A kidney disease drug helps fight cancer and ageing

Toshio Miyata, a nephrologist in Japan, knew he needed to do something when he had run out of treatment options for his patients. “Kidney inflammation and fibrosis can be life threatening, and there were very few renal medicines available,” he says. “So 20 years ago, we decided to make some ourselves.”

Plasminogen activator inhibitor-1 (PAI-1) — a biomolecule responsible for regulating blood clots — has been on the pharmaceutical industry’s list of potential targets for more than three decades. Blood clots, inflammation and fibrosis, and the mechanism that breaks them down are linked to many diseases including kidney, lung, cardiovascular and liver diseases. Patients with inflammation and fibrosis usually get worse. Managing this process could be a game changer.

In 2003, Miyata, a nephrologist and a physician-scientist at the Tohoku University Graduate School of Medicine in Sendai, Japan, became interested in finding small molecules that can inhibit the function of PAI-1. At the time, only a few small-molecule PAI-1 inhibitors had been reported and studies on PAI-1’s role in biological function were still in their infancy.

Miyata’s lab began searching for PAI-1 inhibitors by performing a virtual screening of a library of chemical compounds against a published structure of human PAI-1. This relies on using ‘docking’ algorithms to predict the binding between the two structures. After simulating the fit of almost 2.25 million compounds, they finally discovered their first hit, a compound they indexed as TM5007¹.

Initial studies of TM5007 on rodent models for blood clots, showed promise — the compound reduced significant blood clots. But its efficacy was too low to be a clinically useful treatment.

Miyata and his team continued to refine the compound to improve its efficacy, but the journey was long. After 15 years and having synthesized more than 1,400 compounds, they finally arrived at TM5614, a compound 3,000 times more efficacious than their original hit. They are now ready to take this compound to clinical studies.

Stem cell interaction

The longer they spent developing TM5614, the more Miyata’s team understood PAI-1 biology. While analysing its crystal structure, they learned that PAI-1 binds to a protein called furin, which activates the release of hematopoietic stem cells — immature cells that develop into blood cells — from the bone-marrow environment. When TM5614 binds to a target site on PAI-1, it activates furin, which drives the release of these stem cells.

Miyata’s team took this idea to Hideo Harigae, a hematologist and director of Tohoku University Hospital, who saw the potential of TM5614 as an adjunct therapy for chronic myelogenous leukemia (CML). “CML is a rare disease,” explains Harigae. “It’s a type of blood cancer that develops when abnormal genes occur in the hematopoietic stem cells.”

Earlier studies on PAI-1 and cancer had focused mostly on its function in thrombotic and fibrinolytic events. While newer findings have hinted at their complex roles in various cancer progression, no-one has ever reported PAI-1 activity on hematopoietic stem cells².

CML patients are usually treated with tyrosine kinase inhibitors (TKIs), which act on mature CML cells that differentiated from CML stem cells. While TKIs improve the survival rate of CML patients, they do not address the root cause of the disease. Because TKIs cannot act on CML stem cells that reside in the bone-marrow environment, the cancer often recurs when the treatment is stopped. Meanwhile, long-term TKI use is expensive and carries potentially fatal side effects.

To overcome this, Miyata’s team suggested a strategy that combines TKI with a PAI-1 inhibitor to treat CML. The idea is to use PAI-1 inhibitors such as TM5614 to lure CML stem cells out of their bone-marrow environment. Once these cells are released, TKIs can attack the exposed cells.

Miyata’s team tested this combination therapy on a CML mouse model and found that the number of CML cells remaining in the bone marrow fell considerably, leading to a greater survival rate.

Following this result, the team proceeded with early and late phase II clinical trials³ in which 33 patients received a daily dose of TKI. Those who received TM5614 on top of their daily dose of TKI for a year achieved a higher rate of deep molecular remission, a desirable outcome for TKI treatment.

Immune checkpoint inhibitors

Other groups had shown that a high expression level of PAI-1 is associated with low survival rates in patients with solid cancer. But the mechanism behind this is poorly understood. Miyata’s team further discovered that PAI-1 may have induced the expression of immune checkpoint molecules on cancer cells and suppresses the anti-tumour immune response.

Immune checkpoint molecules such as programmed death-1 (PD-1) and its ligand (PD-L1) have become popular targets for cancer immunotherapy. While these inhibitors do not act directly on cancer cells, they allow immune T-cells to remain active and attack cancer cells. Despite their promise, the therapeutic effect of anti-PD1/PD-L1 is still limited. “An antibody-based drug is expensive and immune-related side effects are a serious problem,” says Miyata. “There’s a need for a combination drug that increases the response rate of anti-PD-1/PD-L1 with fewer side effects and is less expensive.”

Miyata’s team have showed that TM5614 can suppress tumour growth and enhance the anti-tumour response of anti-PD-1 antibodies in mouse models of melanoma, non-small lung cancer and colorectal cancer. In a phase II clinical study in malignant melanoma, 7 out of 29 patients who initially did not respond well to nivolumab (an antibody drug) began to respond to the drug after 8 weeks of combination therapy with TM5614⁴.

The team has now scheduled other phase II clinical trials for non-small-cell lung cancer and cutaneous angiosarcoma to further confirm the effect of TM5614 on immune checkpoint inhibition in other cancers.

A surprise finding

The discovery of TM5614 illustrates what translational medicine could look like in academia. “Previously, the School of Medicine mainly conducted biological research,” says Harigae. “But the times have changed.” He saw the development as an effort for academic research labs to fill in the clinical needs. “Pharma companies don’t develop all the medicines we need,” he says. “So we have to do it ourselves.”

Miyata’s team has collaborated both nationally and internationally and partnered with contract research organizations to accelerate research progress. In 2017, through a collaboration with scientists at Northwestern University in Illinois, United States, they found another surprising role for PAI-1. After surveying the Amish community in the US state of Indiana, they discovered that those without the PAI-1 gene on average lived 10 years on average longer than those with the gene⁵.

This unexpected finding was only possible through a worldwide academic collaboration and open resource sharing that his team adopted, Miyata says. The team is currently exploring the potential use of PAI-1 inhibitor as an anti-ageing medication.

“Drug discovery and development is very challenging, but also very important,” says Harigae. “I hope young researchers and physician-scientists will follow us in the future.”