Tagged: Lung Cancer

New Study: ALK Rearrangement Among Lung Cancer Patients

In Oncotarget’s Volume 12, Issue 23, cover paper, researchers retrospectively assessed the prevalence of anaplastic lymphoma kinase (ALK) gene rearrangement among nearly 20,000 patients with advanced non-small cell lung cancer.

Lung Cancer x-ray
Lung cancer x-ray
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The identification of an actionable gene mutation or translocation in patients with cancer can give researchers a target for new drug therapies. One such mutation, found in some patients with non-small cell lung cancer (NSCLC), is anaplastic lymphoma kinase (ALK) gene rearrangement. However, the exact population of patients that present with ALK rearrangement has not been fully characterized. Identifying the subpopulation of patients who present with ALK rearrangement may lead to better overall treatment outcomes. 

Researchers—from University of Mississippi Medical CenterRoche Information SolutionsRoche Diagnostics CorporationGenesis Research, and Houston Methodist Hospital—conducted a retrospective study of nearly 20,000 patients with advanced NSCLC (aNSCLC). The researchers assessed ALK rearrangement prevalence in the cohort overall and then categorized the data using patient characteristics. Their paper was published on the cover of Oncotarget’s Volume 12, Issue 23, and entitled, “Anaplastic lymphoma kinase rearrangement prevalence in patients with advanced non-small cell lung cancer in the United States – retrospective real world data”. 

“We performed a retrospective study of a database to acquire real-world clinical data on the frequency of the translocation in a large pool of patients drawn primarily from community hospitals and practices.”

The Study

This cross-sectional, observational study used de-identified data from Flatiron Health’s database, which included 19,895 patients who were diagnosed with aNSCLC in the United States between 2015 and 2019. The average age of patients was 68.5, plus or minus 10 years. The distribution of gender was nearly equal, with men comprising 50.4% (10,029) of the patient cohort, and 68.4% of patients were Caucasian. A large proportion of patients had a non-squamous histology type (80.5%) and smoking history (85.5%).

“Prevalence of ALK rearrangement was assessed overall and then stratified by patient characteristics such as age, gender, race, smoking status and histology.”

The researchers used descriptive statistics to summarize patient characteristics. Characteristics included age, gender, race, geographic location, smoking status, histology, practice type (community or academic), PD-L1 status, prevalence of ALK rearrangement and other biomarkers. 

“Regardless of documented histology, a higher ALK rearrangement rate (8.9%) was observed among patients who had no smoking history compared to patients with a smoking history (1.5% ALK positivity) which represent the largest number of patients in this cohort (17,003).”

Conclusion

Results from the study concluded that ALK rearrangement was present in 2.6% of the total cohort, or 517 patients. The researchers found that ALK rearrangement prevalence varied based on the patients’ demographic characteristics. The rate of ALK rearrangement was the highest among patients younger than 40 years old, and decreased with age. Researchers found no significant difference in ALK rearrangement between men and women. However, when compared to other patients, Asian patients had a higher ALK rearrangement rate (39 out of 623, or 6.3%). Interestingly, the ALK positivity rate was greatest (9.3%) among non-smoking patients with non-squamous histology.

“In summary, this retrospective review of nearly 20,000 patients with aNSCLC and tested for ALK in the United States confirms that ALK rearrangements are found more commonly in younger nonsmokers and patients of Asian descent.”

Click here to read the full research paper, published by Oncotarget.

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Scientific Integrity

Trending With Impact: Unconventional Method Effectively Targets NSCLC

Researchers developed a divergent strategy to treat non-small cell lung cancer (NSCLC).

New ideas

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The mammalian target of rapamycin (mTOR) operates within two distinct protein complexes—mTOR complex 1 (mTORC1) and complex 2 (mTORC2). These protein complexes are not yet fully understood, as they were only recently identified in humans in 1994. What researchers do know is that mTORC1 is involved in the regulation of many cellular processes and is a key mediator of cell growth and proliferation. mTORC1 is activated by growth factor receptor signals through the PI3K–AKT and RAS–ERK mitogen-activated protein kinase (MAPK) pathways.

The PI3K/AKT/mTOR pathway may be an efficacious target in the treatment of patients with non-small cell lung cancer (NSCLC). This theory is based on the identification of particular gene mutations in NSCLC that are associated with the PI3K/AKT/mTOR pathway. However, previous studies have not yet succeeded in defining an effective monotherapy or combination of therapies that targets this pathway while improving NSCLC patient outcome. 

Researchers from Institut CuriePSL UniversityXentechBioPôle AlfortHôpital Foch, and Centre Léon Bérard designed a study using a new methodology to test treatment combinations based on specific targets identified as biomarkers of resistance to PI3K-targeting treatments, and not based on the NSCLC mutations themselves. Their trending research paper was published by Oncotarget in 2021 and entitled, “High in vitro and in vivo synergistic activity between mTORC1 and PLK1 inhibition in adenocarcinoma NSCLC.”

“Our main strategy was therefore, using a panel of NSCLC PDXs, (i) to define predictive markers of response to RAD001 therapy and (ii) to identify possible combinations of treatments that may be able to reverse RAD001 resistance.”

THE STUDY

Researchers tested RAD001/Everolimus (an mTORC1 inhibitor) in vivo using NSCLC Patient-Derived Xenografts (PDXs), which demonstrated high antitumor efficacy. They next aimed to define predictive markers of response to RAD001 using real-time quantitative RT-PCR assays.

“In order to define predictive markers of response to RAD001, we used real-time quantitative RT-PCR assays to quantify the mRNA expression of a large number of selected genes.”

The team found three significantly highly expressed and targetable genes in NSCLC tumors resistant to RAD001: PLK1, CXCR4 and AXL. They then analyzed these genes for their prognostic value among NSCLC patients that were found in the publicly available database KMPLOT. This analysis revealed that of the three genes evaluated, only one high-gene expression was correlated with a negative impact on overall survival of patients with adenocarcinoma: PLK1. Given this data, the researchers next evaluated the in vivo efficacy of RAD001 combined with a PLK1 inhibitor, volasertib, in four PDX models. The RAD001 + volasertib combination demonstrated dramatic efficacy in three of the four models.

“In all tested PDXs, except LCF29, we have observed a significant, but variable, improvement of the antitumor efficacy of RAD001 + volasertib in comparison to each monotherapy (Figure 2A).”

To define this RAD001 + volasertib drug combination’s mechanism of action, the researchers conducted a pharmacodynamics (PD) study. The team then evaluated post-therapeutic proteins involved in the cell cycle, vascularization and carbonic anhydrase IX expression. These results were then validated using in vitro studies. 

CONCLUSION

“Our determination of relevant Pi3K-based therapeutic combination(s) was not supported, by the presence of actual molecular abnormalities, nor by physician therapeutic practices, but by the identification of predictive markers of resistance to Pi3K-based monotherapies.”

In summary, the researchers conclude that their study demonstrates that inhibiting both mTORC1 and PLK1 proteins induces synergistic antitumor activity in multiple models of NSCLC. In the discussion section of this paper, the authors detailed the divergent methodology they used to come to their conclusion. 

“This methodology may promote more relevant clinical trials and avoid non-efficient combinations, inacceptable toxicities, and expensive and time-consuming studies.”

Click here to read the full research paper, published by Oncotarget.

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Trending With Impact: Promising Non-Small Cell Lung Cancer Prodrug

Researchers examined the preclinical prodrug LP-184 and its efficacy in treating non-small cell lung cancers that lack actionable targets or resistance-related genes.

3D illustration of lung cancer

The Trending with Impact series highlights Oncotarget publications attracting higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Oncotarget.com.

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Between 20 and 40% of adults with non-small cell lung cancer (NSCLC) eventually go on to develop brain metastases. Over 40% of patients with NSCLC have limited treatment options due to a lack of actionable therapeutic targets. Treatment for such patients has been limited to non-targeted chemotherapy—an approach which increases the risk of developing drug-resistance due to underlying resistance-associated mutations. 

“Newer drugs that will be more potent and remain efficacious in NSCLC with such mutations could lead to better alternate or combinatorial therapies.”

Lantern Pharma (a pharmaceutical company developing targeted cancer therapies) created a new drug candidate and next generation member of the acylfulvene class of prodrugs, named LP-184. Researchers from Lantern Pharma and REPROCELL (a commercial contract research organization) conducted a study to test the anti-tumor activity of this preclinical compound in a variety of NSCLC cell lines. In 2021, Oncotarget published team’s pape, entitled, “The acylfulvene alkylating agent, LP-184, retains nanomolar potency in non-small cell lung cancer carrying otherwise therapy-refractory mutations.”

The Study

Despite LP-184’s highly-synthetic sounding name, the lead product in this acylfulvene prodrug (Illudins) is derived from, you guessed it, Jack-o-Lantern mushrooms. 

“Acylfulvenes have been derived from cytotoxic agents called Illudins, isolated from Jack-o-Lantern mushroom (Omphalotus illudens), that retain and improve the cytotoxicity of parent Illudins for use as anticancer agents.”

The anti-tumor activity of this compound is based on activation through reductive mechanisms, mediated by enzymes such as Prostaglandin Reductase 1 (PTGR1). PTGR1 is known to be upregulated in some tumors, including in tumors with mutations in KEAP1. LP-184 sensitivity was investigated in NSCLC cell lines with individual or combined mutations in KEAP1, KRAS, TP53, and STK11. 

“There is a high unmet need for effective therapies for NSCLC harboring mutations in these genes that have not only been considered undruggable till date but also are associated with loss of efficacy or resistance to multiple therapeutic strategies, at least in frontline regimens.”

The researchers tested LP-184 in vitro in 19 primary and metastatic NSCLC cell lines to determine the range of NSCLC settings that this compound might work best in. Clinical data analyses were also conducted by the researchers to predict tumor responsiveness to LP-184. In addition, the compound was examined in two mouse models of primary lung cancer. Mouse models were tested for sensitivity to LP-184 in both two- and three-dimensional culture systems.

“We sought to assess LP-184 activity in a panel of selected NSCLC adenocarcinoma cell lines, determine associations between genomic and transcriptomic profiles and responses of cell lines tested, and compare in vitro potency of LP-184 with that of approved chemotherapy agents.”

Conclusion

Among their many findings, the researchers demonstrated that LP-184 has high nanomolar potency in 11 of the 19 NSCLC cell lines tested—indicating broad NSCLC anti-tumor activity. In vivo, LP-184 showed efficacy in terms of tumor regression in one of the two mouse models.

“We propose further evaluation of LP-184 in multiple PTGR1 high NSCLC settings that may not necessarily be mutually exclusive, including in highly prevalent KEAP1 and KRAS mutant tumors (Figure 6), and in patients with lack of actionable targets or resistance-related genes with no effective therapy options available.”

Click here to read the full research paper, published by Oncotarget.

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Trending with Impact: Machine Learning Used to Compare ALK Inhibitors

Researchers use a computer simulated modeling system to highlight the strengths and weaknesses of two ALK inhibitors.

Figure 2: Overview of brigatinib’s and alectinib’s mechanisms of action.
Figure 2: Overview of brigatinib’s and alectinib’s mechanisms of action.

The Trending with Impact series highlights Oncotarget publications attracting higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news and articles about the latest trending publications here, and at Oncotarget.com.

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Despite many therapeutic advances over the years, over half of patients with lung cancer die within one year of diagnosis. Non-small cell lung cancer (NSCLC) comprises 85% of all lung cancer, and around 3–7% of patients with NSCLC present with a rearranged ALK gene (ALK+). This abnormality produces aberrant ALK protein cell signaling pathway activity and causes cancer cells to grow and metastasize. ALK+ NSCLC patients often develop drug resistance to available ALK inhibitor drugs. 

“Consequently, it is of the upmost importance to adequately use the currently available treatments in the correct order to maximize the life span of NSCLC patients.”

In 2021, researchers from Spain conducted a study published in Oncotarget, titled: “Head to head evaluation of second generation ALK inhibitors brigatinib and alectinib as first-line treatment for ALK+ NSCLC using an in silico systems biology-based approach.” This trending paper was authored by researchers practicing at the Hospital Germans Trias i PujolTakeda Farmacéutica EspañaAnaxomics Biotech, and Universitat Pompeu Fabra

The Study

The researchers first began their study by characterizing the pathophysiology of ALK+ NSCLC after completing a detailed review of review papers published in PubMed between 2013 and 2018.

“To carefully characterize the pathophysiology of ALK+ NSCLC, we conducted an extensive and detailed full-length review of relevant review articles over the last 5 years in the PubMed database (from December 3rd 2013 to December 3rd 2018)[…]” 

Next, to compare the strengths and weaknesses of two second generation ALK inhibitor drugs, brigatinib and alectinib, the researchers used a computer simulated modeling system—in silico. They explain that an in silico method of study can be highly useful when analyzing drug characteristics and predicting the biochemical characteristics and drug mechanisms of action.

“Overall, these systems can be employed for the exploration of anticancer drug mechanisms of action and their efficacy in specific patient profiles.”

The in silico system they used is called a Therapeutic Performance Mapping System (TPMS) and is based on artificial intelligence and pattern recognition models. This TPMS system was “trained” by the researchers in this study and given up-to-date biological and clinical data to input into its configuration. The mathematical models used to obtain the ALK inhibitors’ mechanisms of action were generated following the same methodology as described in this study.

“This methodology integrates available biological, pharmacological and medical information to generate mathematical models that simulate the mechanisms of action of drugs in a pathophysiological human context (Figure 4).”

To detect and explain the biological relationships that occur, the team used two distinct modeling methods: artificial neural networks and sampling-based methods. They applied Sobol sensibility analysis over the TPMS mathematical models in order to account for the impact of any noise affecting the final mechanisms of action. The researchers also performed drug-(patho)physiology motive relation finding and evaluated the impact of potential resistances and drug interferences over the mechanisms of action.

Results & Conclusion

“According to the current knowledge and the data herein presented, brigatinib might be more prone to present relevant metabolic and mechanistic interactions with other drugs than alectinib, which might be a safer option in poly-treated patients.” 

“Brigatinib appears to have a wider mechanism of action, presenting targets that potentially act more strongly in most of the ALK+ NSCLC pathophysiological pathways, including invasiveness to the CNS [central nervous system].” 

“On the other side, alectinib-induced RET inhibition might contribute to reducing the tumour immune evasion mechanisms.”

The researchers found that both drugs are known to be well-tolerated and show similar efficacy for the treatment of ALK+ NSCLC in a first-line setting. However, they explain that the differences in their characteristics shown in this study might allow for administration in more targeted patient populations that might see benefits from either brigatinib or alectinib. This deeper classification may also help when considering potential safety concerns in specific patient subpopulations.

“Future clinical studies will be needed to confirm these findings. The used approach can be applied for the evaluation of other next-generation ALKi, even if not yet approved, or exploring other questions, such as optimal treatment sequence.”

Click here to read the full scientific study, published in Oncotarget.

Oncotarget is a unique platform designed to house scientific studies in a journal format that is available for anyone to read—without a paywall making access more difficult. This means information that has the potential to benefit our societies from the inside out can be shared with friends, neighbors, colleagues and other researchers, far and wide.

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Trending with Impact: Novel MicroRNA Underexpressed in Lung Cancer

In search of new ways to target lung cancer cells, researchers in this study demonstrated that miR-708 has anti-tumorigenic properties.

Photomicrograph of fine needle aspiration (FNA) cytology of a pulmonary (lung) nodule showing adenocarcinoma, a type of non small cell carcinoma.
Photomicrograph of fine needle aspiration (FNA) cytology of a pulmonary (lung) nodule showing adenocarcinoma, a type of non small cell carcinoma.

The Trending with Impact series highlights Oncotarget publications attracting higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news and articles about the latest trending publications here, and at Oncotarget.com.

Despite the innumerable biomedical advancements made in the detection, classification, and treatment of cancer since the 1971 National Cancer Act, lung cancer survival rates are still staggeringly low. In addition, every year over $12.1 billion is spent on lung cancer care in the United States. Non-small cell lung cancer (NSCLC) contributes to 85% of lung cancers and within this classification there are two main subtypes: adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC).

“Although tumors are differentiated by subtype, LUAD and LUSC are generally treated with the same chemotherapeutics.”

Researchers, from the New Jersey Medical School’s academic health center, Rutgers Biomedical & Health Sciences, say that discovering new biomarkers that can help better distinguish between NSCLC subtypes is necessary to improve patient outcomes. In 2020, they conducted a study of a microRNA that is dysregulated in lung cancer, miR-708, to clarify its tumor suppressive or oncogenic functions within lung cancer cells.

“Lung cancer is a complex collection of deadly diseases that are generally hard to detect and treat. Therefore, it is crucial to develop novel methods to identify, distinguish, and treat lung cancer.”

The Study

The researchers in this study explain that it is crucial to take the entire tumor microenvironment (TME) into consideration when devising treatments for cancerous tumors. Historically, many chemotherapies that have been developed are successful in targeting tumors, but contribute to damaging the surrounding cells and tissues in the TME—contributing to harm and extending recovery time. In newer treatments being developed, researchers have considered the benefits of targeting the pro-tumor effects of particular immune cells and activating the immune system to attack cancer cells.

“miR-708 has previously been described as being both oncogenic and tumor suppressive in lung cancer [63–65]. Therefore, we aimed to clarify the tumor suppressive or oncogenic functions of miR-708 in lung cancer cells.”

This new potential microRNA with potent anti-tumorigenic effects for non-small cell lung cancer (NSCLC) was identified by the researchers. To determine the clinical relevance of miR-708 in lung cancer patients, the researchers analyzed data from The Cancer Genome Atlas (TCGA) using the TCGA-assembler 2 R software package. They used mammalian cell cultures to perform miRNA and 5-Azacytidine treatments, RNA isolation using TRIzol, quantitative real-time RT-PCR, western blot analysis, plasmids, luciferase reporter assays, Enzyme-Linked Immunosorbent Assay (ELISA) analysis, phenotypic assays; Water Soluble Tetrazolium Salts (WST)-1 assay; Ki-67 staining; Annexin V staining; Cell migration assay, and Bioinformatic and statistical analyses.

“We next examined expression of miR-708 in normal and lung cancer cells to determine if our cell lines faithfully replicated clinical data.”

Results

The researchers discovered miR-708 was underexpressed in lung cancer cells compared to normal lung cells. A lower expression of miR-708 correlated with decreased survival in patients with squamous cell carcinoma non-small cell lung cancer. They demonstrated that miR-708 suppressed the production of the pro-tumorigenic hormone called prostaglandin E2 (PGE2) (located in the arachidonic acid (AA) metabolic inflammatory pathway), by directly repressing the expression of COX-2 and mPGES-1 in lung cancer cells.

“We also demonstrated that miR-708 decreases lung cancer cell metabolism (Figure 5), proliferation (Figure 6), survival (Figure 7), and migration (Figure 8).” 

Conclusion

The researchers were left with some outstanding questions about miR-708. First, they wondered why miR-708 expression is decreased in lung cancer cells compared to normal cells in the lungs. They suggest the cause may be the hypermethylation of the ODZ4 promoter region in lung cancer cells, a loss of tumor suppressive transcription factors, repressed CHOP activity, or specifically, the glucocorticoid receptor-alpha (GRα) repression of CHOP activity.

“Our work has identified novel tumor suppressive miR-708 functions by suppressing oncogenic PGE2 production through targeting of COX-2 and mPGES-1. These findings could be the foundation for identifying novel miR-708 targets, as well as regulators of miR-708 expression in cancer.”

“Moreover, our study highlights the need to better understand lung cancer biology to improve diagnosis and treatment of lung cancer, ultimately aiming to increase positive patient outcomes.”

Click here to read the full scientific study, published in Oncotarget.

Oncotarget is a unique platform designed to house scientific studies in a journal format that is available for anyone to read—without a paywall making access more difficult. This means information that has the potential to benefit our societies from the inside out can be shared with friends, neighbors, colleagues, and other researchers, far and wide.

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Special Collection by Oncotarget: Lung Cancer

Oncotarget Special Collection: Lung Cancer
Oncotarget Special Collection: Lung Cancer
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Lung cancer is still the leading cause of cancer-related mortality worldwide. According to the CDC, smoking cigarettes is linked to 80-90% of lung cancer deaths in the United States. In non-smokers, lung cancer can be caused by exposure to radon, secondhand smoke, air pollution, asbestos, diesel exhaust, and other chemicals and factors. 

Some symptoms of lung cancer include pain in chest or ribs, frequent respiratory infections, shortness of breath, wheezing, fatigue or loss of appetite. As numerous research studies about lung cancer are currently underway, we hope this Special Collection will set future research in motion to discover more causes and treatments for this disease.

Special Collections: Lung Cancer

Oncotarget publishes open access peer-reviewed literature about research studies, clinical studies, reviews, case reports, and meta-analyses on a variety of different topics pertaining to cancer. Lung cancer continues to be an area of interest for researchers, therefore, the Special Collection on Lung Cancer was created by Oncotarget for scientists and researchers to discover new biomarkers, mechanisms, and therapies to treat this cancer.

All content submitted for publication has been reviewed by a diligent board of academic editors and world-renowned scientists and researchers. In this Special Collection, the content focussing on lung cancer is organized together in one place, including papers such as “Molecular pathways and therapeutic targets in lung cancer” by Emma Shtivelman, Thomas Hensing, George R. Simon, Phillip A. Dennis, Gregory A. Otterson, Raphael Bueno, and Ravi Salgia. This review is a summary of the pathways and mechanisms involved in current treatment methods for lung cancer of various types.

This meta-analysis examines the relationship between exposure to PM2.5 (particulate matter or fine particles) and lung cancer incidence and mortality: “Relationship between exposure to PM2.5 and lung cancer incidence and mortality: A meta-analysis” by Feifei Huang, Bing Pan, Jun Wu, Engeng Chen, and Liying Chen.

This review focuses on improved anticancer agents and therapy options for lung cancer patients with acquired EGFR TKI (chemotherapy) resistance: “Clinical strategies for acquired epidermal growth factor receptor tyrosine kinase inhibitor resistance in non-small-cell lung cancer patients” by Lijun Dong, Dan Lei, and Haijun Zhang.

Read more about lung cancer on Oncotarget.com.

Oncotarget is a unique platform designed to house scientific studies in a journal format that is available for anyone to read—without a paywall making access more difficult. This means information that has the potential to benefit our societies from the inside out can be shared with friends, neighbors, colleagues and other researchers, far and wide.