scholarly journals In Silico Drug Prescription for Targeting Cancer Patient Heterogeneity and Prediction of Clinical Outcome

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1361
Author(s):  
Elena Piñeiro-Yáñez ◽  
María José Jiménez-Santos ◽  
Gonzalo Gómez-López ◽  
Fátima Al-Shahrour
Keyword(s):  
Cancer Patients ◽  
In Silico ◽  
Tumour Progression ◽  
Drug Prescription ◽  
A Priori ◽  
Growth Factor Receptor ◽  
Clonal Diversity ◽  
Molecular Alterations ◽  
Patient Heterogeneity ◽  
Epidermal Growth

In silico drug prescription tools for precision cancer medicine can match molecular alterations with tailored candidate treatments. These methodologies require large and well-annotated datasets to systematically evaluate their performance, but this is currently constrained by the lack of complete patient clinicopathological data. Moreover, in silico drug prescription performance could be improved by integrating additional tumour information layers like intra-tumour heterogeneity (ITH) which has been related to drug response and tumour progression. PanDrugs is an in silico drug prescription method which prioritizes anticancer drugs combining both biological and clinical evidence. We have systematically evaluated PanDrugs in the Genomic Data Commons repository (GDC). Our results showed that PanDrugs is able to establish an a priori stratification of cancer patients treated with Epidermal Growth Factor Receptor (EGFR) inhibitors. Patients labelled as responders according to PanDrugs predictions showed a significantly increased overall survival (OS) compared to non-responders. PanDrugs was also able to suggest alternative tailored treatments for non-responder patients. Additionally, PanDrugs usefulness was assessed considering spatial and temporal ITH in cancer patients and showed that ITH can be approached therapeutically proposing drugs or combinations potentially capable of targeting the clonal diversity. In summary, this study is a proof of concept where PanDrugs predictions have been correlated to OS and can be useful to manage ITH in patients while increasing therapeutic options and demonstrating its clinical utility.

Two different patterns of lung adenocarcinoma with concomitant EGFR mutation and ALK rearrangement

2021 ◽  
pp. 030089162110055
Author(s):  
Dashi Zhao ◽  
Jun Fan ◽  
Li Peng ◽  
Bo Huang ◽  
Yili Zhu ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Egfr Mutation ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Alk Rearrangement ◽  
Molecular Alterations ◽  
Anaplastic Lymphoma ◽  
Sporadic Cases ◽  
Epidermal Growth ◽  
Rare Group

Epidermal growth factor receptor ( EGFR) mutations and anaplastic lymphoma kinase ( ALK) rearrangements are considered mutually exclusive in non-small cell lung cancer (NSCLC), especially in lung adenocarcinoma (LUAC). However, sporadic cases harboring concomitant EGFR and ALK alterations have been increasingly reported. There is no consensus opinion regarding the treatment of patients positive for both molecular alterations. NSCLC with EGFR/ ALK coalterations should be separated into two subtypes: unifocal and multifocal LUAC. Here, we present an overview of the available literature regarding this rare group of patients to provide useful suggestions for therapeutic strategies.

scholarly journals Genetic variants of the EGFR ligand-binding domain and their association with structural alterations in Arab cancer patients

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Maryam Marzouq ◽  
Ali Nairouz ◽  
Noureddine Ben Khalaf ◽  
Sonia Bourguiba-Hachemi ◽  
Raed Quaddorah ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cancer Patients ◽  
Genetic Variants ◽  
Growth Factor Receptor ◽  
Genomic Analysis ◽  
Egfr Ligand ◽  
Energetic State ◽  
Epidermal Growth ◽  
The Common ◽  
Heterozygous Form

Abstract Objective This study aimed to identify novel genetic variants in the CR2 extracellular domain of the epidermal growth factor receptor (EGFR) in healthy individuals and patients with six different types of adenocarcinoma, in Arabian peninsula populations. It also aimed to investigate the effects of these variants on the EGFR structure and their eventual relevance to tumorigenesis. Results We detected seven new EGFR genetic variants in 168 cancer patients and 114 controls. A SNP rs374670788 was more frequent in bladder cancer but not significantly associated to. However, a missense mutation (V550M) was significantly associated to colon, ovary, lung, bladder and thyroid cancer samples (p < 0.05). Three mutations (H590R, E602K and T605T) were found in the heterozygous form only in colon cancer patients. Genomic analysis of the synonymous mutation (G632G) showed that the T/A genotype could be associated to thyroid cancer in Arab patients (p < 0.05). An additional novel SNP rs571064657 was observed in control individuals. Computational analysis of the genetic variants revealed a reduction in the stabilization of the EGFR tethered form for both V550M and the common R521K variant with low energetic state (− ∆∆G). Molecular interactions analysis suggested that these mutations might affect the receptor’s function and promote tumorigenesis.

Molecular Modeling of Novel Fluorophoric Thiazolo- [2, 3-B] Quinazolinones to Study Epidermal Growth Factor Receptor Tyrosine Kinase Inhibition Potency

2021 ◽  
Author(s):  
Showkat Mir ◽  
Ganesh Chandra Dash ◽  
Kumar Sambhav Chopdar ◽  
Prajna Mohanta ◽  
Pranab Kishor Mohapatra ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Active Site ◽  
In Silico ◽  
Growth Factor Receptor ◽  
Cancer Therapeutics ◽  
Tk Inhibitors ◽  
Epidermal Growth

Epidermal growth factor receptor tyrosine kinase (EGFR-TK) is one of the key regulators that exhibit pivotal role in proliferation of cancer cell. Quinazolinones are studiedly widely as effective EGFR-TK inhibitor because of their higher affinity to bind with adenosine triphosphate (ATP) binding site of receptor tyrosine kinases. However, their toxicity due to non-specific binding to tyrosine kinase in non-cancerous normally dividing cells of the body limits its applicability as a cancer therapeutics. In the present investigation a series of thirty-four novel synthesized thiazolo- [2, 3-b] quinazolinones were studied in silico as EGFR-TK inhibitors. All the thirty-four compounds were screened against EGFR-TK domain using multiple software’s (AutoDock Vina, Argus Lab, YASARA, and MOE). The interactions of the ligands with amino acid residues, namely, Lys721, Met769 and Asp831 of the active site were through the functional groups on aryl substituents at position 3 and 5 of the thiazolo- [2, 3-b] quinazolinone scaffold. The methyl substituents at position 8 of the ligands had prominent hydrophobic interactions in the active site cavity of EGFR-TK domain. The compounds 5ab, 5aq, and 5bq were predicted to be non-toxic and drug-like by in silico ADMET investigations. These compounds were considered for further investigation due to their non-toxicity and higher docking score ranking in different docking methods. The molecular dynamics (MD) simulation for 100 ns of docked complexes revealed the stability of these compounds. The binding free energy determined using Molecular Mechanics Generalized Born Model and Solvent Accessibility (MM-GBSA) method indicate that thiazolo- [2, 3-b] quinazolinone has high inhibitory efficacy similar to the standard drug, erlotinib (5ab - 22.45, 5aq -22.23, 5bq -20.76, and erlotinib -24.11 kcal/mol). In silico studies and MD simulations indicated that compounds (5ab, 5aq and 5bq) could be potential EGFR-TK inhibitors and require further validation as cancer therapeutics using carcinoma cell lines.<br><p></p>

scholarly journals Targeted Therapy for Advanced Solid Tumors on the Basis of Molecular Profiles: Results From MyPathway, an Open-Label, Phase IIa Multiple Basket Study

2018 ◽  
Vol 36 (6) ◽  
pp. 536-542 ◽  
Author(s):  
John D. Hainsworth ◽  
Funda Meric-Bernstam ◽  
Charles Swanton ◽  
Herbert Hurwitz ◽  
David R. Spigel ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Targeted Therapy ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Molecular Alterations ◽  
Epidermal Growth ◽  
Tumor Types ◽  
Murine Sarcoma

Purpose Detection of specific molecular alterations in tumors guides the selection of effective targeted treatment of patients with several types of cancer. These molecular alterations may occur in other tumor types for which the efficacy of targeted therapy remains unclear. The MyPathway study evaluates the efficacy and safety of selected targeted therapies in tumor types that harbor relevant genetic alterations but are outside of current labeling for these treatments. Methods MyPathway ( ClinicalTrials.gov identifier: NCT02091141) is a multicenter, nonrandomized, phase IIa multiple basket study. Patients with advanced refractory solid tumors harboring molecular alterations in human epidermal growth factor receptor-2, epidermal growth factor receptor, v-raf murine sarcoma viral oncogene homolog B1, or the Hedgehog pathway are treated with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. The primary end point is investigator-assessed objective response rate within each tumor-pathway cohort. Results Between April 1, 2014 and November 1, 2016, 251 patients with 35 different tumor types received study treatment. The efficacy population contains 230 treated patients who were evaluated for response or discontinued treatment before evaluation. Fifty-two patients (23%) with 14 different tumor types had objective responses (complete, n = 4; partial, n = 48). Tumor-pathway cohorts with notable objective response rates included human epidermal growth factor receptor-2–amplified/overexpressing colorectal (38% [14 of 37]; 95% CI, 23% to 55%) and v-raf murine sarcoma viral oncogene homolog B1 V600-mutated non–small-cell lung cancer (43% [six of 14]; 95% CI, 18% to 71%). Conclusion The four currently approved targeted therapy regimens in the MyPathway study produced meaningful responses when administered without chemotherapy in several refractory solid tumor types not currently labeled for these agents.

scholarly journals Epidermal Growth Factor Receptor Protein Detection in Head and Neck Cancer Patients: A Many-Faceted Picture

2012 ◽  
Vol 18 (5) ◽  
pp. 1313-1322 ◽  
Author(s):  
Juliette Thariat ◽  
Marie-Christine Etienne-Grimaldi ◽  
Dominique Grall ◽  
René-Jean Bensadoun ◽  
Anne Cayre ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Head And Neck Cancer ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Head And Neck ◽  
Cancer Patients ◽  
Growth Factor Receptor ◽  
Protein Detection ◽  
Receptor Protein ◽  
Epidermal Growth
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