Stratification of tumors based on mTOR-pathway biomarkers.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23097-e23097
Author(s):  
Jean-Francois Laes ◽  
S Bastien Sauvage ◽  
Gregori Ghitti
Keyword(s):  
Mtor Pathway ◽  
Loss Of Function ◽  
Pathway Activity ◽  
Pten Loss ◽  
Pathway Activation ◽  
Activating Mutation ◽  
Ffpe Samples ◽  
Cancer Types ◽  
Poor Outcomes ◽  
The Relationship

e23097 Background: The mTOR pathway is often activated in human cancers. In this study, a total of 538 samples representing 40 different cancer types were analysed to evaluate the relationship between mTOR pathway activity and mutations in the upstream genes PIK3CA and PTEN. Methods: FFPE samples were analysed both by NGS (PIK3CA, PTEN, mTOR, TSC1, TSC2) and IHC (PTEN, 4pEBP1). Results: Overall, mTOR-pathway activation was identified in 83% of the samples, functional mutations were found in either or both PIK3CA and PTEN genes in 32% of the samples but there was no signification association between them. However when separating samples by cancer types, potential associations were identified. One example is the combination of PIK3CA activating mutation and PTEN loss of function which was associated with mTOR-pathway activation, most notably in the breast-cancer samples. Such combination has been associated with poor outcomes to some treatments (trastuzumab). Conclusions: In conclusion, our results show that stratification of tumors using the combination of mTOR-pathway biomarkers (and combined NGS and IHC technologies in their assessment) is potentially more informative than using a single biomarker to select the best treatment.

Identification of pan-cancer Ras pathway activation with deep learning

2020 ◽  
Author(s):  
Xiangtao Li ◽  
Shaochuan Li ◽  
Yunhe Wang ◽  
Shixiong Zhang ◽  
Ka-Chun Wong
Keyword(s):  
Deep Learning ◽  
Superior Performance ◽  
Recent Attempt ◽  
Precision Oncology ◽  
Pathway Activity ◽  
Ras Pathway ◽  
Cancer Data ◽  
Pathway Activation ◽  
Cancer Types ◽  
Pan Cancer

Abstract The identification of hidden responders is often an essential challenge in precision oncology. A recent attempt based on machine learning has been proposed for classifying aberrant pathway activity from multiomic cancer data. However, we note several critical limitations there, such as high-dimensionality, data sparsity and model performance. Given the central importance and broad impact of precision oncology, we propose nature-inspired deep Ras activation pan-cancer (NatDRAP), a deep neural network (DNN) model, to address those restrictions for the identification of hidden responders. In this study, we develop the nature-inspired deep learning model that integrates bulk RNA sequencing, copy number and mutation data from PanCanAltas to detect pan-cancer Ras pathway activation. In NatDRAP, we propose to synergize the nature-inspired artificial bee colony algorithm with different gradient-based optimizers in one framework for optimizing DNNs in a collaborative manner. Multiple experiments were conducted on 33 different cancer types across PanCanAtlas. The experimental results demonstrate that the proposed NatDRAP can provide superior performance over other benchmark methods with strong robustness towards diagnosing RAS aberrant pathway activity across different cancer types. In addition, gene ontology enrichment and pathological analysis are conducted to reveal novel insights into the RAS aberrant pathway activity identification and characterization. NatDRAP is written in Python and available at https://github.com/lixt314/NatDRAP1.

scholarly journals Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity

2007 ◽  
Vol 104 (18) ◽  
pp. 7564-7569 ◽  
Author(s):  
Lao H. Saal ◽  
Peter Johansson ◽  
Karolina Holm ◽  
Sofia K. Gruvberger-Saal ◽  
Qing-Bai She ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Signature ◽  
Pi3k Pathway ◽  
Negative Regulator ◽  
Mrna Levels ◽  
Pathway Activity ◽  
Pten Loss ◽  
Expression Signature ◽  
Cancer Management ◽  
Pathway Activation

Pathway-specific therapy is the future of cancer management. The oncogenic phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in solid tumors; however, currently, no reliable test for PI3K pathway activation exists for human tumors. Taking advantage of the observation that loss of PTEN, the negative regulator of PI3K, results in robust activation of this pathway, we developed and validated a microarray gene expression signature for immunohistochemistry (IHC)-detectable PTEN loss in breast cancer (BC). The most significant signature gene was PTEN itself, indicating that PTEN mRNA levels are the primary determinant of PTEN protein levels in BC. Some PTEN IHC-positive BCs exhibited the signature of PTEN loss, which was associated to moderately reduced PTEN mRNA levels cooperating with specific types of PIK3CA mutations and/or amplification of HER2. This demonstrates that the signature is more sensitive than PTEN IHC for identifying tumors with pathway activation. In independent data sets of breast, prostate, and bladder carcinoma, prediction of pathway activity by the signature correlated significantly to poor patient outcome. Stathmin, encoded by the signature gene STMN1, was an accurate IHC marker of the signature and had prognostic significance in BC. Stathmin was also pathway-pharmacodynamic in vitro and in vivo. Thus, the signature or its components such as stathmin may be clinically useful tests for stratification of patients for anti-PI3K pathway therapy and monitoring therapeutic efficacy. This study indicates that aberrant PI3K pathway signaling is strongly associated with metastasis and poor survival across carcinoma types, highlighting the enormous potential impact on patient survival that pathway inhibition could achieve.

Targeting the PI3K/AKT/mTOR Pathway: Biomarkers of Success and Tribulation

2013 ◽  
pp. e395-e401 ◽  
Author(s):  
Taofeek K. Owonikoko ◽  
Fadlo R. Khuri
Keyword(s):  
Therapeutic Strategy ◽  
Pik3ca Mutation ◽  
Mtor Pathway ◽  
Genetic Profile ◽  
Loss Of Function ◽  
Allosteric Inhibitors ◽  
Pten Loss ◽  
Genetic Biomarkers ◽  
Oncogenic Driver

PI3K/AKT/mTOR pathway is an established oncogenic driver in humans. Targeted biologic agents against components of this pathway have shown promising activity leading to the approval of the allosteric inhibitors of mTOR, everolimus, and temsirolimus for the treatment of advanced cancers of the kidney, breast, and pancreas. Despite the established and promising activity of this therapeutic strategy, the duration and quality of benefit remains suboptimal in unselected patients. Improved understanding of the biologic consequence of altered PI3K/AKT/mTOR signaling is informing the development of protein (phosphorylated forms of S6, AKT, eIF4e) and genetic ( PIK3CA mutation, PTEN loss of function, TSC1 and TSC2 mutation, PIK3CA-GS genetic profile) biomarkers to identify patients most likely to benefit from this therapeutic strategy. This review provides an overview of the biologic rational and promising results of protein and genetic biomarkers for selecting patients appropriate for therapy with inhibitors of this pathway.

scholarly journals GPR37 promotes the malignancy of lung adenocarcinoma via TGF-β/Smad pathway

Open Medicine ◽  
2020 ◽  
Vol 16 (1) ◽  
pp. 024-032
Author(s):  
Jian Wang ◽  
Min Xu ◽  
Dan-Dan Li ◽  
Wujikenayi Abudukelimu ◽  
Xiu-Hong Zhou
Keyword(s):  
Lung Adenocarcinoma ◽  
Biological Function ◽  
Migration And Invasion ◽  
Loss Of Function ◽  
Malignant Phenotype ◽  
Smad Pathway ◽  
Smad3 Phosphorylation ◽  
Poor Outcomes ◽  
Tgf Β1

AbstractThis paper aimed to research the function and in-depth mechanism of GPR37 in lung adenocarcinoma (LUAD). Herein, based on TCGA and Oncomine databases, we revealed that GPR37 was expressed at high levels in LUAD, and upregulation of GPR37 was related to the poor outcomes. Furthermore, biological function experiments in vitro were utilized to assess whether GPR37 impacts malignant phenotype of LUAD cells. Gain- or loss-of-function assays indicated that the upregulation of GPR37 contributed to improving the proliferation, migration, and invasion of LUAD cells in vitro, while knockdown of GPR37 can inhibit the malignant biological behaviors. Then, we found that depletion of GPR37 resulted in a decrease in the expression of TGF-β1 as well as the extents of Smad2 and Smad3 phosphorylation, while overexpression of GPR37 presented opposite outcomes. Altogether, our findings indicated that GPR37 is a potential oncogene of LUAD, and its promoting effects on the malignant progression of LUAD may be realized via TGF-β/Smad pathway.

scholarly journals PTEN loss correlates with T cell exclusion across human cancers

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ziying Lin ◽  
Lixia Huang ◽  
Shao Li Li ◽  
Jincui Gu ◽  
Xiaoxian Cui ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Helper Cells ◽  
Pi3k Pathway ◽  
T Helper ◽  
Immune Microenvironment ◽  
Pten Loss ◽  
Pathway Activation ◽  
Tumor Types ◽  
T Cell Exclusion

Abstract Background Recent evidences had shown that loss in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was associated with immunotherapy resistance, which may be attributed to the non-T-cell-inflamed tumor microenvironment. The impact of PTEN loss on tumor microenvironment, especially regarding T cell infiltration across tumor types is not well understood. Methods Utilizing The Cancer Genome Atlas (TCGA) and publicly available dataset of immunotherapy, we explored the correlation of PTEN expressing level or genomic loss with tumor immune microenvironment and response to immunotherapy. We further investigated the involvement of PI3K-AKT-mTOR pathway activation, which is known to be the subsequent effect of PTEN loss, in the immune microenvironment modulation. Results We reveal that PTEN mRNA expression is significantly positively correlated with CD4/CD8A gene expression and T cells infiltration especially T helpers cells, central memory T cell and effector memory T cells in multiples tumor types. Genomic loss of PTEN is associated with reduced CD8+ T cells, type 1 T helper cells, and increased type 2 T helper cells, immunosuppressed genes (e.g. VEGFA) expression. Furthermore, T cell exclusive phenotype is also observed in tumor with PI3K pathway activation or genomic gain in PIK3CA or PIK3CB. PTEN loss and PI3K pathway activation correlate with immunosuppressive microenvironment, especially in terms of T cell exclusion. PTEN loss predict poor therapeutic response and worse survival outcome in patients receiving immunotherapy. Conclusion These data brings insight into the role of PTEN loss in T cell exclusion and immunotherapy resistance, and inspires further research on immune modulating strategy to augment immunotherapy.

scholarly journals Risk factors for severe outcomes in people with diabetes hospitalised for COVID-19: a cross-sectional database study

BMJ Open ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. e051237
Author(s):  
Emilio Ortega ◽  
Rosa Corcoy ◽  
Mònica Gratacòs ◽  
Francesc Xavier Cos Claramunt ◽  
Manel Mata-Cases ◽  
...  
Keyword(s):  
Hospital Mortality ◽  
Invasive Mechanical Ventilation ◽  
The Elderly ◽  
Cross Sectional Study ◽  
Cross Sectional ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Male Sex ◽  
Poor Outcomes ◽  
The Relationship

AimThis study’s objective was to assess the risk of severe in-hospital complications of patients admitted for COVID-19 and diabetes mellitus (DM).DesignThis was a cross-sectional study.SettingsWe used pseudonymised medical record data provided by six general hospitals from the HM Hospitales group in Spain.Outcome measuresMultiple logistic regression analyses were used to identify variables associated with mortality and the composite of mortality or invasive mechanical ventilation (IMV) in the overall population, and stratified for the presence or absence of DM. Spline analysis was conducted on the entire population to investigate the relationship between glucose levels at admission and outcomes.ResultsOverall, 1621 individuals without DM and 448 with DM were identified in the database. Patients with DM were on average 5.1 years older than those without. The overall in-hospital mortality was 18.6% (N=301), and was higher among patients with DM than those without (26.3% vs 11.3%; p<0.001). DM was independently associated with death, and death or IMV (OR=2.33, 95% CI: 1.7 to 3.1 and OR=2.11, 95% CI: 1.6 to 2.8, respectively; p<0.001). In subjects with DM, the only variables independently associated with both outcomes were age >65 years, male sex and pre-existing chronic kidney disease. We observed a non-linear relationship between blood glucose levels at admission and risk of in-hospital mortality and death or IMV. The highest probability for each outcome (around 50%) was at random glucose of around 550 mg/dL (30.6 mmol/L), and the risks flattened above this value.ConclusionThe results confirm the high burden associated with DM in patients hospitalised with COVID-19 infection, particularly among men, the elderly and those with impaired kidney function. Moreover, hyperglycaemia on admission was strongly associated with poor outcomes, suggesting that personalised optimisation could help to improve outcome during the hospital stay.

scholarly journals Profilin-1; a novel regulator of DNA damage response and repair machinery in keratinocytes

2021 ◽  
Author(s):  
Chang-Jin Lee ◽  
Min-Ji Yoon ◽  
Dong Hyun Kim ◽  
Tae Uk Kim ◽  
Youn-Jung Kang
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Response ◽  
Recovery Time ◽  
Actin Polymerization ◽  
Loss Of Function ◽  
Dna Double Strand Breaks ◽  
Pten Loss ◽  
Damage Response ◽  
Specific Regulation

AbstractProfilin-1 (PFN1) regulates actin polymerization and cytoskeletal growth. Despite the essential roles of PFN1 in cell integration, its subcellular function in keratinocyte has not been elucidated yet. Here we characterize the specific regulation of PFN1 in DNA damage response and repair machinery. PFN1 depletion accelerated DNA damage-mediated apoptosis exhibiting PTEN loss of function instigated by increased phosphorylated inactivation followed by high levels of AKT activation. PFN1 changed its predominant cytoplasmic localization to the nucleus upon DNA damage and subsequently restored the cytoplasmic compartment during the recovery time. Even though γH2AX was recruited at the sites of DNA double strand breaks in response to DNA damage, PFN1-deficient cells failed to recruit DNA repair factors, whereas control cells exhibited significant increases of these genes. Additionally, PFN1 depletion resulted in disruption of PTEN-AKT cascade upon DNA damage and CHK1-mediated cell cycle arrest was not recovered even after the recovery time exhibiting γH2AX accumulation. This might suggest PFN1 roles in regulating DNA damage response and repair machinery to protect cells from DNA damage. Future studies addressing the crosstalk and regulation of PTEN-related DNA damage sensing and repair pathway choice by PFN1 may further aid to identify new mechanistic insights for various DNA repair disorders.

Prognostic Effects of Neutrophil-Lymphocyte Rates in Serum and Pleural Fluids in Malignant Pleural Fluids

2021 ◽  
Author(s):  
Filiz Güldaval ◽  
Ceyda Anar ◽  
Mine Gayaf ◽  
Gulru Polat ◽  
Merve Ayık Türk ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Prognostic Factor ◽  
Eastern Cooperative Oncology Group ◽  
Cost Effective ◽  
Clinical Impact ◽  
Neutrophil To Lymphocyte Ratio ◽  
Lymphocyte Ratio ◽  
Appropriate Therapy ◽  
Cancer Types ◽  
The Relationship

Objective: Various studies have reported that the neutrophil-to-lymphocyte ratio in the serum (sNLR) may serve as a cost-effective and useful prognostic factor in patients with various cancer types. We investigated the clinical impact of NLR as a prognostic factor in malign pleural effusion (MPE) and sNLR on prognosis in MPE. Method: We retrospectively reviewed all of the patients who were diagnosed MPE. The relationship between sNLR and neutrophil-to-lymphocyte ratio in the malign pleural effusion (mNLR) value, age, Eastern Cooperative Oncology Group (ECOG), histopathologic type, serum albumin and lactate dehydrogenase (LDH) with survival were investigated. Results: A total of 222 patients with a mean age of 65.7±11.5 were included in the study. Patients with a mNLR value ≥0.42 and a serum NLR value ≥4.75 had a shorter survival (p: 0.000). Multivariate analysis, which showed that survival was significantly related mNLR value > 0.42 and/or sNLR value > 4.75 (Odds Ratio (OR): 2.66, %95 CI, 1,65-4,3 p: 0.001), serum LDH > 210 (OR = 1.8, %95 CI, 1,33-2,46 p: 0.001) and age > 65 (OR = 1.9, %95 CI, 1,41-2,55 p = 0.001). Conclusion: sNLR and mNLR may act as a simple, useful, and cost-effective prognostic factor in patients with MPE. Furthermore, these results may serve as the cornerstone of further research into the mNLR in the future. Although further studies are required to generalize our results, this information will benefit clinicians and patients in determining the most appropriate therapy for patients with MPE.

EXTH-55. TARGETING RECURRENT IDH MUTANT GLIOMA WITH CDK4/6 INHIBITION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi175-vi175
Author(s):  
Julie Miller ◽  
Daniel Cahill ◽  
Lisa Melamed ◽  
Hiroaki Nagashima
Keyword(s):  
Gene Deletion ◽  
Homozygous Deletion ◽  
Therapeutic Strategies ◽  
Enhanced Sensitivity ◽  
Rb Pathway ◽  
Cancer Types ◽  
Xenograft Models ◽  
The Relationship ◽  
Inhibitor Treatment

Abstract Despite initial responsiveness to standard treatments like radiation and chemotherapy, IDH mutant gliomas inevitably recur, become more clinically aggressively and lead to untimely death. Recurrent IDH mutant tumors are less responsive to conventional treatments, highlighting the need for improved therapeutic strategies at this stage of the disease. At least 20% of recurrent IDH mutant gliomas exhibit homozygous loss of CDKN2A, which results in aberrant signaling through the CDK-RB pathway. We hypothesized that CDKN2A loss leads to enhanced sensitivity to CDK4/6 inhibitors, which are approved for use in a variety of other cancer types. We examined the relationship between CDK4/6 inhibitor sensitivity and CDKN2A loss using patient-derived models of IDH mutant glioma with endogenous CDKN2A homozygous deletion as well as with CRIPSR-mediated gene deletion. We observed enhanced cytotoxicity in glioma models with CDKN2A loss in vitro. Studies to examine the efficacy of CDK4/6 inhibitor treatment on slowing tumor growth in patient-derived xenograft models are ongoing. These preclinical results provide foundational data for design of a biomarker-driven clinical trial of CDK4/6 inhibitors in patients with recurrent IDH mutant glioma.

Molecular Alterations in Pediatric Low-Grade Gliomas That Led to Death

2021 ◽  
Author(s):  
Jared T Ahrendsen ◽  
Claire Sinai ◽  
David M Meredith ◽  
Seth W Malinowski ◽  
Tabitha M Cooney ◽  
...  
Keyword(s):  
Braf V600e ◽  
Molecular Characteristics ◽  
Low Grade ◽  
Diffuse Astrocytoma ◽  
Term Survival ◽  
Pten Loss ◽  
Low Grade Gliomas ◽  
Molecular Alterations ◽  
Idh1 R132h ◽  
Poor Outcomes

Abstract Pediatric low-grade gliomas (PLGGs) have excellent long-term survival, but death can occasionally occur. We reviewed all PLGG-related deaths between 1975 and 2019 at our institution: 48 patients were identified; clinical data and histology were reviewed; targeted exome sequencing was performed on available material. The median age at diagnosis was 5.2 years (0.4–23.4 years), at death was 13.0 years (1.9–43.2 years), and the overall survival was 7.2 years (0.0–33.3 years). Tumors were located throughout CNS, but predominantly in the diencephalon. Diagnoses included low-grade glioma, not otherwise specified (n = 25), pilocytic astrocytoma (n = 15), diffuse astrocytoma (n = 3), ganglioglioma (n = 3), and pilomyxoid astrocytoma (n = 2). Recurrence occurred in 42/48 cases, whereas progression occurred in 10. The cause of death was direct tumor involvement in 31/48 cases. Recurrent drivers included KIAA1549-BRAF (n = 13), BRAF(V600E) (n = 3), NF1 mutation (n = 3), EGFR mutation (n = 3), and FGFR1-TACC1 fusion (n = 2). Single cases were identified with IDH1(R132H), FGFR1(K656E), FGFR1 ITD, FGFR3 gain, PDGFRA amplification, and mismatch repair alteration. CDKN2A/B, CDKN2C, and PTEN loss was recurrent. Patients who received only chemotherapy had worse survival compared with patients who received radiation and chemotherapy. This study demonstrates that PLGG that led to death have diverse molecular characteristics. Location and co-occurring molecular alterations with malignant potential can predict poor outcomes.

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