Pancreatic Cancer

Background | Top Products | Literature | Pathways

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.

Pancreatic Cancer Product Areas

Background

KRAS Mutations | Tumor Microenvironment | Pancreatic Tumor Organoids

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.

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.

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

Literature

• Angiogenesis in Cancer Poster
• Cancer Metabolism Poster
• Cell Cycle & DNA Damage Repair Poster
• Cell Cycle and DNA Damage Research Product Guide
• Epigenetics in Cancer Poster
• Stem Cells Poster
• Stem Cell Research Product Guide
• Stem Cell Workflow Poster
• TPD and Induced Proximity Research Product Guide

Pathways

• JAK-STAT Signaling Pathway
• mTOR Signaling Pathway
• Notch Signaling Pathway
• TGF-β Signaling Pathway
• VEGF Signaling Pathway