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Oncotarget published this trending research paper on June 15, 2022 in Volume 13, entitled, "Alectinib after failure to crizotinib in patients with ALK-positive non-small cell lung cancer: results from the Spanish early access program" by researchers from Department of Medical Oncology, Hospital Virgen del Rocío, Sevilla, Spain; Department of Medical Oncology, Hospital Universitario Ramon y Cajal, Madrid, Spain; Department of Medical Oncology, Hospital Universitario A Coruña, A Coruña, Spain; Department of Medical Oncology, ICO Bellvitge, Hospitalet Llobregat, Barcelona, Spain; Department of Medical Oncology, Hospital Universitario Miguel Servet, Zaragoza, Spain; Department of Medical Oncology, Hospital General Yague, Burgos, Spain; Department of Medical Oncology, Hospital Insular de Gran Canaria, Las Palmas de Gran Canaria, Spain; Department of Medical Oncology, Hospital Marqués de Valdecilla, Santander, Spain; Department of Medical Oncology, Hospital Universitario Donostia, Donostia-San Sebastián, Spain; Department of Medical Oncology, Hospital Universitario Virgen Macarena, Sevilla, Spain; Department of Medical Oncology, Hospital Universitario La Princesa, Madrid, Spain; Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Department of Medical Oncology, Complejo Asistencial Universitario de León, León, Spain; Roche Farma, S.A., Madrid, Spain; Department of Medical Oncology, Hospital Universitario La Paz, Madrid, Spain.

DOI - https://doi.org/10.18632/oncotarget.28244

Correspondence to - Reyes Bernabé-Caro - reyesbernab@yahoo.es

Abstract

This retrospective observational study analyzed the clinical characteristics, treatment patterns and outcomes of 120 patients with advanced ALK-positive non-small-cell lung cancer (ALK+ NSCLC) according to data collected between November 2019 and October 2020 in 38 Spanish hospitals. Patients had progressed after 1–5 prior treatment lines (which included crizotinib in any prior line) and received subsequent therapy with alectinib in a local expanded access program. Median age was 58.7 years, 50% of patients were female, 64.1% had ECOG PS of 0–1, 85% presented stage IV, 95% had adenocarcinoma histology and 20.8% had brain metastases. After a median 9.6 months of alectinib treatment, objective response rate (ORR) was 54.5%, disease control rate (DCR) was 80%, median progression-free survival (PFS) was 9.4 months and median overall survival (OS) was 24.1 months. Patients with brain metastases achieved an intracranial DCR of 71.4%. Adverse events (AEs) were reported in 35.8% of patients (14.2% of AEs were grade ≥3). Over 40% of patients received some treatment after alectinib, most frequently lorlatinib (65.2%) and brigatinib (32.6%). This study provides information on real-world treatment patterns and confirms the tolerability and prolonged PFS and OS observed with alectinib in clinical trials, in unselected pretreated patients with advanced ALK+ NSCLC.

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Keywords - lung cancer, ALK-positive NSCLC, ALK inhibitor, crizotinib, alectinib, unselected patient

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Trending With Impact: Real-World Treatment Patterns of Alectinib in Unselected Spanish ALK+ NSCLC Patients

Dr. Alexander Pohlman from Rush Medical College, Rush University Medical Center, Chicago, IL, describes a recent review published by Oncotarget that he co-authored entitled, “The role of IGF-pathway biomarkers in determining risks, screening, and prognosis in lung cancer.”

DOI - https://doi.org/10.18632/oncotarget.28202

Correspondence to - Jeffrey A. Borgia - jeffrey_a_borgia@rush.edu

Abstract

Background: Detection rates of early-stage lung cancer are traditionally low, which contributes to inconsistent treatment responses and high rates of annual cancer deaths. Currently, low-dose computed tomography (LDCT) screening produces a high false discovery rate. This limitation has prompted research to identify biomarkers to more clearly define eligible patients for LDCT screening, differentiate indeterminate pulmonary nodules, and select individualized cancer therapy. Biomarkers within the Insulin-like Growth Factor (IGF) family have come to the forefront of this research.

Main Body: Multiple biomarkers within the IGF family have been investigated, most notably IGF-I and IGF binding protein 3. However, newer studies seek to expand this search to other molecules within the IGF axis. Certain studies have demonstrated these biomarkers are useful when used in combination with lung cancer screening, but other findings were not as conclusive, possibly owing to measurement bias and non-standardized assay techniques. Research also has suggested IGF biomarkers may be beneficial in the prognostication and subsequent treatment via systemic therapy. Despite these advances, additional knowledge of complex regulatory mechanisms inherent to this system are necessary to more fully harness the potential clinical utility for diagnostic and therapeutic purposes.

Conclusions: The IGF system likely plays a role in multiple phases of lung cancer; however, there is a surplus of conflicting data, especially prior to development of the disease and during early stages of detection. IGF biomarkers may be valuable in the screening, prognosis, and treatment of lung cancer, though their exact application requires further study.

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Keywords - IGF, lung cancer, biomarkers, screening, prognostication

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Behind the Study: IGF-pathway Biomarkers and Lung Cancer

Oncotarget published this trending research paper on May 25, 2022 in Volume 13, entitled, "Identification of lung cancer drivers by comparison of the observed and the expected numbers of missense and nonsense mutations in individual human genes" by researchers from the Department of Medicine, Baylor College of Medicine, Houston, TX; Department of Statistics, Rice University, Houston, TX.

DOI - https://doi.org/10.18632/oncotarget.28231

Correspondence to - Olga Y. Gorlova - Olga.Gorlova@bcm.edu

Abstract

Largely, cancer development is driven by acquisition and positive selection of somatic mutations that increase proliferation and survival of tumor cells. As a result, genes related to cancer development tend to have an excess of somatic mutations in them. An excess of missense and/or nonsense mutations in a gene is an indicator of its cancer relevance. To identify genes with an excess of potentially functional missense or nonsense mutations one needs to compare the observed and expected numbers of mutations in the gene. We estimated the expected numbers of missense and nonsense mutations in individual human genes using (i) the number of potential sites for missense and nonsense mutations in individual transcripts and (ii) histology-specific nucleotide context-dependent mutation rates. To estimate mutation rates defined as the number of mutations per site per tumor we used silent mutations reported in the Catalog Of Somatic Mutations In Cancer (COSMIC). The estimates were nucleotide context dependent. We have identified 26 genes with an excess of missense and/or nonsense mutations for lung adenocarcinoma, 18 genes for small cell lung cancer, and 26 genes for squamous cell carcinoma of the lung. These genes include known genes and novel lung cancer gene candidates.

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Keywords - lung cancer; somatic mutations, driver genes, Catalog Of Somatic Mutations In Cancer (COSMIC)

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Trending With Impact: Genetic Drivers of Lung Cancer by Number of Mutations

Oncotarget published this trending research paper on May 24, 2022 in Volume 13, entitled, "NF-κB over-activation portends improved outcomes in HPV-associated head and neck cancer" by researchers from the Department of Otolaryngology/Head and Neck Surgery, UNC, Chapel Hill, NC; Department of Surgery, Otolaryngology, Yale, New Haven, CT; Department of Pharmacology and Bioengineering, University of Illinois at Chicago, Chicago, IL;  Bioinformatics Core, University of Illinois Cancer Center, Chicago, IL; Department of Medicine, Yale School of Medicine, New Haven, CT;  Lineberger Cancer Center, UNC, Chapel Hill, NC; Department of Pathology and Laboratory Medicine, UNC, Chapel Hill, NC; Yale Cancer Center, Yale School of Medicine, New Haven, CT.

DOI - https://doi.org/10.18632/oncotarget.28232

Correspondence to - Wendell G. Yarbrough - dell@med.unc.edu, and Natalia Issaeva - natalia.isaeva@med.unc.edu

Abstract

Evolving understanding of head and neck squamous cell carcinoma (HNSCC) is leading to more specific diagnostic disease classifications. Among HNSCC caused by the human papilloma virus (HPV), tumors harboring defects in TRAF3 or CYLD are associated with improved clinical outcomes and maintenance of episomal HPV. TRAF3 and CYLD are negative regulators of NF-κB and inactivating mutations of either leads to NF-κB overactivity. Here, we developed and validated a gene expression classifier separating HPV+ HNSCCs based on NF-κB activity. As expected, the novel classifier is strongly enriched in NF-κB targets leading us to name it the NF-κB Activity Classifier (NAC). High NF-κB activity correlated with improved survival in two independent cohorts. Using NAC, tumors with high NF-κB activity but lacking defects in TRAF3 or CYLD were identified; thus, while TRAF3 or CYLD gene defects identify the majority of tumors with NF-κB activation, unknown mechanisms leading to NF-kB activity also exist. The NAC correctly classified the functional consequences of two novel CYLD missense mutations. Using a reporter assay, we tested these CYLD mutations revealing that their activity to inhibit NF-kB was equivalent to the wild-type protein. Future applications of the NF-κB Activity Classifier may be to identify HPV+ HNSCC patients with better or worse survival with implications for treatment strategies.

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Press release - https://www.oncotarget.com/news/pr/oncotarget-nf-b-over-activation-portends-improved-outcomes-in-hpv-associated-head-and-neck-cancer/

Keywords - HPV, head and neck cancer, CYLD, TRAF3, NF-κB

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Trending With Impact: NF-κB Activity Classifies HPV+ HNSCC Prognosis

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

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Trending With Impact: CancerOmicsNet for Anti-Cancer Drug Profiling

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

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