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State of the art in oncologic imaging of lungs.

Posted in Biomarkers & Medical Diagnostics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Health Economics and Outcomes Research, HealthCare IT, Imaging-based Cancer Patient Management, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Population Health Management, Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Uncategorized, tagged American Cancer Society, Cancer - General, cancer deaths, cancer imaging, cancer mortality, Clinical trial, CT, FDA, health, lung, lung adenocarcinoma, Lung cancer, medicine, National Institutes of Health, NCI, Non-small cell lung cancer, PET, PET/CT, relative survival rate, research, science on January 23, 2013| 5 Comments »

State of the art in oncologic imaging of lungs.

Author and Curator: Dror Nir, PhD

This is the second post in a series in which I will address the state of the art in oncologic imaging based on a review paper; Advances in oncologic imaging ^†^‡ that provides updates on the latest approaches to imaging of 5 common cancers: breast, lung, prostate, colorectal cancers, and lymphoma. This paper is published at CA Cancer J Clin 2012. © 2012 American Cancer Society.

The paper gives a fair description of the use of imaging in interventional oncology based on literature review of more than 200 peer-reviewed publications.

In this post I summaries the chapter on lung cancer imaging.

Lung Cancer Imaging

“Lung cancer remains the most common cause of death from cancer worldwide, having resulted in 1.38 million deaths (18.2% of all cancer deaths) in 2008.48 It also represents the leading cause of death in smokers and the leading cause of cancer mortality in men and women in the United States. In 2012, it was estimated that 226,160 new cases of lung cancer would be diagnosed (accounting for about 14% of cancer diagnoses) and that lung cancer would cause 160,340 deaths (about 29% of cancer deaths in men and 26% of cancer deaths in women) in the United States.1 The 1-year relative survival rate for the disease increased from 35% to 43% from 1975 through 1979 to 2003 through 2006.49 The 5-year survival rate is 53% for disease that is localized when first detected, but only 15% of lung cancers are diagnosed at this early stage.”

For cancer with such poor survival rates removal of the primary lesion by surgery at an early-stage disease is the best option. The current perception in regards to lung cancr is that patients may have subclinical disease for years before presentation. It is also known that early lung cancer lesions; adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) are slow-growing, doubling time which can exceed 2 years.52 But, since at present, no lung cancer early-detection biomarker is clinically available, the diagnosis of this disease is primarily based on symptoms, and detection often occurs after curative intervention and when it’s already too late – see: Update on biomarkers for the detection of lung cancer and also Diagnosing lung cancer in exhaled breath using gold nanoparticles. Until biomarker is found, the burden of screening for this disease is on imaging.

“AIS and MIA generally appear as a single peripheral ground-glass nodule on CT. A small solid component may be present if areas of alveolar collapse or fibroblastic proliferation are present,50, 51 but any solid component should raise concern for a more invasive lesion (Fig. 8). Growth over time on imaging can often be difficult to assess due to the long doubling time of these AIS and MIA, which can exceed 2 years.52 However, indicators other than growth, such as air bronchograms, increasing density, and pleural retraction within a ground-glass nodule are suggestive of AIS or MIA.

CT image shows a ground glass nodule, which is the typical appearance of AIS, in the right upper lobe.

CT (A) demonstrated extensive consolidation with air bronchograms in the left upper lobe, which at surgical resection were found to represent adenocarcinoma of mixed subtype with predominate (70%) mucinous bronchioloalveolar subtype. PET imaging in the same patient (B) demonstrated uptake in the lingula higher than expected for bronchioloalveolar carcinoma and probably due to secondary inflammation/infection. CT (C) obtained 3 years after images (A) and (B) demonstrated biopsy-proven recurrent soft-tissue mass near surgical site. Fused FDG/PET images (D) demonstrate no uptake in the area. This finding is consistent with the decreased uptake usually seen in tumors of bronchioloalveolar histology (new terminology of MIA).

In August 2011 the results of the “National Lung Screening Trial “ which was funded by the National Cancer Institute (NCI) were published in NEJM; Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening. This randomized study results showed that with low-dose CT screening of high-risk persons, there was a significant reduction of 20% in the mortality rate from lung cancer as compared to chest radiographs screening.

Based on these results one can find the following information regarding Lung Cancer Screening on the NCI web-site:

“Three screening tests have been studied to see if they decrease the risk of dying from lung cancer.

The following screening tests have been studied to see if they decrease the risk of dying from lung cancer:

Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.
Sputum cytology: Sputum cytology is a procedure in which a sample of sputum (mucus that is coughed up from the lungs) is viewed under a microscope to check for cancer cells.
Low-dose spiral CT scan (LDCT scan): A procedure that uses low-dose radiation to make a series of very detailed pictures of areas inside the body. It uses an x-ray machine that scans the body in a spiral path. The pictures are made by a computer linked to the x-ray machine. This procedure is also called a low-dose helical CT scan.

Screening with low-dose spiral CT scans has been shown to decrease the risk of dying from lung cancer in heavy smokers.

A lung cancer screening trial studied people aged 55 years to 74 years who had smoked at least 1 pack of cigarettes per day for 30 years or more. Heavy smokers who had quit smoking within the past 15 years were also studied. The trial used chest x-rays or low-dose spiral CT scans (LDCT) scans to check for signs of lung cancer.

LDCT scans were better than chest x-rays at finding early-stage lung cancer. Screening with LDCT also decreased the risk of dying from lung cancer in current and former heavy smokers.

A Guide is available for patients and doctors to learn more about the benefits and harms of low-dose helical CT screening for lung cancer.

Screening with chest x-rays or sputum cytology does not decrease the risk of dying from lung cancer.

Chest x-ray and sputum cytology are two screening tests that have been used to check for signs of lung cancer. Screening with chest x-ray, sputum cytology, or both of these tests does not decrease the risk of dying from lung cancer.”

The authors of Advances in oncologic imaging^†^‡ found out that for pre-treatment staging and post treatment follow-up of lung cancer patients mainly involves CT (preferably contrast enhanced, FDG PET and PET/CT. “Integrated PET/CT has been found to be more accurate than PET alone, CT alone, or visual correlation of PET and CT for staging NSCLC (Non-small-cell lung carcinoma).59 “

The standard treatment of choice for localized disease remains surgical resection with or without chemo-radiation therapy (stage dependant). “The current recommendations for routine follow-up after complete resection of NSCLC are as follows: for 2 years following surgery a contrast-enhanced chest CT scan every 4 to 6 months and then yearly non-contrast chest CT scans.62 Detection of recurrence on CT is the primary goal in the initial years, and therefore, optimally, a contrast-enhanced scan should be obtained to evaluate the mediastinum. In subsequent years, when identifying an early second primary lung cancer becomes of more clinical importance, a non-contrast CT chest scan suffices to evaluate the lung parenchyma.

CT (A) of 78-year-old male who was status post–left lobe lobectomy and left upper lobe wedge resection shows recurrent nodule at the surgical resection site. Fused PET/CT (B) demonstrates increased [18F]FDG uptake in the corresponding nodule at the surgical resection site consistent with recurrent tumor.

In patients undergoing chemotherapies: “ [¹⁸F]FDG PET response correlates with histologic response.63 [¹⁸F]FDG PET scan data can provide an early readout of response to chemotherapy in patients with advanced-stage lung cancer.64

In patients treated by recently developed “Targeted Therapies” such as Radiofrequency ablation (RFA) the authors found out that PET/CT is the preferred imaging modality for post treatment follow-up.

“ Most patients treated with pulmonary ablation will have had a pre-procedure CT or a fusion PET/CT scan, which allows more precise anatomic localization of abnormalities seen on PET. Generally, either CT or PET/CT is performed within a few weeks of the procedure to provide a new baseline to which future images can be compared to assess for changes in size, degree of enhancement or [¹⁸F]FDG avidity.67”

CT (A) demonstrates new left upper lobe mass representing new primary NSCLC in a patient who had a status post–right pneumonectomy for a prior NSCLC. CT (B) obtained in the same patient 2 weeks after radiofrequency ablation (RFA) demonstrates the postablation density in the left upper lobe. Fused PET/CT (C) obtained 4 months after RFA demonstrates mild [18F]FDG uptake at RFA site in the left upper lobe consistent with posttreatment inflammation. Fused PET/CT (D) obtained 7 months after RFA demonstrates new focal [18F]FDG uptake at post-RFA-opacity consistent with recurrent tumor.

Prostate Cancer Imaging

To be followed…

Other research papers related to the management of Lung cancer were published on this Scientific Web site:

Diagnosing lung cancer in exhaled breath using gold nanoparticles

Lung Cancer (NSCLC), drug administration and nanotechnology

Non-small Cell Lung Cancer drugs – where does the Future lie?

Comprehensive Genomic Characterization of Squamous Cell Lung Cancers

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Mitochondrial fission and fusion: potential therapeutic targets?

Posted in Autophagy, Autophagy-Modulating Proteins, Biochemical pathways, Biological Networks, Gene Regulation and Evolution, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Disease Biology, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Metabolic Immuno-Oncology, Metabolism, Metabolomics, Oxidative phosphorylation, Warburg effect, tagged Apoptosis, Autophagy, calcineurin, Cancer - General, cardiomyocytes, Cdk1, cell division, cell proliferation, CyclinB, cytosolic, Drp-1, Drp1, dynamin, Dynamin related protein, E3 ubiquitin ligase, energetics, GTPases, hFis1, lung adenocarcinoma, Lung cancer, membrane, Mfn-1, Mfn-2, Mfn1, Mfn2, MicroRNA, miR-30, miR-484, miR-499, mitochondria, Mitochondrial DNA, mitochondrial fission, mitochondrial fusion, mitofusion 1, mitofusion 2, mtDNA, nucleoids, Opa1, p53, PKA, Reactive oxygen species, ROS, sumoylation, ubiquitination on October 31, 2012| 7 Comments »

Author and Curator: Ritu Saxena, Ph.D.

Introduction: Mitochondrial fission & fusion

Mitochondria, double membranous and semi-autonomous organelles, are known to convert energy into forms that are usable to the cell. Apart from being sites of cellular respiration, multiple roles of mitochondria have been emphasized in processes such as cell division, growth and cell death. Mitochondria are semi-autonomous in that they are only partially dependent on the cell to replicate and grow. They have their own DNA, ribosomes, and can make their own proteins. Mitochondria have been discussed in several posts published in the Pharmaceutical Intelligence blog.

Mitochondria do not exist as lone organelles, but are part of a dynamic network that continuously undergoes fusion and fission in response to various metabolic and environmental stimuli. Nucleoids, the assemblies of mitochondrial DNA (mtDNA) with its associated proteins, are distributed during fission in such a way that each mitochondrion contains at least one nucleoid. Mitochondrial fusion and fission within a cell is speculated to be involved in several functions including mtDNA DNA protection, alteration of cellular energetics, and regulation of cell division.

Proteins involved in mitochondrial fission & fusion

Multiple mitochondrial membrane GTPases that regulate mitochondrial networking have recently been identified. They are classified as fission and fusion proteins:

Fusion proteins: Members of dynamin family of protein, mitofusin 1 (Mfn-1) and mitofusin 2 (Mfn-2), are involved in fusion between mitochondria by tethering adjacent mitochondria. These proteins have two transmembrane segments that anchor them in the mitochondrial outer membrane. Mutations in Mitofusin proteins gives rise to fragmented mitochondria, but this can be reversed by mutations in mammalian Drp1. Mitochondrial inner membranes are fused by dynamin family members called Opa1.

Fission proteins: Another member of the dynamin family of proteins, dynamin-related protein 1 (Drp-1) mediates fission of mitochondria. Drp-1 is activated by phosphorylation. Drp-1 proteins are largely cytosolic, but cycle on and off of mitochondria as needed for fission. Fission is a complex process and involves a series of well-defined stages and proteins. Cytosolic Drp-1 is activated by calcineurin or other cytosolic signaling proteins after which it translocates to the mitochondrial tubules where it assembles into foci through its interaction with another protein, hFis1. Once Drp-1 rings assemble on the constricted spots, outer membrane of mitochondria undergoes fission through GTP hydrolysis. Drp-1 is now left bound to one of the newly formed mitochondrial ends after which it slowly disassembles before returning to the cytoplasm.

Control of mitochondrial fission & fusion

Mitochondrial fission and fusion are controlled by several regulatory mechanisms. Few of which are mentioned as follows:
Drp-1 activation by Cdk1/Cyclin B mediated phosphorylation during mitosis – triggers fission
Drp-1 inactivation by cAMP-dependent protein kinase (PKA) in quiescent cells- prevents fission
Drp-1 activation after reversal of PKA phosphorylation by Calcineurin- triggers fission
Ubiquination of fission and fusion proteins by E3 ubiquitin ligase- alters fission
Sumoylation of fission proteins – regulates fission

Imparied mitochondrial fission leads to loss of mtDNA

Mitochondrial fission plays an important role in mitochondrial and cellular homeostasis. It was reported by Parone et al (2008) that preventing mitochondrial fission by down-regulating expression of Drp-1 lead to loss of mtDNA and mitochondrial dysfunction. An increase in cellular reactive oxygen species (ROS) was observed. Other cellular implications included depletion of cellular ATP, inhibition of cell proliferation and autophagy. The observations were made in HeLa cells.

MicroRNA regulation of mitochondrial fission

Although several factors have been attributed to the regulation of mitochondrial fission, the mechanism still remains poorly understood. Recently, regulation of mitochondrial fission via miRNAs has become a topic of interest. Following miRNAs have been found to be involved in mitochondrial fission:

miR-484: Wang et al (2012) demonstrated that miR-484 was able to regulate mitochondrial fission by suppressing the translation of a fission protein Fis1, leading to inhibition of Fis1-mediated fission and apoptosis in cardiomyocytes and in the adrenocortical cancer cells. The authors showed that Fis1 is necessary for mitochondrial fission and apoptosis, and is upregulated during anoxia, whereas miR-484 is downregulated. Underlying mechanism involved transactivation of miR-484 by a transcription factor, Foxo3a and miR-484 is able to attenuate Fis1 upregulation and mitochondrial fission, by binding to the amino acid coding sequence of Fis1 and inhibiting its translation.
miR-499: miR-499 was reported by Wang et al (2011) to be able to directly target both the α- and β-isoforms of the calcineurin catalytic subunit. Suppression of calcineurin-mediated dephosphorylation of Drp-1 lead to inhibition of the fission machinery ultimately resulting in the inhibition of cardiomyocyte apoptosis. miR-499 levels, by altering mitochondrial fusion were able affect the severity of myocardial infarction and cardiac dysfunction induced by ischemia-reperfusion. Modulation of miR-499 expression could provide a therapeutic approach for myocardial infarction treatment.
miR-30: It was reported by Li et al (2010) that miR-30 family members were able to inhibit mitochondrial fission and also the resulting apoptosis. While exploring the underlying molecular mechanism, the authors identified that miR-30 family members can suppress p53 expression. When cell received apoptotic stimulation, p53 was found to transcriptionally activate the fission protein, Drp-1. Drp-1 was able to induce mitochondrial fission. miR-30 family members were observed to inhibit mitochondrial fission through attenuation of p53 expression and its downstream target Drp-1.

Mitochondrial fission & fusion as a therapeutic target

Since alteration of mitochondrial fission and fusion have been reported to affect various cellular processes including apoptosis, proliferation, ATP consumption, the proteins involved in the process of fission and fusion might be harnessed as therapeutic target.

Mentioned below is a description of research where dynamics of the mitochondrial organelle has been utilized as a therapeutic target:

Inhibition of mitochondrial fission prevents cell cycle progression in lung cancer

A recent article published by Rehman et al (2012) in the FASEB journal drew much attention after interesting observations were made in the mitochondria of lung adenocarcinoma cells. The mitochondrial network of these cells exhibited both impaired fusion and enhanced fission. It was also found that the fragmented phenotype in multiple lung adenocarcinoma cell lines was associated with both a down-regulation of the fusion protein, Mfn-2 and an upregulation of expression of fission protein, Drp-1. The imbalance of Drp-1/Mfn-2 expression in human lung cancer cell lines was reported to promote a state of mitochondrial fission. Similar increase in Drp-1 and decrease in Mfn-2 was observed in the tissue samples from patients compared to adjacent healthy lung. Authors used complementary approaches of Mfn-2 overexpression, Drp-1 inhibition, or Drp-1 knockdown and were able to observe reduction of cancer cell proliferation and an increase spontaneous apoptosis. Thus, the study identified mitochondrial fission and Drp-1 activation as a novel therapeutic target in lung cancer.