Genomic characterization of patient-derived xenograft models established from fine needle aspirate biopsies of a primary pancreatic ductal adenocarcinoma and from patient-matched metastatic sites

Allaway, Robert J.; Fischer, Donald R.; Abreu, Francine B. de; Gardner, Timothy B.; Gordon, Stuart R.; Barth, Richard J.; Colacchio, Thomas A.; Wood, Matthew D.; Kacsoh, Balint Z.; Bouley, Stephanie J.; Cui, Jingxuan; Hamilton, Joanna M.; Choi, Justin; Lange, Joshua T.; Peterson, Julie; Padmanabhan, Vijayalakshmi; Tomlinson, Craig R.; Tsongalis, Gregory J.; Suriawinata, Arief A.; Greene, Casey S.; Sánchez, Yolanda; Smith, Kerrington D.

doi:10.18632/oncotarget.7718

Cited by 43 publications

(36 citation statements)

References 58 publications

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“…BET bromodomains recruit CDK9, the catalytic subunit of P-TEFb, which catalyses the phosphorylation of serine 2 in the heptapeptide repeat sequence within the C-terminal domain of RNA polymerase II, a post-translational modification associated with transcriptional elongation 66. Importantly, Dinaciclib has been reported to abrogate PDAC growth and progression in vitro and in vivo69 70 and is currently being evaluated for its therapeutic potential in patients with PDAC in combination with the poly [ADP-ribose] polymerase (PARP) inhibitor veliparib (NCT01434316) and MK2206-mediated Akt inhibition (NCT01783171). Interestingly, CDK9 and BET inhibitors were also shown to function synergistically 71.…”

Section: Translational Approaches To Tackle Epigenetic Dysregulation mentioning

confidence: 99%

Epigenetic treatment of pancreatic cancer: is there a therapeutic perspective on the horizon?

Heßmann¹,

Johnsen²,

Siveke

2016

Gut

107

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Pancreatic ductal adenocarcinoma (PDAC) constitutes one of the most aggressive malignancies with a 5-year survival rate of <7%. Due to growing incidence, late diagnosis and insufficient treatment options, PDAC is predicted to soon become one of the leading causes of cancer-related death. Although intensified cytostatic combinations, particularly gemcitabine plus nab-paclitaxel and the folinic acid, fluorouracil, irinotecan, oxaliplatin (FOLFIRINOX) protocol, provide some improvement in efficacy and survival compared with gemcitabine alone, a breakthrough in the treatment of metastatic pancreatic cancer remains out of sight. Nevertheless, recent translational research activities propose that either modulation of the immune response or pharmacological targeting of epigenetic modifications alone, or in combination with chemotherapy, might open highly powerful therapeutic avenues in GI cancer entities, including pancreatic cancer. Deregulation of key epigenetic factors and chromatin-modifying proteins, particularly those responsible for the addition, removal or recognition of post-translational histone modifications, are frequently found in human pancreatic cancer and hence constitute particularly exciting treatment opportunities. This review summarises both current clinical trial activities and discovery programmes initiated throughout the biopharma landscape, and critically discusses the chances, hurdles and limitations of epigenetic-based therapy in future PDAC treatment.

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Section: Translational Approaches To Tackle Epigenetic Dysregulation mentioning

confidence: 99%

Epigenetic treatment of pancreatic cancer: is there a therapeutic perspective on the horizon?

Heßmann¹,

Johnsen²,

Siveke

2016

Gut

107

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“…46 More recently it has been shown that cfDNA also contains circulating tumor DNA that can contain mutations similar to those seen in a patient's tumor in xenograft models and in patient plasma samples. [46][47][48] One promising aspect of the liquid biopsy is in the use of blood testing to monitor patients with solid tumors for progression of disease and development of resistance as a complement to or replacement for additional imaging studies and tissue biopsy. 49,50 Clinical Challenges, Number of Genes, Number of Mutations, Reporting/Interpretation As a complex yet common disease, cancer causes enormous morbidity and mortality worldwide.…”

Section: Technical Issues To Consider For Implementing Somatic Mutatimentioning

confidence: 99%

Somatic Mutation Analysis of Human Cancers: Challenges in Clinical Practice

Tsongalis

Coleman

2017

The Journal of Clinical Pharma

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Somatic mutation analysis of human cancers has become the standard of practice. Whether screening for single gene variants or sequencing hundreds of cancer-related genes, this genomic information is the basis for precision medicine initiatives in oncology. Genomic profiling results in information that allows oncologists to make a more educated selection of appropriate therapeutic strategies that more often combine traditional cytotoxic chemotherapy and radiation with novel targeted therapies. Here we discuss the nuances of implementing somatic mutation testing in a clinical setting. Keywordsclinical genomics, oncology, precision medicine, pharmacogenomics, somatic mutation Novel therapies, including the use of directed monoclonal antibodies, tyrosine kinase inhibitors, and immunotherapies, have come to fruition as our understanding of the etiology of human cancer expands. From the identification of the first oncogenes and tumor-suppressor genes to current full gene sequencing for the identification of somatic mutations, knowledge of tumor-cell genetic variant profiles has become critical to the management of the cancer patient.1-3 One projection of the Human Genome Project was to gain a more fundamental understanding of human disease at the genomic level such that novel therapeutics could be designed to provide a more personalized approach to disease management. The identification of numerous driver mutations in various human cancers, which are causally implicated in establishing growth advantages to a cell, have also become the target of novel therapies that confer more efficacious outcomes. 4,5 The rapid development of targeted therapies is also resulting in more advanced and focused clinical trial designs whereby testing protocols aim to match patients whose tumors harbor specific somatic mutations with those specific therapies targeting the gene or pathway affected. 6,7 Precision Medicine in OncologyWith respect to the cancer patient, the concept of targeted or individualized therapy can include 2 aspects of what is often termed pharmacogenomics. The first is the more traditional concept that encompasses how an individual may metabolize, absorb, transport, and excrete therapeutic drugs differently based on polymorphisms in the genes that code for these functions. This type of individual variation in metabolism was first described in 510 BC when Pythagoras recognized hemolytic anemia developing in some individuals who consumed fava beans.8 This phenotype was later attributed to a glucose-6-phosphate dehydrogenase deficiency. 9 We have termed pharmacogenomic concepts linked to drug metabolism PGX m , which corresponds to genetic variants that determine drug disposition, also referred to as drug pharmacokinetics.10,11 The conversion of a parent compound to an inactive metabolite or to one that is more easily excreted and the conversion of a prodrug to its active metabolite are examples of PGX m .PGX t is the second aspect of pharmacogenomics that involves the selection of a therapeutic drug based on the...

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“…We showed that deletion of CTK1 was synthetic lethal with loss of the yeast NF1 homolog IRA2. Furthermore, we have found that inhibitors of this process (dinaciclib, SNS-032) can inhibit other types of RASdysregulated tumor cells [9].…”

Section: Introductionmentioning

confidence: 99%

A machine learning classifier trained on cancer transcriptomes detects NF1 inactivation signal in glioblastoma

Way

Allaway

Bouley

et al. 2016

Preprint

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Background: We have identified molecules that exhibit synthetic lethality in cells with loss of the neurofibromin 1 (NF1) tumor suppressor gene. However, recognizing tumors that have inactivation of the NF1 tumor suppressor function is challenging because the loss may occur via mechanisms that do not involve mutation of the genomic locus. Degradation of the NF1 protein, independent of NF1 mutation status, phenocopies inactivating mutations to drive tumors in human glioma cell lines. NF1 inactivation may alter the transcriptional landscape of a tumor and allow a machine learning classifier to detect which tumors will benefit from synthetic lethal molecules.

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Genomic characterization of patient-derived xenograft models established from fine needle aspirate biopsies of a primary pancreatic ductal adenocarcinoma and from patient-matched metastatic sites

Cited by 43 publications

References 58 publications

Epigenetic treatment of pancreatic cancer: is there a therapeutic perspective on the horizon?

Epigenetic treatment of pancreatic cancer: is there a therapeutic perspective on the horizon?

Somatic Mutation Analysis of Human Cancers: Challenges in Clinical Practice

A machine learning classifier trained on cancer transcriptomes detects NF1 inactivation signal in glioblastoma

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