Project title: Angiopoietin-2/Tie2 signaling regulation of liver metastasis in pNETs

Description

Kim will use a pancreatic NET mouse model to determine the significance of Angiopoietin-2(Ang2)/Tie2 signaling on liver metastasis and anti-VEGF drug efficacy.

What question will the researchers try to answer?

What is the contribution of the Ang2/Tie2 pathway to liver metastasis and anti-VEGF therapy resistance in pancreatic NET?

Why is this important?

The project will unravel potential mechanistic pathways for effectively promoting tumor vascular normalization, which will increase drug delivery and suppress tumor metastasis in patients with pancreatic NETs.

What will researchers do?

Researchers will identify the mechanism by which Ang2/Tie2 signaling promotes tumor cell metastasis to the liver in pancreatic NETs. In laboratory experiments, researchers will determine whether targeting Ang2 will reduce liver metastasis and increase anti-VEGF drug efficacy in a spontaneous pancreatic NET mouse model.

How might this improve the treatment of NETs?

Ang2 is expected to promote vessel destabilization in the liver, which can facilitate tumor cell metastasis. By targeting the Ang2/Tie2 pathway, Kim hopes to extend and improve current anti-VEGF drug treatment response for pancreatic NET patients.

What is the next step?

Kim’s experiments may develop data to support further preclinical research of the complementary therapeutic combination targeting the Ang2 and VEGF pathway.

Outcomes:

Neuroendocrine tumors can arise from different sites of the body, including the endocrine tissues of the pancreas leading to pancreatic neuroendocrine tumors (PNETs), and their incidence has steadily increased over the past few decades. Distant metastases to liver are identified at diagnosis in about 40% of patients with PNETs. However, few FDA-approved targeted drugs are available for the treatment of PNETs. PNETs develop abundant new blood vessels through a process known as angiogenesis, which led to intensive preclinical and clinical research aimed at inhibiting the formation of new blood vessels termed “antiangiogenic therapy” as a treatment modality. Although such antiangiogenic drugs have made significant advances in the treatment of PNETs, the emergence of resistance to drugs has limited their therapeutic efficacy as seen in other advanced solid tumors.

Our proposed work focused on determining the significance of vascular leakiness by angiopoietin-2 (Ang2)/Tie2 signaling on promoting liver metastasis. From this pilot project, we learned that Ang2 levels are significantly increased in liver metastasis of PNET mouse and human samples. Furthermore, pharmacological inhibition of Ang2 suppressed metastatic growth in the liver and increased T-cell infiltration into the liver metastasis of PNET mice. Our finding demonstrated the vascular modulation of metastatic growth through immunostimulation and could shift clinical practice paradigms for suppressing metastatic growth in the liver and increasing therapeutic efficacy of current antiangiogenics as well as immunotherapy.

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