Scientific highlights

10.03.2022

Promising target for the treatment of pituitary neuroendocrine tumors

Pituitary neuroendocrine tumors (PitNETs) are a common type of brain tumor. PitNETs can often either produce lots of hormones (functioning tumors), or none at all (non-functioning). The main-stay therapy is surgery. Non-functioning (NF) PitNETs are often already aggressive at the time of diagnosis and cannot be completely cut away, and this leads to high relapse rates and increased chance of death. Current medical treatments fail against these tumors, so identifying new therapeutic targets is essential. A research group, head by Natalia S. Pellegata, has discovered a novel pathway activated in NF-PitNETs, which looks like a promising target for therapy.

Pituitary adenomas are the third most common head tumor and have a big impact on patients’ health. Recently, these tumors have been renamed pituitary neuroendocrine tumors (PitNETs) to increase awareness about the fact that, although usually benign, they often invade surrounding areas and cannot be cured using standard treatments. 

Nonfunctioning (NF) pituitary tumors (NF-PitNETs) are often not detected until later stages in tumor development, as they do not release hormones, which could be detected more easily. At this late stage, 50% of the tumors have invaded surrounding areas, and cannot be completely removed by surgery. Therefore, they often return, causing serious health problems for the patients. Standard-of-care treatments for PitNETs include drug therapy with dopamine activators, synthetic somatostatin or temozolomide (a chemotherapy agent), and radiation therapy. NF-PitNETs do not respond to these mentioned drugs, and radiation therapy causes severe side effects. Therefore, we need new treatment options for NF-PitNETs.

 

Cancer is a dynamic process driven by the interaction of different cells and molecules which make up the tumormicroenvironment. Among the cells present in the tumor microenvironment are endothelial cells (ECs). These cells are involved in the formation of new blood vessels, a process called angiogenesis. Angiogenesis is necessary to supply oxygen and nutrients to growing tumors, and to remove waste products. Among the molecules regulating angiogenesis are angiopoietins (Angpt), which are signaling molecules that bind the receptor called Tie2 located on the cell membrane of ECs and regulates blood vessels. The most well known members of this family are Angpt1 and Angpt2. Angpt1 activates the Tie2 receptor and promotes vessel stability, whereas Angpt2 activates the receptor only when present at high concentration. In tumors, ECs secrete high levels of Angpt2, which is the main molecule binding to Tie2 , and promotes angiogenesis. It has been reported that tumor cells can also create and secrete Angpt2. Increased levels of Angpt2 in the blood have been reported in patients with various solid tumors, which correlates with a more advanced disease stage and/or worse expected outcome.

The main goal of the study, led by Natalia S. Pellegata’s team, was to identify new drug targets for NF-PitNETs in order to improve the clinical management of the patients. The study started from the observation that NF-PitNET patients have elevated levels of Angpt2 in the blood, and these levels correlate with tumor aggressiveness. This finding prompted the scientists to study the levels and the role of Angpt2 in NF-PitNETs in more detail. 

Using cells in a dish, they could show that NF-PitNETs have high levels of Angpt2 and secrete it, which causes tumor cell growth. When they looked at zebrafish embryos, this caused angiogenesis. 

Interestingly, NF-PitNETs also have the Tie2 receptor, which is located on the cell membrane and can be activated by Angpt2. Similar to ECs, Tie2 stimulates cell division in tumor cells. This creates a situation where  Angpt2 and Tie2  self-sustain tumor cell survival and growth. Indeed, if receptor Tie2 is deleted in PitNET cells, their growth is suppressed. 

To prove that the Angpt2/Tie2 pathway is a possible treatment target, drugs blocking this pathway were tested in experimental models of NF-PitNET. The scientists demonstrated that blocking of Angpt2/Tie2 signaling reduced tumor cell growth in cells and in animal models.

The Angpt2/Tie2 pathway emerges as a promising therapeutic target in NF-PitNETs, thereby addressing an unmet clinical need. The ability of tumor cells to use angiogenesis signals, normally thought to only exist in ECs, expands our view on the microenvironmental signals essential for tumor growth. Blocking of Angpt2/Tie2 in tumors is a new concept in anti-cancer strategies applicable not only to NF-PitNETs but also potentially to other tumors producing these molecules.

Group leader Natalia Pellegata says: “We have discovered a new signaling route, which is active in NF-PitNET cells, the Angpt2/Tie2 pathway, which supports tumor cell growth and is the cross-talk between tumor cells and ECs in the tumor microenvironment. Our study suggests that drugs targeting the Angpt2/Tie2 system should be used in clinics for the treatment of NF-PitNET patients”.