EML4-ALK positive lung cancer

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Micrograph showing ALK positive lung adenocarcinoma. H&E stain. ALK positive lung adenocarcinoma -- low mag.jpg
Micrograph showing ALK positive lung adenocarcinoma. H&E stain.

EML4-ALK positive lung cancer is a primary malignant lung tumor whose cells contain a characteristic abnormal configuration of DNA wherein the echinoderm microtubule-associated protein-like 4 ( EML4 ) gene is fused to the anaplastic lymphoma kinase (ALK) gene. This abnormal gene fusion leads to the production of a protein (EML4-ALK) that appears, in many cases, to promote and maintain the malignant behavior of the cancer cells. [1]

Lung essential respiration organ in many air-breathing animals

The lungs are the primary organs of the respiratory system in humans and many other animals including a few fish and some snails. In mammals and most other vertebrates, two lungs are located near the backbone on either side of the heart. Their function in the respiratory system is to extract oxygen from the atmosphere and transfer it into the bloodstream, and to release carbon dioxide from the bloodstream into the atmosphere, in a process of gas exchange. Respiration is driven by different muscular systems in different species. Mammals, reptiles and birds use their different muscles to support and foster breathing. In early tetrapods, air was driven into the lungs by the pharyngeal muscles via buccal pumping, a mechanism still seen in amphibians. In humans, the main muscle of respiration that drives breathing is the diaphragm. The lungs also provide airflow that makes vocal sounds including human speech possible.

Cell (biology) the basic structural and functional unit of all organisms. Includes the plasma membrane and any external encapsulating structures such as the cell wall and cell envelope.

The cell is the basic structural, functional, and biological unit of all known living organisms. A cell is the smallest unit of life. Cells are often called the "building blocks of life". The study of cells is called cell biology or cellular biology.

DNA Molecule that encodes the genetic instructions used in the development and functioning of all known organisms and many viruses

Deoxyribonucleic acid is a molecule composed of two chains that coil around each other to form a double helix carrying the genetic instructions used in the growth, development, functioning, and reproduction of all known organisms and many viruses. DNA and ribonucleic acid (RNA) are nucleic acids; alongside proteins, lipids and complex carbohydrates (polysaccharides), nucleic acids are one of the four major types of macromolecules that are essential for all known forms of life.

Contents

The transforming EML4-ALK fusion gene was first reported in non-small cell lung carcinoma (NSCLC) in 2007. [2]

Classification

Most lung carcinomas containing the EML4-ALK gene fusion are adenocarcinomas.

Adenocarcinoma of the lung non-small cell lung carcinoma that derives from epithelial cells of glandular origin

Adenocarcinoma of the lung is the most common type of lung cancer, and like other forms of lung cancer, it is characterized by distinct cellular and molecular features. It is classified as one of several non-small cell lung cancers (NSCLC), to distinguish it from small cell lung cancer which has a different behavior and prognosis. Lung adenocarcinoma is further classified into several subtypes and variants. The signs and symptoms of this specific type of lung cancer are similar to other forms of lung cancer, and patients most commonly complain of persistent cough and shortness of breath. Adenocarcinoma is more common in patients with a history of cigarette smoking, and is the most common form of lung cancer in younger women and Asian populations. The pathophysiology of adenocarcinoma is complicated, but generally follows a histologic progression from cells found in healthy lungs to distinctly dysmorphic, or irregular, cells. There are several distinct molecular and genetic pathways that contribute to this progression. Like many lung cancers, adenocarcinoma of the lung is often advanced by the time of diagnosis. Once a lesion or tumor is identified with various imaging modalities, such as computed tomography (CT) or X-ray, a biopsy is required to confirm the diagnosis. Treatment of this lung cancer is based upon the specific subtype and the extent of spread from the primary tumor. Surgical resection, chemotherapy, radiotherapy, targeted therapy and immunotherapy are used in attempt to eradicate the cancerous cells based upon these factors.

Some studies suggest that the papillary adenocarcinoma and the signet ring cell adenocarcinoma [3] variants are more likely to carry this fused gene than other histological variants.

Papillary adenocarcinoma is a histological form of lung cancer that is diagnosed when the malignant cells of the tumor form complex papillary structures and exhibit compressive, destructive growth that replaces the normal lung tissue.

Signs and symptoms

The signs and symptoms of this lung cancer variant seem to mimic those of the underlying major cell type.

Screening

Micrograph showing an ALK positive adenocarcinoma of the lung. ALK immunostain. ALK positive lung adenocarcinoma - ALK IHC -- high mag.jpg
Micrograph showing an ALK positive adenocarcinoma of the lung. ALK immunostain.

Screening for ALK positive lung cancer is now a standard of care in the United States and Canada. Screening can be done with immunostaining or FISH.

Fluorescence <i>in situ</i> hybridization

Fluorescence in situ hybridization (FISH) is a molecular cytogenetic technique that uses fluorescent probes that bind to only those parts of a nucleic acid sequence with a high degree of sequence complementarity. It was developed by biomedical researchers in the early 1980s to detect and localize the presence or absence of specific DNA sequences on chromosomes. Fluorescence microscopy can be used to find out where the fluorescent probe is bound to the chromosomes. FISH is often used for finding specific features in DNA for use in genetic counseling, medicine, and species identification. FISH can also be used to detect and localize specific RNA targets in cells, circulating tumor cells, and tissue samples. In this context, it can help define the spatial-temporal patterns of gene expression within cells and tissues.

Treatment

Crizotinib is a targeted therapy (FDA approved in 2011), manufactured by Pfizer and marketed under the brand name Xalkori and Crizalk that targets the EML4/ALK fusion gene.

Crizotinib chemical compound

Crizotinib is an anti-cancer drug acting as an ALK and ROS1 inhibitor, approved for treatment of some non-small cell lung carcinoma (NSCLC) in the US and some other countries, and undergoing clinical trials testing its safety and efficacy in anaplastic large cell lymphoma, neuroblastoma, and other advanced solid tumors in both adults and children.

Ceritinib is a second generation targeted therapy (FDA approved in 2014), manufactured by Novartis and sold under the brand name Zykadia that also targets the EML4 fusion gene, but as a second generation drug it has a smaller molecule that allows superior penetration of the Blood Brain Barrier (BBB) over Crizotinib and is more capable of protecting the Central Nervous System (CNS).

Alectinib another second generation targeted therapy and was approved (for this) by Japan in 2014 [4] and by US FDA in 2015. [5] , manufactured by Genentec and marketed under the brand name Alecensa.

Brigatinib a second generation targeted therapy (FDA approved in 2017), manufactured by Takeda and is marketed under the brand name Alunbrig.

Ensartinib is a second generation targeted therapy (trial drug X-396), manufactured by XCovery.

Lorlatinib is a third generation targeted therapy (awaiting FDA approval under trial drug PF-6463922), manufactured by Pfizer.

TPX-0005 is a new third generation targeted therapy drug trial.

Prognosis

Treatment with crizotinib achieves 60% response rate [6] . However, crizotinib showed no improvement on overall survival compared to chemotherapy [7] . This may be due to the fact that there was a 70% crossover rate to crizotinib in patients treated initially with chemotherapy. [8] Also, patients who tested negative for EML4/ALK fusion had a response rate to crizotinib of up to 35% [9] .

Epidemiology

EML4-ALK gene fusions occur almost exclusively in carcinomas arising in non-smokers. [10] [11] About 4% of non-small-cell lung carcinomas involve an EML4-ALK tyrosine kinase fusion gene. [12] 46% of lung adenocarcinomas involve the fusion gene. [6]

EML4-ALK mutation rarely occurs in combination with K-RAS or EGFR mutations.

Related Research Articles

Gefitinib chemical compound

Gefitinib (ZD1839) is a drug used for certain breast, lung and other cancers. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor (EGFR) in target cells. Therefore, it is only effective in cancers with mutated and overactive EGFR. It is marketed by AstraZeneca and Teva.

Anaplastic large-cell lymphoma non-Hodgkin lymphoma involving aberrant T-cells

Anaplastic large-cell lymphoma (ALCL) is a type of non-Hodgkin lymphoma involving aberrant T cells or null lymphocytes. It is described in detail in the "Classification of Tumours of the Haematopoietic and Lymphoid Tissues" edited by experts of the World Health Organisation (WHO). The term anaplastic large-cell lymphoma (ALCL) encompasses at least four different clinical entities, all sharing the same name, which histologically share the presence of large pleomorphic cells that express CD30 and T-cell markers. Two types of ALCL present as systemic disease and are considered as aggressive lymphomas, while two types present as localized disease and may progress locally. Anaplastic large cell lymphoma is associated with various types of medical implants.

Targeted therapy

Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.

Non-small-cell lung carcinoma type of tumour

Non-small-cell lung carcinoma (NSCLC) is any type of epithelial lung cancer other than small cell lung carcinoma (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to small cell carcinoma. When possible, they are primarily treated by surgical resection with curative intent, although chemotherapy has been used increasingly both pre-operatively and post-operatively.

Anaplastic lymphoma kinase protein-coding gene in the species Homo sapiens

Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 is an enzyme that in humans is encoded by the ALK gene.

ROS1 protein-coding gene in the species Homo sapiens

Proto-oncogene tyrosine-protein kinase ROS is an enzyme that in humans is encoded by the ROS1 gene.

Treatment of lung cancer refers to the use of medical therapies, such as surgery, radiation, chemotherapy, immunotherapy, percutaneous ablation, and palliative care, alone or in combination, in an attempt to cure or lessen the adverse impact of malignant neoplasms originating in lung tissue.

Targeted therapy of lung cancer refers to using agents specifically designed to selectively target molecular pathways responsible for, or that substantially drive, the malignant phenotype of lung cancer cells, and as a consequence of this (relative) selectivity, cause fewer toxic effects on normal cells.

HOHMS is the medical acronym for "Higher-Order HistoMolecular Stratification", a term and concept which was first applied to lung cancer research and treatment theory.

Carlo Gambacorti-Passerini Italian oncologist and hematologist

Carlo Gambacorti-Passerini is an Italian oncologist and hematologist known for his contributions to cancer research. He is Professor of Internal Medicine and Hematology at the University of Milan Bicocca in Italy and Director of the Hematology Department at S. Gerardo Hospital, Monza, Italy. He was Senior Investigator and Head of the Oncogenic Fusion Proteins Unit at the National Cancer Institute, Milan Italy from 1990 to 2003, and Professor of Oncology and Hematology at McGill University, Montreal, Quebec, Canada, from 2004 to 2007.

ALK inhibitor class of pharmaceutical drugs

ALK inhibitors are potential anti-cancer drugs that act on tumours with variations of anaplastic lymphoma kinase (ALK) such as an EML4-ALK translocation.

Brigatinib chemical compound

Brigatinib is a small-molecule targeted cancer therapy being developed by ARIAD Pharmaceuticals, Inc. Brigatinib acts as both a anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) inhibitor.

Targeted molecular therapy for neuroblastoma involves treatment aimed at molecular targets that have a unique expression in this form of cancer. Neuroblastoma, the second most common pediatric malignant tumor, often involves treatment through intensive chemotherapy. A number of molecular targets have been identified for the treatment of high-risk forms of this disease. Aiming treatment in this way provides a more selective way to treat the disease, decreasing the risk for toxicities that are associated with the typical treatment regimen. Treatment using these targets can supplement or replace some of the intensive chemotherapy that is used for neuroblastoma. These molecular targets of this disease include GD2, ALK, and CD133. GD2 is a target of immunotherapy, and is the most fully developed of these treatment methods, but is also associated with toxicities. ALK has more recently been discovered, and drugs in development for this target are proving to be successful in neuroblastoma treatment. The role of CD133 in neuroblastoma has also been more recently discovered and is an effective target for treatment of this disease.

Squamous-cell carcinoma of the lung lung cancer

Squamous-cell carcinoma (SCC) of the lung is a histologic type of non-small-cell lung carcinoma (NSCLC). It is the second most prevalent type of lung cancer after lung adenocarcinoma and it originates in the bronchi. Its tumor cells are characterized by a squamous appearance, similar to the one observed in epidermal cells. Squamous-cell carcinoma of the lung is strongly associated with tobacco smoking, more than any other form of NSCLC.

Ceritinib chemical compound

Ceritinib is a prescription-only drug used for the treatment non-small cell lung cancer (NSCLC). It was developed by Novartis and received FDA approval for use in April 2014. It is available as a 150 mg capsule with a one-time daily dosing requirement of 750 mg for NSCLC.

ALK+ large B-cell lymphoma is a type of lymphoma. It was first reported in 1997. It is a rare, aggressive large B-cell process that shows ALK expression. It is distinct from anaplastic large cell lymphoma, a T-cell lymphoma.

Alectinib chemical compound

Alectinib is an oral drug that blocks the activity of anaplastic lymphoma kinase (ALK) and is used to treat non-small-cell lung cancer (NSCLC). It was developed by Chugai Pharmaceutical Co. Japan, which is part of the Hoffmann-La Roche group.

Entrectinib chemical compound

Entrectinib is an investigational drug with preliminary antitumor activity. It is a selective tyrosine kinase inhibitor (TKI), of the tropomyosin receptor kinases (Trk) A, B and C, C-ros oncogene 1 (ROS1) and anaplastic lymphoma kinase (ALK).

References

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  3. Koh Y, Kim DW, Kim TM, et al. (May 2011). "Clinicopathologic characteristics and outcomes of patients with anaplastic lymphoma kinase-positive advanced pulmonary adenocarcinoma: suggestion for an effective screening strategy for these tumors". J Thorac Oncol. 6 (5): 905–12. doi:10.1097/JTO.0b013e3182111461. PMID   21358343.
  4. Japan becomes first country to approve Roche’s alectinib for people with a specific form of advanced lung cancer
  5. New Oral Therapy To Treat ALK-Positive Lung Cancer. Dec 2015
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  12. Kumar, V; Abbas AK; Aster JC (2013). "Chapter 5". Robbins Basic Pathology (9th ed.). Elsevier Saunders. p. 212. ISBN   978-1-4377-1781-5.