Tagged: Oncology

Trending With Impact: Genes Identified in Endocrine Therapy Resistance

Researchers studied the dynamic behavior of gene expression during the development of endocrine therapy resistance in breast cancer.

Figure 4: Tissue-specific protein-protein interaction network for modules 1 and 2 candidate genes.
Figure 4: Tissue-specific protein-protein interaction network for modules 1 and 2 candidate genes.

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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Hormones can cause tumor growth in some subtypes of breast cancer. Endocrine therapy, also known as hormone therapy, is a type of cancer treatment that removes or blocks the hormones which fuel breast cancer growth. This treatment is often given as adjuvant therapy after breast cancer surgery to lower the risk of cancer reoccurrence. In some cases, endocrine therapy may be used as a first-line treatment for hormone receptor-positive breast cancers, such as estrogen receptor-positive (ER-positive) breast cancer. However, ER-positive tumors frequently become unresponsive to endocrine therapy, and tumor regrowth can occur after treatment. The underlying causes of endocrine resistance are mostly undetermined.

“Endocrine therapies have been successful at improving cancer outcomes; however, the development of endocrine resistance, or resistance to inhibition of ER actions, remains a roadblock in breast cancer treatment.”

Recently, researchers—from UTHealth HoustonUniversity of ChicagoUniversity of Texas MD Anderson Cancer Center, and the University of Houston—used a new statistical and computational pipeline method of analysis to study the dynamic behavior of gene expression during the development of endocrine resistance in breast cancer. Their trending research paper published in Oncotarget on April 06, 2022, is entitled, “A novel group of genes that cause endocrine resistance in breast cancer identified by dynamic gene expression analysis.”

The Pipeline

“In this study, we explored the dynamic behavior of the entire gene population to identify novel genes that play fundamental roles in the development and progression of endocrine-resistant breast cancer.” 

Pipeline analysis in biology is a method of studying and analyzing a group of genes or proteins in order to understand their structure and function. The pipeline can be used to determine gene dynamics, clusters, similarities, and networks. In this case, the researchers used it to understand how endocrine resistance develops over time.

“The pipeline provides three main functions. First, statistical hypothesis testing determines a set of dynamic response genes (DRGs) that exhibit significant changes over time. Next, these DRGs are clustered into gene response modules (GRMs), sets of DRGs with similar time course expression patterns. Finally, the GRMs associations and regulatory effect are analyzed as a gene regulatory network using ordinary differential equations.”

The Study

To begin this study, the researchers first aimed to select a cell-based model that represents endocrine resistance in patients as closely as possible. They gathered data from breast cancer patients who were either resistant or sensitive to endocrine therapies and compared them with publicly available gene expression data. Results showed that the LTED MCF7 cell model displayed similar endocrine resistance to patient tumor data.

Next, the researchers observed the development of endocrine therapy resistance in the LTED MCF7 cell model, as well as the changes in gene expression over time. This data was collected and used to develop a mathematical model of gene expression dynamics during endocrine therapy resistance development. After statistical and computational pipeline analysis, the team identified a group of 254 genes whose time course expression significantly changed during the development of endocrine therapy resistance. They then aimed to validate their findings and used multiple bioinformatics approaches to narrow down this group of candidate genes.

“To further refine the genes common to endocrine resistance development and progression, we utilized several bioinformatic approaches designated to rank and prioritize the 254 common genes.”

The Results

Candidate genes were narrowed down to a novel group of 34 genes whose time course expression most significantly changed during LTED MCF7 cell modeling of endocrine-resistant breast cancer development. In addition, microarray analysis also showed that a subset of these genes was differentially expressed in triple-negative breast cancer (TNBC). This suggests that there may be shared genetic mechanisms between endocrine-resistant breast cancer and TNBC.

“As these two subtypes of breast cancer are the most fatal breast cancers with no known effective therapeutic approaches available to date, research on underlying genetic factors is of great importance.”

Conclusion

Their analysis led to the identification of a novel group of 34 genes that may play a role in endocrine resistance. Interestingly, some of these genes were also differentially expressed in TNBC. These findings could potentially lead to the development of new therapeutic strategies to overcome endocrine therapy resistance in some of the most difficult to treat and fatal breast cancers.

“Our analysis identified novel candidate genes with potential significance in endocrine-resistant breast cancer as well as TNBC, which opens new doors for designing novel therapeutic approaches for endocrine-resistant breast cancer and TNBC.”

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

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Oncotarget is an open-access journal that publishes primarily oncology-focused research papers in a continuous publishing format. These papers are available at no cost to readers on Oncotarget.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.

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Novel Therapeutic Strategies Against Endometrial Cancer

In a new study, researchers investigated the role of the (pro)renin receptor in endometrial cancer cell growth.

In a new study, researchers investigated the role of the (pro)renin receptor in endometrial cancer cell growth.
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In the United States and worldwide, the incidence and mortality rates of endometrial cancer among women have been increasing in recent years. While endometrial cancer is highly treatable, the primary treatment is a surgical hysterectomy. Hysterectomies can have serious side effects and painful personal consequences.

The rise of this gynecological cancer has driven researchers to investigate viable targets and biomarkers for use in endometrial cancer diagnosis, prognosis prediction and alternative therapeutic strategies. In a new study, researchers—from the University of NewcastleUniversity of Technology SydneyMonash University, and the University of Melbourne—investigated the (pro)renin receptor ((P)RR) and its role and interactions in the biology of endometrial cancer. Their trending research paper, published in Oncotarget on April 1, 2022, was entitled, “Role of the prorenin receptor in endometrial cancer cell growth.”

The Study

The ATPase H(+)-transporting lysosomal accessory protein 2 (ATP6AP2) gene encodes the (P)RR, and the terms can be used interchangeably. The (P)RR is a membrane protein that plays a key role in activating the renin-angiotensin system (RAS). It is widely expressed in various tissues and organs, such as the kidney, heart, lung, and endometrium. In endometrial cancer, the (P)RR has been shown to be overexpressed in cancerous tissue compared to normal endometrium tissue. Expression levels of this receptor are associated with endometrial cancer progression and poor prognosis. However, the precise role of the (P)RR in endometrial cancer has remained largely unknown.

In this in vitro analysis, the researchers first conducted a proteomic screening of the ATP6AP2 protein and mRNA expression in three endometrial cancer cell lines: Ishikawa, AN3CA and HEC-1-A. To silence (P)RR expression in each of the three cell lines, the team employed an siRNA-mediated knockdown of ATP6AP2. Next, they used an xCELLigence RTCA DP instrument that measures cell invasion and migration to evaluate the impact of (P)RR knockdown on cellular proliferation. They then used a resazurin assay to examine the effects of (P)RR knockdown on cancer cell viability.

A proteomic screening was also carried out to explore potential pathways (P)RR is involved in in the physiology of endometrial cancer. In addition, the enzyme-linked immunosorbent assay (ELISA) was used to measure circulating soluble prorenin receptor (s(P)RR) levels in the endometrial cancer cell lines (before and after the knockdown of (P)RR expression) and in plasma and uterine fluid samples donated by endometrial cancer patients.

The Results

This study was the first to report the mRNA and protein expression of (P)RR in three endometrial epithelial cancer cell lines. The results showed that the (P)RR was critical for endometrial cancer cell growth—contributing both to its cell viability and proliferative capacity. However, the data confirmed their previous observations that (P)RR mRNA and protein levels do not correlate with tumor grade in primary endometrial tumor samples. The researchers stated that the (P)RR’s contribution to endometrial cancer progression is likely mediated through proteins reduced after (P)RR expression knockdown, such as MGA, SLC4A7, SLC7A11, or DHRS2.

“Notably, (P)RR mRNA and protein levels were independent of tumour grade, with the highest expression detected in Ishikawa cells (grade 1), followed by AN3CA cells (grade 3) and finally HEC-1-A cells (grade 2).

They also observed that s(P)RR levels in their plasma samples were significantly higher in patients with endometrial cancer than in age-matched controls. Intriguingly, as cancer grade increased, so did s(P)RR levels. This indicated that s(P)RR may be a viable predictive or diagnostic marker for patients with endometrial cancer.

“Our data confirms that the (P)RR is important for endometrial cancer development, contributing to both its viability and proliferative capacity. Moreover, our quantitative proteomics approach uncovered several putative protein interactions and pathways that rely on (P)RR for disease progression and may represent novel therapeutic targets in the treatment of endometrial cancer. Finally, we contend that circulating s(P)RR levels may have substantial potential as a novel biomarker for cancer diagnosis and prognosis.”

Conclusion

This study sheds new light on the role of the (P)RR in endometrial cancer. The researchers suggest that future studies should aim to vet their findings in endometrial cancer patients.

“Collectively, our data indicate that targeting the (P)RR by an siRNA approach (such as in this study) or with an alternative anti-(P)RR monoclonal antibody approach currently being explored by Wang et al. [29] may be a viable therapeutic strategy against endometrial cancer.”

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

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Oncotarget is an open-access journal that publishes primarily oncology-focused research papers in a continuous publishing format. These papers are available at no cost to readers on Oncotarget.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.

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

A Remote Weight Loss Strategy for Breast Cancer Survivors

Researchers Jennifer Y. Sheng and Vered Stearns discussed the results of a study that compared weight loss interventions among overweight or obese survivors of breast cancer.

Weight loss for survivors of breast cancer
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After being diagnosed with breast cancer, up to 96% of women have reported gaining weight. Medications, inactivity, food choice, and food quantity can all lead to weight gain. Studies have shown that weight gain can increase the risk of breast cancer recurrence by 40–50% and breast cancer-related mortality by 53–60%. Thus, for women with breast cancer and those who have survived breast cancer, weight management is a potentially life-saving intervention.

In an editorial paper published by Oncotarget in 2021, researchers Jennifer Y. Sheng and Vered Stearns from Johns Hopkins School of Medicine and the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center discussed the results of the 2020 POWER-Remote Trial—a study among breast cancer survivors on the results of a remote-based weight loss program compared with a self-directed approach. Their editorial paper is entitled, “Innovating and expanding weight loss strategies for breast cancer survivors.”

The POWER Intervention

The Practice-based Opportunities for Weight Reduction (POWER) intervention is a 12-week behavioral weight loss program designed for overweight and obese participants. The POWER program strategy focuses on physical activity and behavioral changes, nutrition education and setting individual goals. Researchers developed the POWER-remote intervention to enable participants to engage in this weight loss program remotely through weekly video conferences and phone calls. In the current editorial paper, the researchers discussed the results from a study that adapted the POWER-remote intervention for breast cancer survivors: the POWER-Remote Trial.

“The original Practice-based Opportunities for Weight Reduction (POWER) study in obese individuals with a risk for cardiovascular disease demonstrated equivalent weight loss outcomes between in-person coaching and a remote intervention [24].”

The POWER-Remote Trial

The POWER-Remote Trial was a randomized, controlled comparative effectiveness trial that evaluated the POWER-remote intervention compared to a self-directed weight loss approach among overweight or obese breast cancer survivors. Between 2013 and 2015, 87 overweight or obese women with stage 0-III breast cancer (who completed local therapy and chemotherapy) were evaluable for analysis in this study. Forty-five women were enrolled in the POWER-remote arm of the study and 42 women were enrolled in the self-directed arm.

“Our group compared the remote-based POWER intervention (telephone calls by a coach, access to online learning materials, online self-directed dietary/activity monitoring) to self-directed weight loss in overweight or obese survivors of early-stage breast cancer [25].”

Over the course of the study, the researchers found high adherence in the POWER-remote arm, with only one participant lost in follow-up. At the 12-month mark, 51% of the POWER-remote participants lost greater than or equal to 5% of their baseline body weight. Among the self-directed participants, 17% lost 5% or more of their baseline body weight. The results of this study suggest that the POWER-remote intervention is an effective weight loss strategy. It is a cost-effective, scalable and conscientious solution to assist with weight loss among many breast cancer survivors.

Conclusion

Despite the significant improvements in weight, body composition, fitness, and quality of life seen by over half of the participants in the POWER-remote arm, the researchers also pointed out a problem. The POWER-remote intervention still did not yield significant results in almost half of the other participants. Trouble sleeping was shown as a potential culprit that hindered weight loss, while many other factors inhibiting weight loss in this population are not yet fully understood.

The authors wrote that it may be necessary to further individualize or enhance the POWER intervention to achieve greater success in breast cancer survivors. They also suggested that, in some people, the POWER program may need to be augmented with pharmacological agents to aid in weight loss. In addition, the authors believe that the payer system should be reevaluated to expand coverage for obesity treatments.

“At present, I’m conducting a phase two study to determine whether an adaptor approach with pharmacotherapy can augment obesity treatment in breast cancer survivors. This study is called the A-NEW study, which stands for an Adaptive Nutrition and Exercise Weight Loss Study,” Dr. Jennifer Sheng said in a recent Behind the Study interview with Oncotarget. “We’re also looking forward to analyzing results from the COOIN study, the Cancer, Obesity, Overweight, and Insomnia study, which was led by Dr. Janelle Coughlin.”

Click here to read the full editorial paper published by Oncotarget.

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Scientific Integrity

Trending With Impact: Are NOTCH1 Variants Prognostic in Breast Cancer?

Researchers determined the prognostic ability of three NOTCH1 gene variants by incorporating them into two non-tumorigenic breast cell lines.

Breast cancer illustration
Breast cancer illustration

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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The genetic changes that occur within the protein-coding gene NOTCH1 have not yet been fully studied or classified. Despite a lack in research, previous studies have suggested that NOTCH1 may be a potential target for novel cancer therapies, particularly against triple-negative breast cancer (TNBC). NOTCH1 variants in TNBC tend to cluster in the PEST region and have previously been linked to gamma secretase inhibitor (GSI) sensitivity and chemotherapy resistance.

“Furthermore, TNBC patients with increased Notch1 expression have demonstrated increased aggressive phenotypes and lower median overall survival [25].”

Since TNBC is well-known for a lack of actionable therapeutic targets, aggressive phenotypes and poor prognoses, there is an important need to develop new targeted therapies—as well as predictive markers for those therapies. Researchers from The Johns Hopkins University School of MedicineVanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center experimented in vitro with NOTCH1 variants and their ability to predict TNBC responsiveness to GSIs and standard of care chemotherapies. Their trending research paper was published by Oncotarget on February 16, 2022, and entitled, “NOTCH1 PEST domain variants are responsive to standard of care treatments despite distinct transformative properties in a breast cancer model.”

The Study

The researchers used three publicly available tumor-associated variant databases to identify three NOTCH1 variants that are commonly mutated in breast cancers; two variants were located in the A2441 site on NOTCH1 and the third variant was located in the PEST region of NOTCH1. To investigate the role of these NOTCH1 variants in TNBC in vitro, the team cultured two non-tumorigenic breast epithelial cell lines. Uniquely, they used an adeno-associated virus (AAV) vector to isogenically incorporate the NOTCH1 variants into the two cell lines. The researchers also developed a wildtype vector for the control arm of the study.

“In addition to the NOTCH1 variants, a targeted wildtype (TWT), which underwent the same gene targeting mechanism with a wildtype vector, was generated for both parental cell lines to act as a control.”

A standard growth factor supplemented media was used to determine if the NOTCH1 variants caused increased proliferation in the non-tumorigenic cell lines. Compared to the controls, no significant change in proliferation was observed. They also removed the epidermal growth factor (EGF) from the cells to determine if these NOTCH1 variants impart a ligand-independent proliferative advantage. In both cell lines, their results demonstrated that the A2441 variants exhibited EGF-independent growth, while the PEST NOTCH1 variant did not. Immunoblot analyses suggested that, in the absence of EGF, the A2441 NOTCH1 variants activated the MAPK pathway. These EGF-independent NOTCH1 variants (not the PEST NOTCH1 variant) conferred an invasive growth phenotype, increased migratory potential, had dysregulated 3D morphology, and significantly altered gene expression in cancer pathway genes.

Next, to measure the responsiveness and susceptibility of these variants to therapeutic agents, the cells were treated with six chemotherapeutic agents and nirogacestat—a GSI drug. Interestingly, none of the three variants demonstrated significantly different responses to the treatments when compared to one another. Furthermore, all of the variants showed sensitivity to these standard therapies used against TNBC. This suggests that these specific genetic changes within NOTCH do not have a large impact on tumor behavior and may not be useful as predictive markers for therapy response.

Conclusion

“Taken together, these data suggest that the oncogenic potential of NOTCH1 PEST domain variants depends on both variant type and amino acid location.”

Contrary to previous studies, the researchers found that the three NOTCH variants did not demonstrate significantly different responses to the GSI or the chemotherapies despite demonstrating distinct phenotypes. The lack of differential responses demonstrated by the variants in this study suggests that there is high variability among NOTCH1 variants. The prognostic potential of NOTCH1 may be dependent on the type of variant and its location, but more expansive research is necessary.

“Future studies involving meticulous characterization of an expansive panel of NOTCH1 variants in a similar model may provide mechanistic insight and predictive and/or prognostic value that is both variant type and site dependent.”

Click here to read the full research paper published by 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.

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Scientific Integrity

Oncotarget’s Top 10 Most-Viewed Papers in 2021

Read the 10 most-viewed oncology-focussed papers on Oncotarget.com in 2021.

Oncotarget's top 10 papers of 2021

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#10: Metformin and berberine, two versatile drugs in treatment of common metabolic diseases

Authors: Haoran Wang, Chen Zhu, Ying Ying, Lingyu Luo, Deqiang Huang, and Zhijun Luo

Institutions: The First Hospital of Nanchang University, Nanchang University and Boston University School of Medicine

Quote: “Metformin has been used as a glucose lowering drug for several centuries and is now a first-line drug for type 2 diabetes mellitus (T2DM). Since the discovery that it activates AMP-activated protein kinase (AMPK) and reduces risk of cancer, metformin has drawn great attentions. Another drug, berberine, extracted from berberis vulgaris L. (root), was an ancient herbal medicine in treating diarrhea.”


#9: Cell fusion as a link between the SARS-CoV-2 spike protein, COVID-19 complications, and vaccine side effects

Author: Yuri Lazebnik

Institution: Lerna Consulting

Quote: “A distinctive feature of the SARS-CoV-2 spike protein is its ability to efficiently fuse cells, thus producing syncytia found in COVID-19 patients. This commentary proposes how this ability enables spike to cause COVID-19 complications as well as side effects of COVID-19 vaccines, and suggests how these effects can be prevented.”


#8: Physical activity and telomere length: Impact of aging and potential mechanisms of action

Authors: Nicole C. Arsenis, Tongjian You, Elisa F. Ogawa, Grant M. Tinsley, and Li Zuo

Institutions: University of Massachusetts Boston, Texas Tech University and The Ohio State University College of Medicine

Quote: “Based on the significance of telomere length in aging and the need to understand the potential association with physical activity, the purpose of this systematic review is to investigate whether physical activity and exercise influence telomere length and to discuss possible mechanisms of action.”


#7: Hedgehog signaling induces PD-L1 expression and tumor cell proliferation in gastric cancer

Authors: Jayati Chakrabarti, Loryn Holokai, LiJyun Syu, Nina G. Steele, Julie Chang, Jiang Wang, Syed Ahmed, Andrzej Dlugosz, and Yana Zavros

Institutions: University of Cincinnati, University of Cincinnati College of Medicine, University of Cincinnati Cancer Institute, University of Michigan

Quote: “Tumor cells expressing programmed cell death ligand 1 (PD-L1) interact with PD-1 on CD8+ cytotoxic T lymphocytes (CTLs) to inhibit CTL effector function. In gastric cancer, the mechanism regulating PD-L1 is unclear. The Hedgehog (Hh) signaling pathway is reactivated in various cancers including gastric. Here we tested the hypothesis that Hh-induced PD-L1 inactivates effector T cell function and allows gastric cancer cell proliferation.”


#6: cGAS-STING pathway in oncogenesis and cancer therapeutics

Authors: Brandon Yi Da Hoong, Yunn Hwen Gan, Haiyan Liu, and Ee Sin Chen

Institutions: National University of Singapore and National University Health System (NUHS) Singapore

Quote: “The host innate immunity offers the first line of defense against infection. However, recent evidence shows that the host innate immunity is also critical in sensing the presence of cytoplasmic DNA derived from genomic instability events, such as DNA damage and defective cell cycle progression. This is achieved through the cyclic GMP-AMP synthase (cGAS)/Stimulator of interferon (IFN) genes (STING) pathway. Here we discuss recent insights into the regulation of this pathway in cancer immunosurveillance, and the downstream signaling cascades that coordinate immune cell recruitment to the tumor microenvironment to destroy transformed cells through cellular senescence or cell death programs.”


#5: Anti-aging: senolytics or gerostatics (unconventional view)

Author: Mikhail V. Blagosklonny

Institution: Roswell Park Cancer Institute

Quote: “Based on lessons of cancer therapy, here I suggest how to exploit oncogene-addiction and to combine drugs to achieve selectivity. However, even if selective senolytic combinations will be developed, there is little evidence that a few senescent cells are responsible for organismal aging. I also discuss gerostatics, such as rapamycin and other rapalogs, pan-mTOR inhibitors, dual PI3K/mTOR inhibitors, which inhibit growth- and aging-promoting pathways.”


#4: Melatonin increases overall survival of prostate cancer patients with poor prognosis after combined hormone radiation treatment

Authors: Gennady M. Zharinov, Oleg A. Bogomolov, Irina V. Chepurnaya, Natalia Yu. Neklasova, and Vladimir N. Anisimov

Institutions: N.N. Petrov National Medical Research Center of Oncology

Quote: “The antitumor and immunomodulating activities of melatonin are widely known. These activities are based upon the multifactorial mechanism of action on various links of carcinogenesis. In the present paper, the long-term results of the clinical use of melatonin in the combined treatment of patients with prostate cancer of various risk groups were evaluated.”


#3: Scent test using Caenorhabditis elegans to screen for early-stage pancreatic cancer

Authors: Ayumu Asai, Masamitsu Konno, Miyuki Ozaki, Koichi Kawamoto, Ryota Chijimatsu, Nobuaki Kondo, Takaaki Hirotsu, and Hideshi Ishii

Institutions: Osaka University and Hirotsu Bio Science Inc.

Quote: “Although early detection and diagnosis are indispensable for improving the prognosis of patients with pancreatic cancer, both have yet to be achieved. Except for pancreatic cancer, other cancers have already been screened through scent tests using animals or microorganisms, including Caenorhabditis elegans.”


#2: Inflammatory responses and inflammation-associated diseases in organs

Authors: Linlin Chen, Huidan Deng, Hengmin Cui, Jing Fang, Zhicai Zuo, Junliang Deng, Yinglun, Xun Wang, and Ling Zhao

Institution: Sichuan Agricultural University

Quote: “Here, we review inflammatory responses within organs, focusing on the etiology of inflammation, inflammatory response mechanisms, resolution of inflammation, and organ-specific inflammatory responses.”


#1: The goal of geroscience is life extension

Author: Mikhail V. Blagosklonny

Institution: Roswell Park Cancer Institute

Quote: “Although numerous drugs seemingly extend healthspan in mice, only a few extend lifespan in mice and only one does it consistently. Some of them, alone or in combination, can be used in humans, without further clinical trials.”


Click here to read the latest papers published by Oncotarget in Volume 13.

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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.

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Scientific Integrity

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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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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Scientific Integrity

New Study: Vaccine Enhances Breast Cancer Treatment

Researchers conducted a study to examine the efficacy of adding the P10s-PADRE vaccine to chemotherapy treatments for patients with HR+/HER2− breast cancer.

Cancer vaccine
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The most common type of breast cancer in the United States is HR+/HER2− breast cancer. Patients with HR+/HER2− breast cancer often face the threat of distant recurrence—long after the completion of their treatment. Previous studies have found that high levels of tumor infiltrating lymphocytes (TILs) were associated with improved outcomes and recurrence-free survival in patients with HR+/HER2− breast cancer. These studies and many others have prompted researchers to further develop and test cancer vaccines in an effort to elicit anti-tumor immune responses in these patients.

“Therefore, a rational combination therapy that enhances the immune-stimulatory properties of NAC [neoadjuvant chemotherapy], can provide long-term survival benefits for this patient population.”

Researchers from University of Arkansas for Medical SciencesUniversity of Texas SouthwesternHighlands Oncology Group, and Université Claude Bernard Lyon 1 conducted a new single-arm Phase Ib clinical trial. Early-stage HR+/HER2− breast cancer patients were treated with carbohydrate-mimetic peptides, the P10s-PADRE vaccine, in combination with chemotherapy treatments. Their paper was chosen as the cover of Oncotarget’s Volume 12, Issue 22, and entitled, “P10s-PADRE vaccine combined with neoadjuvant chemotherapy in ER-positive breast cancer patients induces humoral and cellular immune responses.”

“The main objective of our study was to determine an appropriate schedule to be used for adding the P10s-PADRE vaccine to cancer chemotherapy in the neoadjuvant setting considering the ability of the vaccine to elicit adequate antibody response.”

The Study

After meeting the study’s detailed inclusion/exclusion criteria, a total of 25 patients with HR+/HER2− breast cancer were selected to partake in this single-arm Phase Ib clinical trial. Patients were divided into five cohorts (five patients per cohort): A, B, C, D, and E. Each patient was treated with a combination of four therapies over the course of 22-25 weeks, including three doses of the peptide-based P10s-PADRE cancer vaccine, four doses of Cyclophosphamide (chemotherapy), four doses of Doxorubicin (chemotherapy) and four doses of Docetaxel (chemotherapy). Using a cohort-specific treatment schedule for the previously stated combination of therapies, the researchers assessed the feasibility, safety and immunogenicity achieved in each cohort and each patient.

Additionally, patients underwent surgery between weeks 26 and 33 (four to eight weeks after their last chemotherapy treatment). Each cohort also had a cohort-specific blood draw schedule—blood was drawn at eight different times in the 73-week time frame. Blood draws were used to conduct flow cytometry, measure the concentration of cytokines, natural killer (NK) cells and antibodies, and to determine the presence of anti-peptide antibody response and the percentage of TILs. The researchers observed that all five cohorts saw a significant reduction in tumor size.

“The data suggest that subjects enrolled in schedule C generated a more consistent and robust antibody response, therefore schedule C appears as the schedule of choice for future combination therapy.”

Their findings concluded that, in combination with chemotherapy, P10s-PADRE immunization in HR+/HER2− breast cancer patients induced “acceptable” antibody responses in study cohorts C and E. The treatment schedule in cohort C demonstrated the strongest antibody response by affecting the expression levels of NK-cell markers, stimulating the production of cytokines, T-cells and TILs. However, the researchers note that continued analysis of the blood samples collected could show serum antibodies may begin to appear later on in patients enrolled in the other treatment schedules.

Conclusion

“This Phase Ib clinical trial of the P10s-PADRE vaccine shows that immunization in combination with a standard-of-care NAC is feasible and well-tolerated. Combination therapy induces antibody response, stimulates activation of NK cells, and is associated with infiltration of T cells in tumor microenvironment. Randomized phase II trials focusing on treatment schedule C are needed to validate current findings and evaluate clinical efficacy.”

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

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Scientific Integrity

Trending With Impact: Novel Biomarkers in Bladder Cancer

Researchers from the University of Houston and UT Southwestern Medical Center conducted a study which aimed to screen urine for potentially useful protein biomarkers of bladder cancer.

3D Illustration of the urinary bladder.
3D Illustration of the urinary bladder.

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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Bladder cancer is four times more common among men than women, and it is the sixth most common cancer diagnosis in the United States. However, researchers have found that cystoscopy—the primary method physicians use to diagnose patients with bladder cancer—is relatively invasive, expensive, and has the potential to cause urinary tract infections. 

“In contrast, urine is a noninvasive and readily available biological fluid that can be used for diagnostic tests.” 

In 2021, researchers from the University of Houston and UT Southwestern Medical Center conducted a study which aimed to screen urine for possibly useful protein biomarkers of bladder cancer. The paper they authored was published in Oncotarget’s Volume 12, Issue 8, and entitled: “Urine protein biomarkers of bladder cancer arising from 16-plex antibody-based screens.”

“Urine biomarkers could potentially provide preliminary confirmation of low-grade BC [bladder cancer] before invasive procedures are performed and facilitate surveillance of BC, as reviewed [9].”

The Study

Patients may benefit in a number of different ways by using urine as fluid in diagnostic testing for bladder cancer. Urine is readily bioavailable, non-invasive, and it can also be collected and tested on a regular basis. Patients can even use various cost-effective point-of-care diagnostic tools, including at-home testing. First, the researchers assessed whether there were useful biomarkers of bladder cancer to be found in this fluid. The team used Luminex screening to test for both low and high levels of 16 proteins utilizing highly specific antibody-protein interactions.

“In this study, Luminex screening was used to simultaneously assay the protein abundances of 16 potential biomarkers in different stages of bladder cancer and then compared to urology clinic controls.” 

ELISA validation was then used to determine which proteins were significantly elevated in bladder cancer. They found that levels of three urine proteins were capable of distinguishing between control and bladder cancer urine. One protein was also found to be capable of discriminating between high- and low-grade disease, and the successive clinical stages of bladder cancer.

“Upon ELISA validation, urine IL-1α, IL-1ra, and IL-8 were able to distinguish control urine from urine drawn from various bladder cancer stages, with IL-8 being the best discriminator.”

Conclusion

“These studies indicate that urine IL-1α, IL-1ra, and IL-8 are potential biomarkers of BC, two of which re-affirm previous reports.”

The researchers note that these newer urine biomarkers must be analyzed in larger cohorts, in specific clinical contexts, and compared to the performance of current diagnostic tools, such as the Bladderchek and UroVysion FISH assay.

“Looking forward, systematic studies in larger patient cohorts are warranted to establish the specific clinical contexts in which these markers may be used, including the following: (i) for initial diagnosis of BC, (ii) for surveillance of tumor recurrence, and/or (ii) for assessing treatment response following BCG therapy or other therapeutic modalities.”

Click here to read the full scientific study, published by 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.

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

Trending with Impact: The Vitamin D Binding Protein in Thyroid Cancer


Researchers compared vitamin D binding protein expression in papillary thyroid cancer tissues among Filipino American and European American patients.

3D rendered medically accurate illustration of thyroid cancer.
3D rendered medically accurate illustration of thyroid 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.

On the basis of ethnicity, different gene variants of the vitamin D binding protein (DBP) are expressed among different populations of people around the world. Little is known about this highly polymorphic protein, though, researchers do know that DBP functions dependently and independently of vitamin D. Many previous research studies have examined the vitamin D-dependent correlation between DBP and cancer, however, few studies have examined DBP’s functionality independent of vitamin D, especially regarding the role of DBP expression in thyroid cancer.

“A systemic review demonstrated that a large number of chronic diseases, including cancers, have been associated with DBP variants [29].” 

Filipino Americans are disproportionately affected by thyroid cancer, and researchers from Harbor-UCLA Medical Center, Loma Linda University School of Medicine, and Riverside University Health System conducted a study published in Oncotarget’s Volume 12, Issue #7, entitled, “Differential expression of Vitamin D binding protein in thyroid cancer health disparities.” The researchers compared the expression of DBP in thyroid cancer in Filipino and European Americans. The goal of this research was to further elucidate the functional implications of DBP in different stages of thyroid cancer across ethnicities.

“Although DBP is an essential protein with multifunctional properties, [28, 4147], very few studies are available on its contribution to thyroid cancer oncogenesis.”

The Study

“Thyroid cancer incidence, recurrence, and death rates are higher among Filipino Americans than European Americans.” 

To determine the correlation between differential DBP expression in tumor tissues and cancer staging among Filipino Americans and European Americans, the researchers gathered 200 archival papillary thyroid tissues; 100 from Filipino Americans and 100 from European Americans. They used immunohistochemistry to assay DBP expression in each sample and then analyzed the data with confocal microscopy. 

“Since DBP gene variants showed differential expression across ethnicities [25, 40, 48, 49], DBP level in the tumor microenvironment may implicate the difference in TC [thyroid cancer] prognosis between Filipino and European Americans.” 

First, the team evaluated whether or not there was any relationship between their DBP staining results and age, gender, or body mass index of the patients. They found no correlation between DBP levels and any of these variables, in either ethnicity. The researchers then analyzed the immunohistochemistry DBP staining results by ethnicity. They found moderate to strong intensity DBP staining across the European American cancer tissues and significantly low to no DBP staining in the Filipino American cancer tissues. The researchers also determined an inverse relationship between DBP expression and cancer stage—the lower the DBP expression, the poorer the prognosis. 

“These data implied that DBP’s presence might play protective roles in cancer progression in European Americans compared to Filipino Americans, supporting the aggressive phenotype observed in Filipino Americans.” 

Next, to observe the effects on cell migration and proliferation, DBP knockdown and overexpression (almost 90%) was achieved in the papillary thyroid tumor cells. The researchers demonstrated increased cancer cell proliferation and migration after the knockdown of the DBP gene. When the researchers overexpressed DBP, they observed a significant reduction in papillary thyroid cancer cell proliferation and migration.

Conclusion

“In conclusion, we demonstrate that the presence or absence of DBP inversely correlates to thyroid cancer staging in two ethnicities.”

The researchers note that while this study demonstrated low vitamin D binding protein expression in the advanced thyroid tumors of Filipino Americans, they acknowledge the need to determine the progressive loss of DBP throughout the stages of thyroid cancer.

“A future study is underway to determine the DBP regulation and its downstream pathways to elucidate strategies to eliminate the observed thyroid cancer health disparities.”

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.

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

Oncotarget Participating in Virtual AACR 2021 Annual Meeting

Oncotarget, exhibited by its publisher Impact Journals, will be participating virtually at the AACR Annual Meeting this year, from April 10-15 and May 17-21, 2021.

Oncotarget participating in the Annual AACR Meeting 2021 #AACR
Oncotarget participating in the Annual AACR Meeting 2021 #AACR
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The American Association for Cancer Research (AACR) organizes an annual meeting program covering some of the most recent discoveries in cancer research. The conference aims to highlight work from the best minds in research and medicine from institutions all over the world. Oncotarget, exhibited by its publisher Impact Journals, will be participating virtually at the AACR Annual Meeting this year. 

As of June 2020, Scopus released their latest 2019 Journal Rankings on Oncology. Oncotarget is among their highest rated (Q1) journals and ranked number one in total citations in oncology. The journal has published outstanding papers and reviews by authors including Bert Vogelstein, Peter K. Vogt, Pier Paolo Pandolfi, Arnold J. Levine, Brian Druker, and Carol Prives. Founding Oncotarget Editorial Board members include Nobel Laureates Andrew V. Schally and Gregg L. Semenza; Lasker Award recipients Alexander Varshavsky, Brian J. Druker, and Gregg L. Semenza; and 16 members of the US National Academy of Sciences. Oncotarget is indexed and archived in PubMed, PubMed Central, Scopus, EMBASE, and META (Chan Zuckerberg Initiative) .

The 2021 AACR conference, a two-week online event, will take place from April 10-15 and May 17-21, 2021. Topics include population science and prevention, cancer biology, translational and clinical studies, survivorship, and advocacy. 

In 2019, Oncotarget participated in the AACR Annual Meeting at the Georgia World Congress Center in Atlanta, Georgia, USA, and “AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics,” at the Hynes Convention Center in Boston, Massachusetts, USA. The total registration count from the 2019 AACR Annual Meeting was over 21,000—nearly 16,000 of which were scientific attendees from all over the world. Click here to view photos from Oncotarget’s participation in the 2019 AACR Annual Meeting.

Follow the Oncotarget Twitter account (@Oncotarget) for live updates about the conference using the #AACR21 hashtag.

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.