Cancer Research

Oncotarget

Oncotarget published this trending research paper on May 19, 2022 in Volume 13, entitled, "CancerOmicsNet: a multi-omics network-based approach to anti-cancer drug profiling" by researchers from the Center for Computation and Technology, Louisiana State University, Baton Rouge, LA; Department of Biological Sciences, Louisiana State University, Baton Rouge, LA; Division of Electrical and Computer Engineering, Louisiana State University, Baton Rouge, LA.

DOI - https://doi.org/10.18632/oncotarget.28234

Correspondence to - Michal Brylinski - michal@brylinski.org

Abstract

Development of novel anti-cancer treatments requires not only a comprehensive knowledge of cancer processes and drug mechanisms of action, but also the ability to accurately predict the response of various cancer cell lines to therapeutics. Numerous computational methods have been developed to address this issue, including algorithms employing supervised machine learning. Nonetheless, high prediction accuracies reported for many of these techniques may result from a significant overlap among training, validation, and testing sets, making existing predictors inapplicable to new data. To address these issues, we developed CancerOmicsNet, a graph neural network with sophisticated attention propagation mechanisms to predict the therapeutic effects of kinase inhibitors across various tumors. Emphasizing on the system-level complexity of cancer, CancerOmicsNet integrates multiple heterogeneous data, such as biological networks, genomics, inhibitor profiling, and gene-disease associations, into a unified graph structure. The performance of CancerOmicsNet, properly cross-validated at the tissue level, is 0.83 in terms of the area under the receiver operating characteristics, which is notably higher than those measured for other approaches. CancerOmicsNet generalizes well to unseen data, i.e., it can predict therapeutic effects across a variety of cancer cell lines and inhibitors. CancerOmicsNet is freely available to the academic community at https://github.com/pulimeng/CancerOmicsNet.

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Press release - https://www.oncotarget.com/news/pr/oncotarget-anti-cancer-drug-profiling-with-canceromicsnet/

Keywords - cancer growth rate, kinase inhibitors, differential gene expression, gene-disease association, cancer-specific networks

About Oncotarget

Oncotarget is a peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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Trending With Impact: CancerOmicsNet for Anti-Cancer Drug Profiling

Aging (Aging-US)

Aging-US published this trending review in Volume 14, Issue 9, entitled, "Hallmarks of cancer and hallmarks of aging" by Dr. Mikhail V. Blagosklonny from Roswell Park Comprehensive Cancer Center, Buffalo, NY. 

DOI - https://doi.org/10.18632/aging.204082

Corresponding author - Mikhail V. Blagosklonny - Blagosklonny@oncotarget.com, Blagosklonny@rapalogs.com

Abstract

A thought-provoking article by Gems and de Magalhães suggests that canonic hallmarks of aging are superficial imitations of hallmarks of cancer. I took their work a step further and proposed hallmarks of aging based on a hierarchical principle and the hyperfunction theory.

To do this, I first reexamine the hallmarks of cancer proposed by Hanahan and Weinberg in 2000. Although six hallmarks of cancer are genuine, they are not hierarchically arranged, i.e., molecular, intra-cellular, cellular, tissue, organismal and extra-organismal. (For example, invasion and angiogenesis are manifestations of molecular alterations on the tissue level; metastasis on the organismal level, whereas cell immortality is observed outside the host).

The same hierarchical approach is applicable to aging. Unlike cancer, however, aging is not a molecular disease. The lowest level of its origin is normal intracellular signaling pathways such as mTOR that drive developmental growth and, later in life, become hyperfunctional, causing age-related diseases, whose sum is aging. The key hallmark of organismal aging, from worms to humans, are age-related diseases. In addition, hallmarks of aging can be arranged as a timeline, wherein initial hyperfunction is followed by dysfunction, organ damage and functional decline.

Press release - https://aging-us.com/news_room/hallmarks-of-cancer-and-hallmarks-of-aging-reviewed

Keywords - aging, oncology, carcinogenesis, geroscience, mTOR, rapamycin, hyperfunction theory

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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Paper Spotlight: Hallmarks of Cancer and Hallmarks of Aging

Oncotarget published this trending research paper on May 11, 2022 in Volume 13, entitled, "Proteomic analysis reveals dual requirement for Grb2 and PLCγ1 interactions for BCR-FGFR1-Driven 8p11 cell proliferation" by researchers from the Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA; Proteomics Facility, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA; UCSD Moores Cancer Center, University of California San Diego, La Jolla, CA.

DOI - https://doi.org/10.18632/oncotarget.28228

Correspondence to - Daniel J. Donoghue - ddonoghue@ucsd.edu

Abstract

Translocation of Fibroblast Growth Factor Receptors (FGFRs) often leads to aberrant cell proliferation and cancer. The BCR-FGFR1 fusion protein, created by chromosomal translocation t(8;22)(p11;q11), contains Breakpoint Cluster Region (BCR) joined to Fibroblast Growth Factor Receptor 1 (FGFR1). BCR-FGFR1 represents a significant driver of 8p11 myeloproliferative syndrome, or stem cell leukemia/lymphoma, which progresses to acute myeloid leukemia or T-cell lymphoblastic leukemia/lymphoma. Mutations were introduced at Y177F, the binding site for adapter protein Grb2 within BCR; and at Y766F, the binding site for the membrane associated enzyme PLCγ1 within FGFR1. We examined anchorage-independent cell growth, overall cell proliferation using hematopoietic cells, and activation of downstream signaling pathways. BCR-FGFR1-induced changes in protein phosphorylation, binding partners, and signaling pathways were dissected using quantitative proteomics to interrogate the protein interactome, the phosphoproteome, and the interactome of BCR-FGFR1. The effects on BCR-FGFR1-stimulated cell proliferation were examined using the PLCγ1 inhibitor U73122, and the irreversible FGFR inhibitor futibatinib (TAS-120), both of which demonstrated efficacy. An absolute requirement is demonstrated for the dual binding partners Grb2 and PLCγ1 in BCR-FGFR1-driven cell proliferation, and new proteins such as ECSIT, USP15, GPR89, GAB1, and PTPN11 are identified as key effectors for hematopoietic transformation by BCR-FGFR1.

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Keywords - oncogenic fusion protein, chromosomal translocation, protein interactome, phosphoproteome, stem cell leukemia/lymphoma

About Oncotarget

Oncotarget is a peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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Trending With Impact: Grb2 and PLCγ1 Required in BCR-FGFR1-Driven SCLL

Oncotarget published this trending research paper on May 5, 2022 in Volume 13, entitled, "Combined treatment with niclosamide and camptothecin enhances anticancer effect in U87 MG human glioblastoma cells" by researchers from the Department of Molecular Science, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX.

DOI - https://doi.org/10.18632/oncotarget.28227

Correspondence to - Xiaoqian Fang - xiaoqian.fang@utrgv.edu

Abstract

Glioblastoma multiforme (GBM) is one of the deadliest cancers of the brain. Its ability to infiltrate healthy brain tissues renders it difficult to remove surgically. Furthermore, it exhibits high rates of radio- and chemoresistance, making the survival rates of patients with GBM poor. Therefore, novel effective therapies for GBM remain urgently in demand. Niclosamide is an anti-helminthic drug and recently it has been receiving attention due to its reported anticancer effects in cancer models, including GBM. Furthermore, camptothecin (CPT) is a naturally-occurring alkaloid and has been previously reported to be a potential chemotherapeutic agent by targeting the nuclear topoisomerase I. In the present study, the possible combined chemotherapeutic effects of niclosamide and CPT on the human glioblastoma cell line U87 MG was investigated by MTT assay and western blot analysis. Niclosamide exhibited synergistic activities with CPT to suppress the proliferation of U87 MG cells. Additionally, niclosamide suppressed cell proliferation and induced cell death mainly by triggering ER stress and autophagy, whilst CPT induced cell apoptosis mainly through p53-mediated mitochondrial dysfunction and activation of the MAPK (ERK/JNK) pathways. Overall, these findings suggest that co-administration of niclosamide and CPT may provide a novel therapeutic treatment strategy for GBM.

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Keywords - glioblastoma, niclosamide, camptothecin, cancer, chemotherapy

About Oncotarget

Oncotarget is a peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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Trending With Impact: Combined Treatment Approach Fights Glioblastoma

Aging (Aging-US) published this trending editorial in Volume 14, Issue 8, entitled, “SNCA-AS1 in aging and Parkinson’s disease” by researchers from the Pediatric Research Center “Romeo ed Enrica Invernizzi”, Department of Biomedical and Clinical Sciences "L. Sacco", University of Milano, Milano, Italy; Department of Women, Mothers and Neonatal Care, Children's Hospital "V. Buzzi", Milano, Italy.

DOI - https://doi.org/10.18632/aging.204025

Corresponding author - Stephana Carelli - stephana.carelli@unimi.it

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Keywords - aging, SNCA-AS1, alpha-synuclein, SNCA, long non-coding RNA, Parkinson's disease

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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Trending With Impact: SNCA-AS1 in Aging and Parkinson’s Disease

Aging (Aging-US) published this research paper as the cover for Volume 14, Issue 8, entitled, "Wild type and gain of function mutant TP53 can regulate the sensitivity of pancreatic cancer cells to chemotherapeutic drugs, EGFR/Ras/Raf/MEK, and PI3K/mTORC1/GSK-3 pathway inhibitors, nutraceuticals and alter metabolic properties" by researchers the Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC; Department of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy; Department of Medicine and Surgery, Re.Mo.Bio.S. Laboratory, Anatomy Section, University of Parma, Parma, Italy; Department of Molecular Physiology and Neurobiology, University of Wroclaw, Wroclaw, Poland.

DOI - https://doi.org/10.18632/aging.204038

Corresponding author - James A. McCubrey - mccubreyj@ecu.edu

Abstract

TP53 is a master regulator of many signaling and apoptotic pathways involved in: aging, cell cycle progression, gene regulation, growth, apoptosis, cellular senescence, DNA repair, drug resistance, malignant transformation, metastasis, and metabolism. Most pancreatic cancers are classified as pancreatic ductal adenocarcinomas (PDAC). The tumor suppressor gene TP53 is mutated frequently (50–75%) in PDAC. Different types of TP53 mutations have been observed including gain of function (GOF) point mutations and various deletions of the TP53 gene resulting in lack of the protein expression. Most PDACs have point mutations at the KRAS gene which result in constitutive activation of KRas and multiple downstream signaling pathways. It has been difficult to develop specific KRas inhibitors and/or methods that result in recovery of functional TP53 activity. To further elucidate the roles of TP53 in drug-resistance of pancreatic cancer cells, we introduced wild-type (WT) TP53 or a control vector into two different PDAC cell lines. Introduction of WT-TP53 increased the sensitivity of the cells to multiple chemotherapeutic drugs, signal transduction inhibitors, drugs and nutraceuticals and influenced key metabolic properties of the cells. Therefore, TP53 is a key molecule which is critical in drug sensitivity and metabolism of PDAC.

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Keywords - aging, TP53, targeted therapy, PDAC, metabolic properties, chemotherapeutic drugs 

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

Please visit our website at http://www.Aging-US.com​​ or connect with us:

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Aging-US is published by Impact Journals, LLC: http://www.ImpactJournals.com​​

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Paper Spotlight: Restoration of Wild-Type TP53 in Pancreatic Cancer

Dr. Mark Woodford, Assistant Professor at the Department of Urology, SUNY Upstate Medical University, Syracuse, NY, describes his experience publishing the meeting report, “Seventh BHD international symposium: recent scientific and clinical advancement,” with Oncotarget.

DOI - https://doi.org/10.18632/oncotarget.28176

Correspondence to - Mehdi Mollapour - mollapom@upstate.edu

Abstract
The 7th Birt-Hogg-Dubé (BHD) International Symposium convened virtually in October 2021. The meeting attracted more than 200 participants internationally and highlighted recent findings in a variety of areas, including genetic insight and molecular understanding of BHD syndrome, structure and function of the tumor suppressor Folliculin (FLCN), therapeutic and clinical advances as well as patients’ experiences living with this malady.

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Keywords - Birt-Hogg-Dubé syndrome, folliculin, FLCN, tuberous sclerosis complex, LDHA

About Oncotarget

Oncotarget is a peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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Author Testimonial: Dr. Mark Woodford - SUNY Upstate Medical University, Syracuse

Oxford Nanopore Technologies

Oxford Nanopore sequencing devices enable direct, real-time analysis of short to ultra-long fragments of DNA/RNA in fully scalable formats. 

It’s possible to target regions of DNA in real time using adaptive sampling on nanopore devices. The nanopore has the ability to read the strand sequence in real time, if it is not the strand of interest, the strand is ejected, but if it is, the nanopore recognises this and continues to read the strand. Researchers then get more of the sequence they are interested in within a shorter period of time, allowing faster and easier analysis. 

Adaptive Sampling: Target Regions of DNA in Real Time

Oncotarget published this research paper on April 22, 2022 in Volume 13, entitled, "Bladder cancer survival in patients with NOD2 or CDKN2A variants" by researchers from the Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland; Department of Clinical and Molecular Biochemistry, Pomeranian Medical University, Szczecin, Poland; School of Biomedical Sciences and Pharmacy, Centre for Information-Based Medicine, Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW 2305, Australia; Division of Molecular Medicine, Pathology North, NSW Pathology, Newcastle, NSW 2305, Australia.

DOI - https://doi.org/10.18632/oncotarget.28226

Correspondence to - Elżbieta Złowocka-Perłowska - elzunik@wp.pl

Abstract

Purpose: The association between the NOD2 c.3020insC allele and CDKN2A missense variant c.442G>A (p.P.A148T) and survival of patients with bladder or kidney cancer remains controversial.

Materials and Methods: We compared the allele frequencies of NOD2 c.3020insC and CDKN2A p.A148T allele in 706 patients with bladder cancer, 410 cases with kidney cancer against two control groups. The Cox proportional hazards model was used to determine whether there were any survival differences between carriers of the NOD2 c.3020insC or the CDKN2A p.A148T variant.

Results: Among the three patient subgroups: patients under 60 years of age, non-smokers and a third with histological features of low grade noninvasive papillary bladder cancer, we observed that the c.3020insC allele had a nominal statistically significant effect on survival. We also observed that the NOD2 c.3020insC variant was more frequent in patients with bladder cancer aged between 51 and 60 years.

There was some nominal evidence that the CDKN2A p.A148T polymorphism reduced survival in the subgroup of bladder cancer patients under 60 years of age. We observed that in kidney cancer patients, the incidence of the NOD2 variant appeared to be lower in the group aged between 60 and 70 years, however, this was not statistically significant. In addition, in patients with histological features of grade III chromophobic kidney cancer, the c.3020insC allele also appeared to be over-represented but this too was not statistically significant.

Conclusion: We have shown that the NOD2 c.3020insC allele and the CDKN2A p.A148T polymorphism does not play a role in the survival of patients with bladder cancer.

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Keywords - bladder cancer, kidney cancer, NOD2, CDKN2A, survival

About Oncotarget

Oncotarget is a peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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