PI3K inhibitors could treat HHT

Lab mouse

Preclinical research suggests PI3K inhibitors could treat hereditary hemorrhagic telangiectasia (HHT).

Experiments in mice and patient samples revealed that loss of ALK1 function induces vascular hyperplasia and increases activity of the PI3K pathway.

Pharmacological inhibition of PI3K was able to eliminate vascular hyperplasia in mouse models.

Francesc Viñals, PhD, of Institut Catala d’Oncologia in Barcelona, Spain, and his colleagues described this research in Arteriosclerosis, Thrombosis and Vascular Biology.

“Our group has been working with endothelial cells for a long time, focusing on how they are affected by changes in the TGF-beta signaling pathway from a basic research perspective,” Dr Viñals noted.

The group was especially interested in ALK1, a receptor for the TGF-beta factor BMP9 that is expressed by endothelial cells. Mutations in ALK1 have been associated with HHT.

The researchers developed a model for the formation of blood vessels in the retina of mice that lacked a copy of the gene for the ALK1 receptor. These models exhibited an excess of endothelial cells and errors in the formation of blood vessels.

These results corresponded with the researchers’ theory. The team thought that, if members of the TGF-beta family usually act as a “brake” for cellular proliferation, mutations in one of the family’s components should lead to uncontrolled proliferation. The researchers replicated and confirmed their results in in vitro cultures.

Further investigation revealed the role of the PI3K pathway. The researchers found that stimulation of PI3K acts as an “accelerator” for endothelial cells to proliferate.

BMP9 (through ALK1) acts as a brake, inhibiting VEGF-mediated PI3K signaling by increasing PTEN activity. When ALK1 is mutated, there is no brake, and endothelial cells proliferate more thanks to the PI3K pathway.

The researchers discovered this mechanism via experiments in human umbilical vein endothelial cells. However, experiments in HHT2 patient samples supported these findings.

The team found that mutations in ALK1 increased endothelial cell proliferation in vessels from patients with HHT2. The researchers also found overexpression of genes linked to PI3K/AKT signaling in telangiectasial tissue from patients with HHT2, as compared to normal tissue from either HHT2 patients or healthy individuals.

Going back to murine experiments, the researchers found that loss of both PI3K and ALK1 function stabilizes the proliferation of endothelial cells.

The team tested LY294002, a pan-PI3K inhibitor, in mice and found that PI3K inhibition can reverse the vascular hyperplasia induced by loss of ALK1 function.

“Now, the next step is clear,” Dr Viñals said. “We have to assess the effects of PI3K inhibitors in patients. PI3K inhibitors are currently used in the treatment of patients with cancer or patients who require immunosuppression after organ transplantation, and it has been observed that, in patients with these pathologies and HHT, treatment results in a reduction of the issues caused by HHT, which is a very encouraging fact.”

Lab mouse

Preclinical research suggests PI3K inhibitors could treat hereditary hemorrhagic telangiectasia (HHT).

Experiments in mice and patient samples revealed that loss of ALK1 function induces vascular hyperplasia and increases activity of the PI3K pathway.

Pharmacological inhibition of PI3K was able to eliminate vascular hyperplasia in mouse models.

Francesc Viñals, PhD, of Institut Catala d’Oncologia in Barcelona, Spain, and his colleagues described this research in Arteriosclerosis, Thrombosis and Vascular Biology.

“Our group has been working with endothelial cells for a long time, focusing on how they are affected by changes in the TGF-beta signaling pathway from a basic research perspective,” Dr Viñals noted.

The group was especially interested in ALK1, a receptor for the TGF-beta factor BMP9 that is expressed by endothelial cells. Mutations in ALK1 have been associated with HHT.

The researchers developed a model for the formation of blood vessels in the retina of mice that lacked a copy of the gene for the ALK1 receptor. These models exhibited an excess of endothelial cells and errors in the formation of blood vessels.

These results corresponded with the researchers’ theory. The team thought that, if members of the TGF-beta family usually act as a “brake” for cellular proliferation, mutations in one of the family’s components should lead to uncontrolled proliferation. The researchers replicated and confirmed their results in in vitro cultures.

Further investigation revealed the role of the PI3K pathway. The researchers found that stimulation of PI3K acts as an “accelerator” for endothelial cells to proliferate.

BMP9 (through ALK1) acts as a brake, inhibiting VEGF-mediated PI3K signaling by increasing PTEN activity. When ALK1 is mutated, there is no brake, and endothelial cells proliferate more thanks to the PI3K pathway.

The researchers discovered this mechanism via experiments in human umbilical vein endothelial cells. However, experiments in HHT2 patient samples supported these findings.

The team found that mutations in ALK1 increased endothelial cell proliferation in vessels from patients with HHT2. The researchers also found overexpression of genes linked to PI3K/AKT signaling in telangiectasial tissue from patients with HHT2, as compared to normal tissue from either HHT2 patients or healthy individuals.

Going back to murine experiments, the researchers found that loss of both PI3K and ALK1 function stabilizes the proliferation of endothelial cells.

The team tested LY294002, a pan-PI3K inhibitor, in mice and found that PI3K inhibition can reverse the vascular hyperplasia induced by loss of ALK1 function.

“Now, the next step is clear,” Dr Viñals said. “We have to assess the effects of PI3K inhibitors in patients. PI3K inhibitors are currently used in the treatment of patients with cancer or patients who require immunosuppression after organ transplantation, and it has been observed that, in patients with these pathologies and HHT, treatment results in a reduction of the issues caused by HHT, which is a very encouraging fact.”

Lab mouse

Preclinical research suggests PI3K inhibitors could treat hereditary hemorrhagic telangiectasia (HHT).

Experiments in mice and patient samples revealed that loss of ALK1 function induces vascular hyperplasia and increases activity of the PI3K pathway.

Pharmacological inhibition of PI3K was able to eliminate vascular hyperplasia in mouse models.

Francesc Viñals, PhD, of Institut Catala d’Oncologia in Barcelona, Spain, and his colleagues described this research in Arteriosclerosis, Thrombosis and Vascular Biology.

“Our group has been working with endothelial cells for a long time, focusing on how they are affected by changes in the TGF-beta signaling pathway from a basic research perspective,” Dr Viñals noted.

The group was especially interested in ALK1, a receptor for the TGF-beta factor BMP9 that is expressed by endothelial cells. Mutations in ALK1 have been associated with HHT.

The researchers developed a model for the formation of blood vessels in the retina of mice that lacked a copy of the gene for the ALK1 receptor. These models exhibited an excess of endothelial cells and errors in the formation of blood vessels.

These results corresponded with the researchers’ theory. The team thought that, if members of the TGF-beta family usually act as a “brake” for cellular proliferation, mutations in one of the family’s components should lead to uncontrolled proliferation. The researchers replicated and confirmed their results in in vitro cultures.

Further investigation revealed the role of the PI3K pathway. The researchers found that stimulation of PI3K acts as an “accelerator” for endothelial cells to proliferate.

BMP9 (through ALK1) acts as a brake, inhibiting VEGF-mediated PI3K signaling by increasing PTEN activity. When ALK1 is mutated, there is no brake, and endothelial cells proliferate more thanks to the PI3K pathway.

The researchers discovered this mechanism via experiments in human umbilical vein endothelial cells. However, experiments in HHT2 patient samples supported these findings.

The team found that mutations in ALK1 increased endothelial cell proliferation in vessels from patients with HHT2. The researchers also found overexpression of genes linked to PI3K/AKT signaling in telangiectasial tissue from patients with HHT2, as compared to normal tissue from either HHT2 patients or healthy individuals.

Going back to murine experiments, the researchers found that loss of both PI3K and ALK1 function stabilizes the proliferation of endothelial cells.

The team tested LY294002, a pan-PI3K inhibitor, in mice and found that PI3K inhibition can reverse the vascular hyperplasia induced by loss of ALK1 function.

“Now, the next step is clear,” Dr Viñals said. “We have to assess the effects of PI3K inhibitors in patients. PI3K inhibitors are currently used in the treatment of patients with cancer or patients who require immunosuppression after organ transplantation, and it has been observed that, in patients with these pathologies and HHT, treatment results in a reduction of the issues caused by HHT, which is a very encouraging fact.”