Tagged: Trending With Impact

Oncotarget

Trending with Impact: Novel MicroRNA Underexpressed in Lung Cancer

February 4, 2021

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.

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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.

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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.

For media inquiries, please contact media@impactjournals.com.

Oncotarget

Trending with Impact: New Plant Extracts Reveal Anti-aging Properties

January 29, 2021

In search of natural compounds with previously unknown geroprotective properties, researchers used a strain of budding yeast to test 53 plant extracts for their ability to impact the biology of aging and age-related diseases.

Scientist is sampling a chemical extract from organic natural, research and develop background. Scientific concept is sample project about herbal medicine.

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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As we age, humans are subjected to a wide variety of age-related diseases, such as arthritis, diabetes, heart disease, kidney disease, liver dysfunction, sarcopenia, stroke, neurodegenerative diseases, and many forms of cancer.

Plant extracts have been consumed for hundreds of years in dietary customs and used as traditional herbal medicines in China and in the Mediterranean. Some of these plant extracts are classified by government health agencies, such as Health Canada, as not only safe for human consumption but also as health-improving supplements with clinically proven benefits to human health. Researchers hypothesized that some of these plant extracts (PEs) may have geroprotective properties. A geroprotector is any compound capable of modulating the root cause of aging and age-related diseases to prolong lifespan in modeled organisms and animals. A couple of well-known potential geroprotectors include melatonin and metformin.

In their previous 2016 study, researchers from Concordia University and Idunn Technologies—both located in Quebec, Canada—screened thirty-five plant extracts and identified 6 as capable of prolonging the length of time a cell can survive, or its chronological lifespan (CLS), and delaying chronological aging in the wild type strain of Saccharomyces cerevisiae budding yeast. On a mission to uncover a new set of plant extracts with geroprotectivity, these same researchers conducted a larger screening of plant extracts in a 2020 study. 

“The objective of the present study was to search for previously unknown aging-delaying (geroprotective) PEs. To attain this objective, we conducted a new screen of many extracts from plants used in traditional Chinese and other herbal medicines or the Mediterranean and other diets.”

The Study

In this study, to learn more about new PEs and the mechanisms of aging and longevity, the researchers continued using the wild type strain of Saccharomyces cerevisiae budding yeast. They explained that S. cerevisiae has short and easily measurable replicative (number of times a cell can divide prior to senescence) and chronological lifespans, is completely sequenced, commercially available, and conducive to comprehensive molecular analyses.

Researchers tested 53 new plant extracts on chronologically aging S. cerevisiae budding yeast. The plant extracts were derived from fruits, berries, beans, herbs, flowers, roots, seeds, leaves, stems, whole plants, bulbs, buds, bark, skins, resin, aerial parts, mushroom bodies, and fermented rice.

“In a quest for previously unknown geroprotective natural chemicals, we used a robust cell viability assay to search for commercially available plant extracts that can substantially prolong the chronological lifespan of budding yeast.”

To determine geroprotectivity from these plant extracts, the researchers cultured, diluted, and fed the budding yeast with glucose. Then, after adding the new PEs, they performed a variety of tests and calculated measurements, including: chronological lifespan assay; oxygen consumption assay; plating assay; quantitative assay; fluorescence microscopy; measurements of the frequencies of spontaneous mutations; glucose concentration measurement assay; age-specific mortality rates; the Gompertz slope; the mortality rate coefficient; and mortality rate doubling time.

Results

“We discovered fifteen PEs that extend the longevity of chronologically aging budding yeast.”

The team was able to identify 15 new geroprotective PEs that have not previously been known for their ability to prolong the lifespan of yeast or other organisms. Based on the results of their measurements and assays, the researchers also identified the cellular processes that these PEs engaged in to prolong the yeast’s chronological lifespan.

“Our study provides evidence that each of the fifteen longevity-extending PEs satisfies all the criteria previously proposed for a CRM.”

CR stands for caloric restriction and CRM stands for caloric restriction mimetics. This means that these new PEs were found capable of mimicking the substantial anti-aging effects that calorie restriction has on organisms and animals, without a reduction in calorie intake.

“Each of the fifteen PEs extends the longevity of chronologically aging yeast under non-CR conditions on 2% (w/v) glucose significantly more efficiently than it does under CR conditions on 0.5% (w/v) glucose.”

They found that the PEs extended the longevity of chronologically aging yeast by decreasing the rate of aging, stimulating a hormetic stress response, intensifying mitochondrial respiration, altering the pattern of age-related changes in intracellular reactive oxygen species, and increasing cell resistance to long-term oxidative and thermal stresses.

“Each of the fifteen geroprotective PEs decreases the extent of age-related oxidative damage to cellular proteins, and many of them slow the aging-associated buildup of oxidatively impaired membrane lipids as well as mitochondrial and nuclear DNA.”

In addition to many more findings, the effects of 15 PEs were found to decrease the frequency of mitochondrial DNA mutations in rib2 and rib3 proteins under non-calorie restricted conditions in S. cerevisiae.

Conclusion

The 15 plant extracts in this study that were newly discovered as geroprotective are as follows: berry extract from a small palm commonly known as Saw Palmetto, extract of the aerial parts from a flowering plant commonly known as the St. John’s Wort, extract from the leaf of Yerba Mate, whole plant extract of Yerba Mate, extract from the leaf of Holy Basil Tulsi, extract from the herb of the perennial plant Solidago Virgaurea, Orange fruit extract, whole plant extract from the common Hop (used in beer), Grape skin extract, whole plant extract from the Green Chiretta, root extract from the perennial Goldenseal herb, Fenugreek seed extract, Barberry root bark extract, extract from the leaf, flower, and stem of the common Hawthorn, and leaf extract from the Red-seeded Dandelion.

“Therefore, we are interested in investigating how different combinations of the fifteen geroprotective PEs described here influence the extent of yeast chronological aging delay. We will be looking for the combinations of geroprotective PEs that exhibit synergistic or additive effects on the extent of yeast chronological aging delay.”

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

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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.

For media inquiries, please contact media@impactjournals.com.

Oncotarget

Trending with Impact: Bacterial Therapy Experiments in Prostate Cancer

January 21, 2021

Researchers reveal their positive findings from a study of bacterial cancer therapy using a strain of Salmonella typhimurium in mouse-modeled prostate cancer.

PC-3 human prostate cancer cells stained with blue Coomassie, under a differential interference contrast microscope. - Image
PC-3 human prostate cancer cells stained with blue Coomassie, under a differential interference contrast microscope.

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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Listen to an audio version of this article

Over the past few decades, numerous studies have emerged using the promising strategy of bacteria as vehicles to deliver drugs or genes in tumor‐targeted therapies. Researchers say that bacterial cancer therapy may be able to overcome some of the limitations that conventional cancer therapy is stunted by, including the development of drug resistance. 

Researchers in this study—from Yale University in Connecticut, the University of Missouri, the Harry S. Truman Memorial Veterans Hospital, and the Cancer Research Center in Missouri, and DeSales University in Pennsylvania, U.S.—used a Salmonella typhimurium strain (CRC2631) of bacteria (previously reported to have tumor-targeting capabilities) in prostate cancer-positive mouse-models and evaluated its toxicity, targeting ability, and genetic stability.

“Here, we report the toxicological and in vivo tumor-targeting profiles of CRC2631 in the syngeneic and autochthonous mouse model of aggressive prostate cancer, TRAMP (Transgenic Adenocarcinoma of Mouse Prostate).”

“The B6FVB TRAMP model recapitulates some of the key genetic aspects of human prostate cancer.”

The Study

“VNP20009 is considered as the safety benchmark in bacterial cancer therapy development because it has been safely administered in human cancer patients [7, 30].”

“To determine the safety profile of CRC2631, we performed CRC2631 and VNP20009 comparative toxicological studies in TRAMP animals.”

The team focused on measuring toxicity through treatment-related weight loss and lethality. Groups of 14-week-old B6FVB TRAMP-positive mice were scanned using magnetic resonance imaging. Four mice were dosed with CRC2631, and four were dosed with VNP20009; both treated four times per week. Mice were weighed and monitored daily for four weeks.

Since the CRC2631 bacteria are cleared out through the liver, the researchers also sought to establish the impact of CRC2631 on liver pathology in this bacterial cancer therapy. Two groups of 31-week-old B6FVB TRAMP-positive mice were observed, one treated with four doses of CRC2631 and the other with saline (the control group) at three-day intervals. They used histological staining in the liver to observe differences in necrosis, inflammation, and extramedullary hematopoiesis between CRC2631 and the control group. The team then tested for lethality and the maximum tolerated dose of CRC2631.

“Next, we sought to determine the in vivo tumor-targeting capability of CRC2631 in TRAMP animals.”

Using fluorescence imaging and a chloramphenicol resistance cassette, researchers were able to observe the biodistribution of CRC2631 to determine its tumor-targeting capability in TRAMP-positive mice. Since they knew that CRC2631 is filtered through the liver and that enriched colonies may be found here, researchers used the liver as a way to compare the bacterial load in tumor tissues.

The researchers also tested CRC2631’s genetic stability by gauging its likelihood of regaining toxicity and/or losing tumor targeting capability by performing longitudinal, whole genome sequencing and short nucleotide polymorphism analyses.

“To determine the genetic stability of CRC2631 inside the host, we performed longitudinal whole genome sequencing and short nucleotide polymorphism (SNP) analyses of CRC2631 prior to treatment and tumor-passaged CRC2631 in B6 TRAMP (+) mice.”

In vitro, CRC2631 directly kills prostate cancer cells, however, in vivo, it does not lead to decreased tumor burden. The researchers believe this may be due to the effects of some kind of resistance mechanism in vivo, and tested a combined treatment method of CRC2631 and Invivomab—a checkpoint blockade—in the mouse model.

“CRC2631 targets and directly kills murine and human prostate cancer cells in vitro (Supplementary Figure 2), raising the possibility that unknown resistance mechanisms protect tumor cells from CRC2631-mediated cell death in vivo.”

Results

Researchers explain that in the first two weeks of the study, mice treated with CRC2631 and VNP20009 lost a comparable amount of weight. However, in the second half of the study, VNP20009-treated animals lost progressively more weight than those treated with CRC2631. This revealed that CRC2631 is less toxic than VNP20009.

“Consistent with CRC2631 being less toxic than VNP20009, the median survival time was 142 days for VNP20009 compared to 186 days for CRC2631 (Figure 1F).”

After evaluating effects in the liver from CRC2631, they found no differences between CRC2631 and the control group in liver necrosis, inflammation, or extramedullary hematopoiesis.

“Thus, in contrast to VNP20009, CRC2631 does not cause overt liver pathology.”

They established the maximum tolerated dose to be two doses of 5 × 10^7 colony forming units, administered three days apart. In the model used in fluorescence imaging, they found that CRC2631 was significantly colonized in the tumor tissue of mice when compared to colonization in the liver and, as the dosage increased, CRC2631 quantities in tumor tissues also increased.

“Taken together, these data indicate that CRC2631^iRFP720-cat targets primary tumors and metastases.”

Researchers revealed that it would take approximately 9375 days for CRC2631 to acquire a potential mutation in any specific gene. They determined CRC2631 to be a genetically stable tumor-targeting mechanism. Next, they collected results from the CRC2631 and Invivomab immune checkpoint blockade combination.

“We turned our focus to an interaction between CRC2631 and immune cells and asked whether tumor-targeted CRC2631 generates an anti-tumor immune response that tumors rapidly inhibit via immune checkpoint mechanisms.”

They found that tumor burdens were significantly reduced in the combination treatment method, and ultimately, that CRC2631 treatment with a checkpoint blockade combination reduces the metastatic burden in mouse-modeled prostate cancer.

Conclusion

The study as a whole revealed to the researchers that CRC2631 safely targets primary tumors and metastases, is less toxic than VNP20009, does not cause overt liver pathology, and that, in combination with an immune checkpoint blockade such as Invivomab, it reduces metastatic burden in vivo in B6FVB TRAMP-positive mice.

“These findings indicate that CRC2631 is a genetically stable biologic that safely targets tumors. Moreover, tumor-targeted CRC2631 induces anti-tumor immune activity and concordantly reduces metastasis burden in the setting of checkpoint blockade.”

With more research, this method may soon be studied as an effective clinical treatment option for human prostate cancer.

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

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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.

For media inquiries, please contact media@impactjournals.com.

Oncotarget

Trending with Impact: RNA-Seq Analyses Show Targets in B-cell Lymphoma

January 14, 2021

“The current study is the first of its kind, wherein comprehensive transcriptome analysis using RNA-Seq was performed in Notch2 depleted B-cell lymphoma cells.”

Malignant effusion cytology: microscopic image of diffuse large B-cell lymphoma, a type of non Hodgkin lymphoma.
Malignant effusion cytology: microscopic image of diffuse large B-cell lymphoma, a type of non Hodgkin lymphoma.

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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Listen to an audio version of this article

Splenic marginal zone lymphoma (SMZL) is a rare subtype of non-Hodgkin lymphoma that comprises approximately 10% of all lymphoma cases. Marginal zone lymphomas (MZL) originate from B memory lymphocytes (B-cells) in the marginal zone of secondary lymphoid follicles within the spleen, bone marrow, and blood.

Due to the rarity of SMZL, no randomized trials have yet been reported—only retrospective studies and some prospective studies have been conducted. The irregularity of frequency and the indolent nature of this disease makes SMZL a challenge for doctors to determine a standardized care or treatment plan other than intervention by splenectomy.

Bringing with it great potential, researchers have found that a pivotal gene is mutated in SMZL: the Notch2 gene. The abnormal signaling and increased expression in Notch2 has been observed in a number of cancers, including MZL, chronic lymphocytic leukemia, breast cancer, non-small cell lung cancer, pancreatic cancer, hepatocellular carcinoma, colorectal cancer, bladder cancer, medulloblastoma, and glioblastoma.

“A wide range of Notch2 mutations have been identified with relevance to different cancers, but the role of Notch2 and its downstream pathways in development of B-cell lymphoma has not been comprehensively studied to date.”

Researchers from the School of Biotechnology and Genetic Engineering at Bharathiar University in Coimbatore, India, conducted a study of RNA sequencing analyses to reveal the differentially expressed genes and pathways as Notch2 targets in B-cell lymphoma.

Whole Transcriptome Analysis

The researchers in this study explain that transcriptome analysis and RNA sequencing (RNA-Seq) provided them the opportunity to deeply and unbiasedly screen for the molecular changes that occur in Notch2 deregulated B-cells and to identify the genes and pathways downstream from it as potential targets.

“RNA-Seq is a more sensitive technology than expression profiling analysis using arrays, due to their low sensitivity and cross-hybridization of probes and targets [34]. “

In order to deregulate, or knockdown, Notch2 expression, the researchers employed short, or small, hairpin RNAs (shRNAs). shRNAs are artificially created RNA molecules that can be used to silence target gene expression (Notch2, in this case) via RNA interference.

“To determine the efficacy of Notch2-shRNA in reducing the intracellular levels of Notch2, we treated A549 (lung cancer) and SSK-41 cells (B-cell lymphoma) with viral supernatants of two different shRNA constructs in a lentiviral vector targeting Notch2.” 

“The current study is the first of its kind, wherein comprehensive transcriptome analysis using RNA-Seq was performed in Notch2 depleted B-cell lymphoma cells.”

The Study

 “In the present study, whole transcriptome analysis was performed in B-cells, where Notch2 expression is knocked down using Notch2-shRNA and compared with control scramble-shRNA treated cells.”

In their first step, the researchers identified a total of 15,083 differentially expressed genes and 1067 differentially expressed transcripts in control and Notch2-shRNA treated samples. They used a condition tree, correlation matrix, and principal component analysis test to measure significant reproducibility, similarity, and distance between the treated and untreated group. 

In their second step, a gene enrichment analysis was performed in the differentially expressed genes using the DAVID tool. This resulted in the identification of 208 unique gene ontology (GO) categories and pathways.

Results

“Among the 208 GO categories, 31 pathways were significantly enriched in biological processes (BP), 3 pathways were significantly enriched in cellular components (CC) and 18 pathways were significantly enriched in molecular functions (MF).”

The researchers state that the significantly enriched terms they found could help with further understanding which differentially expressed genes and differentially expressed transcripts play causative roles in the onset of B-cell lymphoma.

“The RNA-Seq and bioinformatics technology revealed notable information regarding gene expression at the transcriptome level and identified multiple significant molecular pathways in response to knockdown of Notch2.”

Figure 9: Pathway analysis. Gene regulatory network analysis for DEGs upon Notch2 knockdown were predicted by Pathreg algorithm and visualized in Cytoscape v2.8.2. Predicted pathways are depicted as rounded rectangles, where shades in red correspond to upregulated genes and shades in green correspond to downregulated genes.
Figure 9: Pathway analysis. Gene regulatory network analysis for differentially expressed genes upon Notch2 knockdown were predicted by Pathreg algorithm and visualized in Cytoscape v2.8.2. Predicted pathways are depicted as rounded rectangles, where shades in red correspond to upregulated genes and shades in green correspond to downregulated genes.

“The results of our gene network analysis suggest that, knockdown of Notch2 modulates multiple important cellular pathways, including immune-related pathways, apoptotic related pathway, PI3K/AKT, BCR, mTOR, VEGF, Wnt and Ca2+ signaling pathways.”

Conclusion

The authors note that the NF-kB signaling pathway is a major pathway that leads to cell survival with the ability to “cross-talk” with other survival pathways, including PI3K/AKT, in various cancers.

“Since activation of PI3K/AKT pathway is known to promote cell proliferation, cell survival, growth and angiogenesis in cancers [40], it is important to know if Notch2 propels cancer progression through activation of this pathway. “

However, the researchers mention that the exact mechanism that Notch2 regulates NF-kB activity through the activation of PI3K/AKT and inhibits apoptosis in B-cell lymphoma still need to be determined. 

“Nevertheless, establishing the role of PI3K/AKT pathway in Notch2 activated cancers could be very important to consider it as an alternative treatment target in mitigating the effects of Notch2 transactivity in these cancers.” 

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

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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.

For media inquiries, please contact media@impactjournals.com.

Oncotarget

Trending with Impact: Nimotuzumab Improves Non-HPV Oropharynx Cancers

January 7, 2021

Researchers perform a subgroup analysis study demonstrating positive results in patients with HPV-negative oropharyngeal cancers due to the addition of nimotuzumab while receiving cisplatin and radiation treatment.

An image depicting the nasopharynx, pharynx, and the oropharynx.
An image depicting the nasopharynx, pharynx, and the oropharynx.

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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Oral cancer in any part of the oropharynx (the back-third of the tongue, tonsils, soft palate, and back and sides of the throat) is called oropharyngeal cancer. Each year, oral cancer accounts for around 53,000 new patient diagnoses in the United States. However, the highest number of cases of oral cancer in the world are found in India, and this number is increasing.

“As opposed to HPV related oropharyngeal cancer, HPV negative oropharyngeal cancers have worse prognosis.”

Researchers from Tata Memorial Hospital and Tata Memorial Centre in Mumbai, India, previously reported that in a phase three randomized study of an epidermal growth factor receptor inhibitor medication and, called cetuximab, showed a trend towards improvement when used in patients with locally advanced head and neck cancers. Compared with results in other similar studies, they believe their results were likely due to a younger cohort of patients with predominantly HPV negative diseases.

“Taking this into consideration, we decided to perform a subgroup analysis of the HPV negative oropharyngeal cancer cohort, to study the absolute improvement in 2-year outcomes with the addition of nimotuzumab. We compared 2 year progression free survival (PFS), disease free survival (DFS), locoregional control (LRC) and overall survival (OS) between both arms.”

The Study

“HPV negative oropharyngeal cancer has unsatisfactory treatment outcomes and is a candidate for escalation of treatment. We wanted to determine whether the addition of nimotuzumab to cisplatin-radiation could improve outcomes in these poor-risk tumors.”

In this study, the researchers gathered 536 patients undergoing definitive chemoradiation for locally advanced head and neck cancers, with 269 having a primary tumor located in the oropharynx. Of these patients, 187 were p16 protein negative and were divided into two treatment arms: 91 in the cisplatin-radiotherapy (CRT) treatment arm and 97 in the nimotuzumab-cisplatin-radiotherapy (NCRT) treatment arm. Nimotuzumab is an antibody that binds to epidermal growth factor receptor IgG1 and a radiosensitizer.

The cohort consisted of only 21 females, therefore the participants were primarily male, with a median age of 54.5, 90% reported tobacco use, and 80% were in disease stage IV. Patients in the CRT treatment arm were given 30mg/m2 of cisplatin weekly, in addition to radiation therapy. In the NCRT treatment arm, in addition to radiation therapy, patients received 200 mg of nimotuzumab and 30 mg/m2 cisplatin weekly. 

Results

Researchers found that the HPV positive/negative interaction test using immunohistochemistry staining taken by each participant was a significant determinant in progression free survival, locoregional control, and overall survival, but not in disease free survival. They suggest this data shows that the addition of nimotuzumab has a differential patient impact on disease free survival with respect to HPV status.

In patients taking nimotuzumab, improvement in locoregional control was largely responsible for their improvement in progression free survival. On average, time to locoregional failure in the CRT treatment arm was 17.3 months, and in the NCRT treatment arm, it was 60.3 months. The team also found that the addition of nimotuzumab led to an 18.6% improvement in 2-year overall survival, jumping from 39.0% to 57.6%.

Figure 4: Restricted mean overall survival plots of both arms. arm = 0 represents the plot of the cisplatin radiotherapy arm while arm = 1 represents the plot of the Nimotuzumab-cisplatin radiotherapy arm.
Figure 4: Restricted mean overall survival plots of both arms. arm = 0 represents the plot of the cisplatin radiotherapy arm while arm = 1 represents the plot of the Nimotuzumab-cisplatin radiotherapy arm.

“Locoregional control, progression-free survival and overall survival were improved with the addition of nimotuzumab to cisplatin and radiation.”

Conclusion

“The addition of nimotuzumab to weekly cisplatin-radiation improves outcomes inclusive of OS in HPV negative oropharyngeal cancers.”

“The results of the current study clarify the importance of treatment intensification in HPV negative oropharyngeal cancers.”

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

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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.

For media inquiries, please contact media@impactjournals.com.

Oncotarget

Trending with Impact: Review of HER2 Variants in Breast Cancer Tumors

December 31, 2020

This review compiles splice variations in HER2 breast cancer, specifically in the context of the tumor environment, and co-expression of variants. The study also provides an up-to-date (as of Nov. 2020) account of HER2 and HER2 variant patterns of resistance to anti-HER2 therapies and other interventions.

Photomicrograph of immunohistochemistry for HER2, showing positive cell membrane staining in this infiltrating ductal carcinoma
Photomicrograph of immunohistochemistry for HER2, showing positive cell membrane staining in this infiltrating ductal 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.

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According to Cancer Research UK, breast cancer occurs in one in every eight women within their lifetime and is the second highest cause of cancer related deaths in the UK. Breast cancer is a blanketed term for a wide variety of tumors that occur in the mammary glands. In over 20% of breast cancers, the human epidermal growth factor receptor two gene, officially named ErbB2 but otherwise known as HER2, is overexpressed. HER2 is a member of the epidermal growth factor receptor family of EGFR, HER2, HER3, and HER4. Overexpression of the HER2 protein was discovered in 1987 as a biomarker associated with poor prognosis and aggressive tumor types in breast cancer. This finding has accelerated research studies and progress in HER2 diagnostic testing and targeted therapeutics. However, the issue of HER2 resistance in these targeted therapies remains problematic.

“At the present time, we have an incomplete understanding of why patients with HER2+ breast cancer exhibit variable responses or resistance to targeted therapies [73, 74].”

Researchers from the Translational and Clinical Research Institute at Newcastle University in the United Kingdom have compiled a review of variations in HER2 breast cancer, specifically in the context of the tumor environment and when multiple variants are co-expressed at altered ratios. Their study also provides an up-to-date (as of Nov. 2020) account of the current landscape of HER2 variants and links this to patterns of resistance against HER2 therapies and other interventions.

“It is clear HER2 expression is not as simple as a single oncogenic overexpressed protein. It is likely many variants, arising from splicing and other mechanisms, are present in tandem. The relative ratios of these are likely to fluctuate depending on cellular conditions, during tumorigenesis and breast cancer progression.”

HER2 Variants & Co-expression

This paper provides an exquisitely detailed description and explanation of the HER2 protein structure, signaling pathways, sub-typing, and in-depth treatment functionality of a number of different HER2 targeted therapeutics. 

“Different forms of the HER2 protein exist within tumours in tandem and can display altered biological activities.” 

The unique interest in researching variations in HER2 breast cancer has increased since the identification of Δ16-HER2: a particular splice variant and link to resistance of anti-HER2 therapies. The “Δ16” in Δ16-HER2 refers to the lack of exon-16, which encodes a small extracellular portion of the DNA. Δ16-HER2 represents approximately 9% of the normal HER2 transcripts and its expression is considered common in breast cancer. Previous studies have identified Δ16-HER2 and HER2 normal transcripts can be co-expressed at varying levels in breast carcinomas. 

In the variant P100, less is known about this truncated HER2 protein. It has been hypothesized that P100 reduces the efficacy of monoclonal antibody HER2 treatments.

The splice variant Herstatin is produced by the retention of intron-8 in the HER2 protein. Herstatin acts as a tumor suppressor by blocking HER2 activity and cell proliferation, while promoting apoptosis. The researchers mention that it is important to note that cells expressing high levels of Herstatin are more sensitive to Tamoxifen.

“It’s noteworthy that one study proposed that the presence of Herstatin transcript does not segregate by tumour grade or size, patient age, lymph node involvement or ER status and that mRNA transcripts were present in matched non-cancerous breast tissue and breast carcinomas [96].”

Researchers in this review note that identifying and assessing the expression ratios of these different variants and classifying them as prognostic and predictive biomarkers may aid in further personalized treatment of breast cancer in HER2 positive patients.

Testing and Research Landscape

“Studying splicing regulation and how this is altered in breast cancer could explain patterns of expression and how these link to treatment resistance [111].”

The researchers write that tests assessing for both HER2 status and HER2 variant expression could potentially refine their predictions of a patients’ response to treatment. One common way that researchers gauge levels of HER2 proteins, and only some HER2 variants, is through immunohistochemistry tests. mRNA assessments are also used to identify gene expression patterns. Another biomarker test the researchers noted that may be best used for prognostic predictions is the Enzyme-Immunoassay—to assess levels of plasma or serum HER2 (sHER2) in the blood produced by cleavage or splicing.

“Cohort studies have identified sHER2 testing as a useful complementary test to IHC owing to the correlations between high sHER2 and aggressive tumour phenotypes such as invasion and metastases.”

Targeted HER2 Treatments

The review elaborates in detail about targeted treatments for HER2 breast cancer, which include: trastuzumab, pertuzumab, lapatinib, and T-DM1. They note that endocrine therapy is utilized for ER positive patients and chemotherapy, radiotherapy, and surgery are all still utilized.

Conclusion

“Work in vitro and in vivo as well as analysis from clinical trials has identified patterns of resistance to the standard of care treatment options in HER2+ patients which are correlated to variant expression.” 

This goal of their review was to summarise the current landscape of HER2 variant research and to explain why researchers should consider HER2 variant levels and ratios when offering the best treatment plan for breast cancer patients.

Click here to read the full review, published in Oncotarget.

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