scholarly journals Tumor-Agnostic Drug Development

2018 ◽  
pp. 184-187 ◽  
Author(s):  
Michael Offin ◽  
Dazhi Liu ◽  
Alexander Drilon
Keyword(s):  
Next Generation Sequencing ◽  
Drug Development ◽  
Molecular Signatures ◽  
Patient Access ◽  
Next Generation ◽  
Basket Trial ◽  
Key Aspects ◽  
Tumor Types ◽  
Generation Sequencing

Therapies designed to target cancers that harbor specific molecular signatures have reshaped the landscape of oncologic drug development, and advances in next generation sequencing have led to an increase in the identification of these alterations across tumor types. Tumor-agnostic trial designs, such as the “basket trial,” have been developed as an approach to study the efficacy of these treatments and increase patient access, especially for patients whose tumors carry these alterations infrequently. We review key aspects of these genomically enriched trial strategies and their impact on drug development and approval.

scholarly journals Analysis of MDM2 Amplification: Next-Generation Sequencing of Patients With Diverse Malignancies

2018 ◽  
pp. 1-14 ◽  
Author(s):  
Shumei Kato ◽  
Jeffrey S. Ross ◽  
Laurie Gay ◽  
Farshid Dayyani ◽  
Jason Roszik ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Mapk Signaling ◽  
Small Subset ◽  
Next Generation ◽  
Investigational Agent ◽  
Mutation Burden ◽  
Tumor Types ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Mdm2 Amplification

Purpose MDM2 amplification can promote tumorigenesis directly or indirectly through p53 inhibition. MDM2 has increasing clinical relevance because inhibitors are under evaluation in clinical trials, and MDM2 amplification is a possible genomic correlate of accelerated progression, known as hyperprogression, after anti–PD-1/PD-L1 immunotherapy. We used next-generation sequencing (NGS) to ascertain MDM2 amplification status across a large number of diverse cancers. Methods We interrogated the molecular profiles of 102,878 patients with diverse malignancies for MDM2 amplification and co-altered genes using clinical-grade NGS (182 to 465 genes). Results MDM2 amplification occurred in 3.5% of patients (3,650 of 102,878). The majority of tumor types had a small subset of patients with MDM2 amplification. Most of these patients (99.0% [3,613/3,650]) had co-alterations that accompanied MDM2 amplification. Various pathways, including those related to tyrosine kinase (37.9% [1,385 of 3,650]), PI3K signaling (25.4% [926 of 3,650]), TP53 (24.9% [910 of 3,650]), and MAPK signaling (23.6% [863 of 3,650]), were involved. Although infrequent, mismatch repair genes and PD-L1 amplification also were co-altered (2.2% [79 of 3,650]). Most patients (97.6% [3,563 of 3,650]) had one or more co-alterations potentially targetable with either a Food and Drug Administration–approved or investigational agent. MDM2 amplifications were less frequently associated with high tumor mutation burden compared with the MDM2 wild-type population (2.9% v 6.5%; P < .001). An illustrative patient who harbored MDM2 amplification and experienced hyperprogression with an immune checkpoint inhibitor is presented. Conclusion MDM2 amplification was found in 3.5% of 102,878 patients, 97.6% of whom harbored genomic co-alterations that were potentially targetable. This study suggests that a small subset of most tumor types have MDM2 amplification as well as pharmacologically tractable co-alterations.

scholarly journals Parallel detection of ancient pathogens via array-based DNA capture

2015 ◽  
Vol 370 (1660) ◽  
pp. 20130375 ◽  
Author(s):  
Kirsten I. Bos ◽  
Günter Jäger ◽  
Verena J. Schuenemann ◽  
Åshild J. Vågene ◽  
Maria A. Spyrou ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Mycobacterium Leprae ◽  
Molecular Signatures ◽  
Next Generation ◽  
Screening Technique ◽  
Parallel Detection ◽  
Left Behind ◽  
Dna Capture ◽  
Generation Sequencing

DNA capture coupled with next generation sequencing is highly suitable for the study of ancient pathogens. Screening for pathogens can, however, be meticulous when assays are restricted to the enrichment of single organisms, which is common practice. Here, we report on an array-based DNA capture screening technique for the parallel detection of nearly 100 pathogens that could have potentially left behind molecular signatures in preserved ancient tissues. We demonstrate the sensitivity of our method through evaluation of its performance with a library known to harbour ancient Mycobacterium leprae DNA. This rapid and economical technique will be highly useful for the identification of historical diseases that are difficult to characterize based on archaeological information alone.

scholarly journals Zombies in TCGA

2015 ◽  
Vol 89 (8) ◽  
pp. 4044-4046 ◽  
Author(s):  
Daniel DiMaio
Keyword(s):  
Human Papillomavirus ◽  
Next Generation Sequencing ◽  
Hela Cells ◽  
Somatic Mutations ◽  
Hpv Infection ◽  
Next Generation ◽  
Human Cancers ◽  
Human Papillomavirus 18 ◽  
Tumor Types ◽  
Generation Sequencing

Next-generation sequencing results obtained to detect somatic mutations in human cancers can also be searched for viruses that contribute to cancer. Recently, human papillomavirus 18 RNA was detected in tumor types not typically associated with HPV infection. Analyses reported in this issue ofJournal of Virologydemonstrate that the apparent presence of HPV18 RNA in these atypical tumors is due in at least some cases to contamination of samples with HeLa cells, which harbor HPV18.

scholarly journals Clinical Targeted Next-Generation Sequencing to Identify Potentially Actionable Alterations in the Majority of Asian Cancer Patients

2018 ◽  
Vol 4 (Supplement 2) ◽  
pp. 88s-88s
Author(s):  
S.L. Poon ◽  
Y.-J. Lu ◽  
R.-S. Jhou ◽  
Y.-T. Yang ◽  
P.-N. Yu ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Targeted Therapies ◽  
Hedgehog Signaling ◽  
Next Generation ◽  
Therapeutic Implications ◽  
Targeted Next Generation Sequencing ◽  
Formalin Fixed Paraffin Embedded ◽  
Ffpe Tissues ◽  
Tumor Types ◽  
Generation Sequencing

Background: Clinically innovative genomic diagnostics may expedite the selection of effective targeted therapies if the patient can be stratified correctly based on their unique cancer driven events/pathways during tumorigenesis. Aim: Here, we performed a pan-cancer analysis on the clinical utility of a targeted gene panel, ACTOnco+, in characterizing the prevalence of actionable mutations. Methods: A total of 229 formalin-fixed, paraffin-embedded (FFPE) tissues from 40 tumor types were subjected to next-generation sequencing (NGS) using the Ion Torrent Proton System. All coding exons in 440 cancer-related genes were assessed at average depth of > 800X. Therapeutic implications were based on information obtained from base substitutions, indels, and copy number alterations (CNAs). Results: 58.5% (n=134) patients harbored at least one actionable mutation while CNAs, including homozygous and heterozygous deletions, were detected in 83.9% (n=191) of patients. Across all tumor types, the most frequently altered pathway that can confer either sensitivity or resistance to targeted therapies was PI3K/AKT/mTOR signaling, contributed by PIK3CA and AKT1 activating mutations as well as NF1, NF2, PTEN, TSC1, STK11 and TSC2 inactivating mutations or deletions. In parallel, dysregulation of cell cycle was mostly owing to CCND1, CDK4 and CDK6 amplification and/or loss of CDKN2A. Notably, on top of BRCA1/ 2 mutations, deletion of BRCAness-related genes ( MRE11, RAD50, PALB2, FANCD2, ATM, ATR, CHEK1 and CHEK2) that may result in homologous recombination deficiency (HRD) was observed in 71.4% breast, 70.6% ovarian, 61.0% lung, 58.3% pancreatic, and 52.2% colorectal cancers. Other targetable alterations on receptor tyrosine kinase (RTK), angiogenic and hedgehog signaling pathways were also observed. Conclusion: A comprehensive pathway-based genomic profiling characterized significant actionable alterations across different solid tumors that may play a role in tissue-agnostic tailored treatment.

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