Targeted Therapies For Treatment of Lung Cancer – Recent Advances

In both men and women, Lung cancer is the number one cause of cancer-related death. The disorder is especially difficult to detect, and often develops for elderly patients at an advanced stage. Within a year of treatment, more than half of those diagnosed with lung cancer die and 5- year survival is less than 18%. Majority of all lung cancer cases are attributed to Non Small Cell Lung Cancer. Significant advancements in research and diagnosis over the past 10 years have though, culminated in the first improvements made in lung cancer survival. New developments in lung cancer’s cellular pathogenesis and biological activity have culminated in the advancement of rationally developed approaches for early detection, prevention, and treatment of this illness. There are currently several novel treatments in clinical practice, including those that target actionable mutations and more recently immunotherapy. This review will outline developments and emerging debates in lung cancer treatment. carcinoma, adenocarcinoma, and large cell carcinoma 2


Introduction
Lung cancer is the world's second-largest cause of death, with an estimated 9.6 million deaths in 2018. It can be broadly classified into two groups: Small Cell Lung Cancer (SCLC), which accounts for roughly 20-25% of bronchiogenic carcinomas and Non Small Cell Lung Cancer (NSCLC), almost all of the remainder (75-80%) 1 . NSCLC is further categorized into three types: squamous cell carcinoma, adenocarcinoma, and large cell carcinoma 2 Adenocarcinoma is the most prevalent subtype which accounts for about 40% of all lung cancer, which develops gradually and typically arises in the outer peripheral areas of the lungs 3 .
Squamous-cell carcinoma accounts for 25-30% of all cases of lung cancer. It is a very slow-growing type of NSCLC that often occurs in one of the bronchi (lung airways) 4 . Large cell (undifferentiated) carcinoma accounts for 5-10% of lung cancers.
It is the rarest subtype of NSCLC, which is growing rapidly and more likely to spread 5 .

Risk Assessment, Early Detection and Prevention
The most important source of carcinogens and tumor promoters is cigarette smoking which accounts for about 90% of the cases in men and 70% of the cases in women 6 . Epidemiological studies find a nearly 2-fold increased risk due to a family history of lung cancer following the management of the sensitivity to tobacco smoke 7 . A substantial chance of developing passive smoking lung cancer was measured to be 1.14 to 5.20 in people who had never smoked but lived with a smoker based on metaanalysis and thorough study 8 . Radon, a naturally occurring poison, is one of the contributing factors associated with lung cancer, and around 21,000 lung cancer deaths in the United States have been linked with Radon toxicity 9 .
Lung cancer is hard to detect and is often detected late, only when signs become clinically evident 10 . Signs and symptoms of lung cancer include dyspnea (shortness of breath) , hemoptysis (coughing up blood), chronic coughing or change in regular coughing pattern, wheezing, chest pain or pain in the abdomen, cachexia (weight loss), fatigue, and loss of appetite, dysphonia (hoarse voice), clubbing of the fingernails (uncommon), dysphasia (difficulty swallowing). Future studies strongly require assessing the therapeutic utility of molecular biomarkers in sputum and blood for monitoring and early diagnosis.

Pharmaceutical and Biosciences Journal
Furthermore, the introduction of screening tests into clinical practice will classify patients at high risk for developing lung cancer (based on irregular results from CT imaging, bronchoscopy, and/or biomarker profiling), and appropriate approaches for selective treatment and surveillance of these individuals will need to be formulated and enforced.

Novel Targeted Or Personalised Targeted Therapies
Treatment for non small cell lung cancer (NSCLC) has advanced in the last decade. Although early diagnosis and surgical treatment contribute to better patient outcomes, most patients are diagnosed with lung cancer at later stages, which are essentially incurable and often need multimodal therapy. Over the past decade, significant improvements in the treatment of advanced stages have been identified largely due to increased knowledge of the molecular complexity and mechanisms of the onset and development of lung cancer, as well as advances in radio and surgical therapies. Different roles for selective therapies arise as standard first-or second-line treatments in patients with identified mutations from clinical trials. Some experimental medicines have been developed specifically for these key components ( Figure   1 and Table 1), and clinical trials have shown promising results so far.

Anti-angiogenic agents
Angiogenesis is one of the hallmarks of cancer, and blocking of receptor-2 (VEGFR-2) vascular endothelin growth factor which blocks the development, propagation and movement of new blood vessels 26

RAS and MEK Pathway Inhibitors
The protooncogenic RAS family (HRAS, KRAS, and NRAS) codes G-proteins associated with 21-kDa plasma membrane that regulate signal transduction pathways affecting the normal differentiation, proliferation and cell survival 30

PI3K/Akt/PTEN pathway inhibitors
Among human cancers, the PI3K signaling system is often triggered through a sequence of events including activation of upstream receptor TKs (including EGFR and PDGFR) and/or PIK3CA mutations, encoding the PI3K catalytic subunit 38 .
Preclinical studies of LY294002, a PI3K inhibitor, revealed that the drug improves the responsiveness of NSCLC cells to chemotherapy and radiation, and phase I trials of this agent are in progress 39

Tumor suppressor gene therapy
The tumor suppressor p53 is a crucial cellular gatekeeper that is triggered by numerous stress signals such as DNA disruption, oncogenes, and hypoxia, culminating in the expression of downstream genes involving cell-cycle arrest, allowing DNA repair or apoptosis initiation. For lung cancer, the most often mutated gene is p53 40  Further trials are awaited to determine the clinical benefit of these gene therapies in lung cancer.

Enhancing apoptosis
A central attribute of cancer cells is their capacity to resist apoptosis 45 . Bcl-2 is a crucial anti-apoptotic protein that is overexpressed in 10% -35% of NSCLCs and 75% -95% of SCLCs 32.
Randomized step II trials with oblimersen in conjunction with chemotherapy are ongoing for SCLC and NSCLC 46 . Also, a potent small-molecule inhibitor of the antiapoptotic proteins Bcl-2, Bcl-XL, and Bcl-w was developed (ABT-737) and showed preclinical action against both NSCLC and SCLC 47 .

Role of immunotherapy
Immunotherapy is a cutting-edge oncology technique that utilizes the body's own natural defense mechanism to fight cancer. Some cancer cells share characteristics with healthy cells and therefore the immune system cannot differentiate between normal and abnormal (cancer) cells in the body 48

Telomerase inhibitors
There is increasing evidence that the enzyme telomerase is  Continued interdisciplinary research efforts will accomplish the ambitious target of reducing mortality rates in the next 50 years.

Conflict of interest
The author's declares that there is no conflict of interest.