Pancreatic Cancer

Pancreatic cancer contributes to 2.5% of all new cancer cases and 4.6% of all cancer deaths worldwide and is one of the most lethal and aggressive cancers, with a 5-year survival rate of less than 9%. Pancreatic cancer is the 4th leading cause of death in developed countries, with these countries also contributing over 50% of new cases. Estimates suggest that pancreatic cancer will become the second major cause of cancer-related deaths. Research is focusing on the tumor microenvironment (TME) and metabolic reprogramming. Early detection of pancreatic cancer is a key area of clinical development, while subtyping, and molecular/genetic landscaping of tumors generates individualized data for integration into treatment modalities to improve survival outcomes.

Research Areas
Literature (15)
Pathways (5)
Pancreatic cancer is a heterogeneous disease and can be broadly classified into two common types: pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine carcinoma (PNEC). PDAC accounts for over 90% of cases and develops from intraepithelial neoplasia (PanIN) within exocrine ducts of the pancreas. Multiple genes have been identified as being associated with PDAC. Inactivating mutations in tumor suppressors are prevalent, including within BRCA1/2, CDKN2A, STK11, MLH1 and TP53, with familial mutations in these genes also increasing hereditary risk. Oncogenic activation of KRAS, GNAS, BRAF, MYC, RNF43, KDM6a, ATG5 and NRF2 are key driving events in the initiation and progression of PDAC. The mutational status of these genes can be detected through in-situ hybridization (ISH) approaches such as RNAscope where multiplexed imaging and analysis of genes can be used to define patient stratification.


KRAS Mutations and Pancreatic Cancer

Mutations in the Ras GTPase KRAS are activated in over 90% of pancreatic tumors. These mutations and activations are a signature feature of PDAC and act as major drivers of tumor progression, adaptation and therapy resistance. KRAS mutations affect the upregulation of cellular pathways impact the resulting tumor phenotype and clinical outcomes. Pancreatic cancer is one of the most hypoxic cancers and creates a highly immunosuppressive tumor microenvironment (TME), which further increases the challenge of finding effective therapeutic options. The effects of KRAS mutations on cellular mechanisms and on the characteristic traits of PDAC are summarized in Table 1.

Table 1. KRAS mutations associated with pancreatic cancer and their effects on cellular processes, the pathways affected and tools that can target the specific genes or pathways.

KRAS Mutation (Prevalence) Trait Downstream Pathway or Mechanism Affected Research Tools
G12D (40%)
G12V (33%)
G12R (15%)
Other mutations (12%)
Endocytosis PI3K-AKT-mTOR
RAF-MEK-ERK
JNK
Rapamycin - mTOR inhibitor
Proliferation AX 15836 - ERK5 inhibitor
Invasion Defactinib - FAK and Pyk2 inhibitor
Hypoxia HIF-1α FM19G11- HIF-1α-subunit inhibitor
Metabolic Changes Glucose Transporters BAY 876 - GLUT1 inhibitor
Macropinocytosis V-ATPase EN6 - V-ATPase inhibitor
Autophagy LKB1 > AMPK > ULK1 MRT 68921 - ULK and autophagy inhibitor
Tumor Microenvironment
(immunosuppressive)
TGFβR
VEGFR
COX2
SB 431542 - TGFβR inhibitor
SU 5416 - VEGFR inhibitor

Previously considered an 'undruggable target', the direct inhibition of KRAS has been a field of intense interest. The first KRAS PROTAC® LC 2 (Cat. No. 7420) has been developed for targeted protein degradation and creates new opportunities for researching the KRAS-based driving mechanisms of PDAC. Indirect inhibition of KRAS interactions can also be used in research to understand how different pathways contribute to the TME and to PDAC progression. For example, the Ras inhibitor BAY 293 (Cat. No. 6857) and the Raf and MAPK inhibitor Sorafenib (Cat. No. 6814) can indirectly inhibit KRAS interactions.

Tumor Microenvironment and Pancreatic Cancer

Whilst KRAS mutations are important in pancreatic cancer, they should not be considered in isolation but also in combination with the TME and the tumor biology. The hypoxic nature of the TME results in increased HIF1A expression, alterations in cellular metabolism, and local immunosuppression. Inhibition of the hypoxic TME, using compounds such as the HIF-1α inhibitor GN 44028 (Cat. No. 5655), could therefore provide information about immunological changes and reveal new immune-oncology targets. The changes resulting from inhibition of the hypoxic state could also be monitored by using a FAM-labelled HIF-1α peptide (Cat. No. 7452).

The hypoxic nature of the TME leads to a shift in metabolism from oxidative-phosphorylation to glycolysis. The increased glucose requirement associated with this is frequently associated with increased glucose transporter expression; increased expression of GLUT1 is also associated with overexpression of RAS and BRAF genes. The effect of inhibited glucose metabolism on glucose uptake can be monitored through inhibition of GLUT1 using BAY 876 (Cat. No. 6199) in combination with the fluorescent glucose uptake indicator 2-NBDG (Cat. No. 6065). Such approaches could also give insights into tumor metabolic adaptation. Expression changes and tumor evolution or resistance mechanisms could be further evaluated using more broad inhibition of KRAS with Salirasib (Cat. No. 4989) and VEGFR using Axitinib (Cat. No. 4350), whilst monitoring expression levels using ISH, forming a well-integrated workflow.

The SUMO pathway is also an important pathway in PDAC, especially in connection with MYC expression which is a known cancer driver. The SUMOylation of proteins can function as a protective role in hypoxia and other stress states. By modulating SUMO with activators, such as N106 (Cat. No. 5681), or inhibitors like HODHBt (Cat. No. 6994) the effect of SUMOylation on the hypoxic response can be studied further.

Pancreatic Tumor Organoids

Another option for studying pancreatic cancer is to take cells from either healthy pancreas or from a pancreatic tumor and culture these in the presence of a synthetic hydrogel scaffold to produce miniature 3-dimensional organs, or pancreatic organoids. Cells taken directly from a patient with a specific type of tumor and cultured to produce a patient-derived organoid could provide a more direct way to assess how well an individual tumor will respond to treatment. Organoids grown in this way can mimic how tumors would grow and invade surrounding tissues so it may be possible to study how the tumor binds to other tissues and metastasises. By altering the structural supports, for example by inhibiting adhesion, it may be possible to explore how a tumor responds to various treatments.

Related Resources from our Sister Brands

Defining the KRAS mutational status is a challenge using traditional immunohistochemistry approaches, so the use of additional technologies such as BaseScope can be used to visualise the mutational state within cells or tissues, and to locate pathways or mutations of interest. Another integrated approach involves the use of liquid biopsies to combine exosome enrichment and BaseScope to define the mutational state of a sample. For example, the detection and localization of mutations such as G12V (BA-Hs-KRAS-G12V) and G12C (BA-Hs-KRAS-G12C) could be compared. Another example would be to target the activated PI3K pathway using the PI3K inhibitor Omipalisib (Cat. No. 6792) in the presence of the G12D mutation. RNA/BaseScope could also be used to spatio-temporally track tumor evolution, understand the response to treatment and to identify differentially expressed genes and targets of interest.

PROTAC® is a registered trademark of Arvinas Operations, Inc., and is used under license.

New and Top Products for Pancreatic Cancer Research

Target Top Products New Products
KRAS LC 2, BAY 293 MRTX 849
EGFR Erlotinib EMI 48
AKT AT 7867  
VTPase SB 590885  
SMARCA4, SMARCA2 SGC SMARCA-BRDVIII  
ERBB4 Neratinib  
STAT3 A 419259  
JAK1 PKF 115584, FH 535  
MYC KJ Pyr 9  
mTOR Torin1, Torin 2  
NOTCH DBZ  
PTEN SL 327  
Wee1   Adavosertib

Literature for Pancreatic Cancer

Tocris offers the following scientific literature for Pancreatic Cancer to showcase our products. We invite you to request* or download your copy today!

*Please note that Tocris will only send literature to established scientific business / institute addresses.


Cancer Research Product Guide

Cancer Research Product Guide

A collection of over 750 products for cancer research, the guide includes research tools for the study of:

  • Cancer Metabolism
  • Epigenetics in Cancer
  • Receptor Signaling
  • Cell Cycle and DNA Damage Repair
  • Angiogenesis
  • Invasion and Metastasis
Cell Cycle and DNA Damage Research Product Guide

Cell Cycle and DNA Damage Research Product Guide

This product guide provides a review of the cell cycle and DNA damage research area and lists over 170 products, including research tools for:

  • Cell Cycle and Mitosis
  • DNA Damage Repair
  • Targeted Protein Degradation
  • Ubiquitin Proteasome Pathway
  • Chemotherapy Targets
Stem Cell Research Product Guide

Stem Cell Research Product Guide

This product guide provides a background to the use of small molecules in stem cell research and lists over 200 products for use in:

  • Self-renewal and Maintenance
  • Differentiation
  • Reprogramming
  • Organoid Generation
  • GMP and Ancillary Material Grade Products
Targeted Protein Degradation Research Product Guide

Targeted Protein Degradation Research Product Guide

This brochure highlights the tools and services available from Bio-Techne to support Targeted Protein Degradation research, including:

  • Active Degraders
  • TAG Degradation Platform
  • Degrader Building Blocks
  • Custom Degrader Services
  • Ubiquitin-Proteasome System Proteins and Assays
  • Assays for Protein Degradation
Autophagy Scientific Review

Autophagy Scientific Review

Written by Patricia Boya and Patrice Codogno, this review summarizes the molecular mechanisms, physiology and pathology of autophagy. The role of autophagy in cell death and its links to disease are also discussed. Compounds available from Tocris are listed.

RAS Oncoproteins Scientific Review

RAS Oncoproteins Scientific Review

Written by Kirsten L. Bryant, Adrienne D. Cox and Channing J. Der, this review provides a comprehensive overview of RAS protein function and RAS mutations in cancer. Key signaling pathways are highlighted and therapeutic vulnerabilities are explored. This review also includes a detailed section on RAS drug discovery and targeting synthetic lethal interactors of mutant RAS. Compounds available from Tocris are listed.

Stem Cells Scientific Review

Stem Cells Scientific Review

Written by Kirsty E. Clarke, Victoria B. Christie, Andy Whiting and Stefan A. Przyborski, this review provides an overview of the use of small molecules in the control of stem cell growth and differentiation. Key signaling pathways are highlighted, and the regulation of ES cell self-renewal and somatic cell reprogramming is discussed. Compounds available from Tocris are listed.

Epigenetics Research Bulletin

Epigenetics Research Bulletin

Produced by Tocris and updated in 2014, the epigenetics research bulletin gives an introduction into mechanisms of epigenetic regulation, and highlights key Tocris products for epigenetics targets including:

  • Bromodomains
  • DNA Methyltransferases
  • Histone Deacetylases
  • Histone Demethylases
  • Histone Methyltransferases
Angiogenesis in Cancer Poster

Angiogenesis in Cancer Poster

Adapted from the 2015 Cancer Product Guide, Edition 3, this poster summarizes the pathogenesis of angiogenesis in cancer, as well as some of the main angiogenesis therapeutic targets.

Autophagy Poster

Autophagy Poster

Autophagy is a cellular process used by cells for degradation and recycling. Written by Patricia Boya and Patrice Codogno, this poster summarizes the molecular machinery, physiology and pathology of autophagy. Compounds available from Tocris are listed.

Cancer Metabolism Poster

Cancer Metabolism Poster

Adapted from the 2015 Cancer Product Guide, Edition 3, this poster summarizes the main targets for cancer metabolism researchers. Genetic changes and epigenetic modifications in cancer cells alter the regulation of cellular metabolic pathways. These distinct metabolic circuits could provide viable cancer therapeutic targets.

Cell Cycle & DNA Damage Repair Poster

Cell Cycle & DNA Damage Repair Poster

In normal cells, each stage of the cell cycle is tightly regulated, however in cancer cells many genes and proteins that are involved in the regulation of the cell cycle are mutated or over expressed. Adapted from the 2015 Cancer Product Guide, Edition 3, this poster summarizes the stages of the cell cycle and DNA repair. It also highlights strategies for enhancing replicative stress in cancer cells to force mitotic catastrophe and cell death.

Epigenetics in Cancer Poster

Epigenetics in Cancer Poster

Adapted from the 2015 Cancer Product Guide Edition 3, this poster summarizes the main epigenetic targets in cancer. The dysregulation of epigenetic modifications has been shown to result in oncogenesis and cancer progression. Unlike genetic mutations, epigenetic alterations are considered to be reversible and thus make promising therapeutic targets.

Stem Cell Workflow Poster

Stem Cell Workflow Poster

Stem cells have potential as a source of cells and tissues for research and treatment of disease. This poster summarizes some key protocols demonstrating the use of small molecules across the stem cell workflow, from reprogramming, through self-renewal, storage and differentiation to verification. Advantages of using small molecules are also highlighted.

Stem Cells Poster

Stem Cells Poster

Written by Rebecca Quelch and Stefan Przyborski from Durham University (UK), this poster describes the isolation of pluripotent stem cells, their maintenance in culture, differentiation, and the generation and potential uses of organoids.

Pathways for Pancreatic Cancer

JAK-STAT Signaling Pathway

JAK-STAT Signaling Pathway

The JAK-STAT signaling pathway has several roles, including the control of cell proliferation and hematopoiesis. It is the main signal transduction cascade from cytokine receptors.
Notch Signaling Pathway

Notch Signaling Pathway

The Notch pathway is involved in determination of cell fate, regulation of pattern formation and other developmental settings. Disrupted signaling can cause developmental defects and a range of adult pathologies.
TGF-β Signaling Pathway

TGF-β Signaling Pathway

The TGF-β signaling pathway is involved in the regulation of growth and proliferation of cells along with migration, differentiation and apoptosis.
VEGF Signaling Pathway

VEGF Signaling Pathway

VEGF signaling pathway is involved in embryonic vascular development (vasculogenesis) and in the formation of new blood vessel (angiogenesis). It also induces cell migration, proliferation and survival.
mTOR Signaling Pathway

mTOR Signaling Pathway

mTOR is a serine/threonine kinase that nucleates at multiprotein complexes mTORC1 and mTORC2. Signaling by these complexes regulates cell growth, proliferation and survival.