Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy

Collisson, Eric A.; Sadanandam, Anguraj; Olson, Peter; Gibb, William J.; Truitt, Morgan; Gu, Shenda; Cooc, J.; Weinkle, Jennifer; Kim, Grace; Jakkula, Lakshmi R.; Feiler, Heidi S.; Ko, Andrew H.; Olshen, Adam B.; Danenberg, Kathleen L; Tempero, Margaret A.; Spellman, Paul T.; Hanahan, Douglas; Gray, Joe W.

doi:10.1038/nm.2344

Cited by 1,467 publications

(1,794 citation statements)

References 35 publications

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“…The squamous subtype of the disease, which overlaps with the quasi-mesenchymal subtype defined by Collisson and colleagues (21), is characterized by an activated MYC pathway (20) and the poorest outcome (20)(21)(22). These observations moreover reinforce MYC being a relevant driver in PDAC and argue that MYC targeting strategies are needed.…”

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confidence: 85%

Concepts to Target MYC in Pancreatic Cancer

Wirth

Mahboobi

Krämer

et al. 2016

Molecular Cancer Therapeutics

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Current data suggest that MYC is an important signaling hub and driver in pancreatic ductal adenocarcinoma (PDAC), a tumor entity with a strikingly poor prognosis. No targeted therapies with a meaningful clinical impact were successfully developed against PDAC so far. This points to the need to establish novel concepts targeting the relevant drivers of PDAC, like KRAS or MYC. Here, we discuss recent developments of direct or indirect MYC inhibitors and their potential mode of action in PDAC.

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confidence: 85%

Concepts to Target MYC in Pancreatic Cancer

Wirth

Mahboobi

Krämer

et al. 2016

Molecular Cancer Therapeutics

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“…Attempts have been made to identify subtypes of PDAC in hopes of developing more specific and effective therapies for use within subtypes [32–34]. Thus far, genome-wide studies of gene mutations in PDAC have not led to selective treatments of PDAC subtypes based on mutation type.…”

Section: Translational Value Of Epigenetics For Gi Disease Diagnosismentioning

confidence: 99%

“…Thus far, genome-wide studies of gene mutations in PDAC have not led to selective treatments of PDAC subtypes based on mutation type. However, transcriptome studies of PDAC samples have suggested the division of this disease into classical, quasimesenchymal, and exocrine-like subtypes on the basis of differential gene expression and histological differences within subtypes [34]. As mentioned above, Dr. Jens Siveke identified different PDAC subtypes based on differential sensitivity to drugs such as HDAC and BET inhibitors [30].…”

Section: Translational Value Of Epigenetics For Gi Disease Diagnosismentioning

confidence: 99%

Epigenetics of gastrointestinal diseases: notes from a workshop

et al. 2018

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International experts gathered at the Mayo Clinic (Rochester MN, USA) on February 27th-28th, 2017 for a meeting entitled ‘Basic and Translational Facets of the Epigenetics of GI Diseases’. This workshop summarized recent advances on the role of epigenetics in the pathobiology of gastrointestinal (GI) diseases. Highlights of the meeting included recent advances on the involvement of different epigenetic mechanisms in malignant and nonmalignant GI disorders and the epigenetic heterogeneity exhibited in these diseases. The translational value of epigenetic drugs, as well as the current and future use of epigenetic changes (i.e., DNA methylation patterns) as biomarkers for early detection tools or disease stratification were also important topics of discussion.

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“…A heterogeneous collection of secondary genetic alterations is also present in patients with pancreatic cancer (Biankin et al, 2012;Yachida & Iacobuzio-Donahue, 2013), giving rise to various PDA subclasses, reflected in a variety of cancerderived cell lines (Deer et al, 2010), which may display different therapeutic responsiveness and thus may require ad hoc intervention strategies (Biankin et al, 2012;Collisson et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

An engineered avian-origin influenza A virus for pancreatic ductal adenocarcinoma virotherapy

Pizzuto

Silic-Benussi

Ciminale

et al. 2016

Journal of General Virology

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Pancreatic ductal adenocarcinoma (PDA) is one of the leading causes of cancer-related deaths worldwide and the development of new treatment strategies for PDA patients is of crucial importance. Virotherapy uses natural or engineered oncolytic viruses (OVs) to selectively kill tumour cells. Due to their genetic heterogeneity, PDA cells are highly variable in their permissiveness to various OVs. The avian influenza A virus (IAV) H7N3 A/turkey/Italy/2962/03 is a potent inducer of apoptosis in PDA cells previously shown to be resistant to other OVs (Kasloff et al., 2014), suggesting that it might be effective against specific subclasses of pancreatic cancer. To improve the selectivity of the avian influenza isolate for PDA cells, here confirmed deficient for IFN response, we engineered a truncation in the NS1 gene that is the major virusencoded IFN antagonist. The recombinant virus (NS1-77) replicated efficiently in PDA cells, but was attenuated in non-malignant pancreatic ductal cells, in which it induced a potent IFN response that acted upon bystander uninfected cancer cells, triggering their death. The engineered virus displayed an enhanced ability to debulk a PDA-derived tumour in xenograft mouse model. Our results highlight the possibility of selecting an IAV strain from the diverse natural avian reservoir on the basis of its inherent oncolytic potency in specific PDA subclasses and, through engineering, improve its safety, selectivity and debulking activity for cancer treatment.

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Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy

Cited by 1,467 publications

References 35 publications

Concepts to Target MYC in Pancreatic Cancer

Concepts to Target MYC in Pancreatic Cancer

Epigenetics of gastrointestinal diseases: notes from a workshop

An engineered avian-origin influenza A virus for pancreatic ductal adenocarcinoma virotherapy

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