increase the response of patients. Ultimately, it could improve the quality of life even with cancer.

Although targeted therapy for lung cancer provides effective control of the disease, still it cannot save lives entirely from lung cancer and other types. So, in summary, it will be developed into new drugs soon by using novel technologies. Therefore, in the future, we may reduce the cancer burden and the patients can have a normal life.

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