Igor Stagljar

The lab’s technology maps cell membrane protein interactions for hundreds of diseases like cancer, Parkinson’s, Alzheimer’s, diabetes and cardiovascular disease

Igor Stagljar likens the process of commercializing his ground-breaking research into cell membrane proteins – which has yielded hundreds of new targets for drug-makers seeking cures for cancer and other deadly diseases – to building a highly automated Tesla factory.

But there’s a key difference: ProteinNetwork Therapeutix will be based here in Canada, not south of the border.

Stagljar, a professor of biochemistry and molecular genetics at the ��Ƶ, initially considered setting up his new venture in Silicon Valley. But he and business partner Ivan Plavec ultimately decided Toronto was a better option.

“The technology is here and the know-how is here,” says Stagljar, citing U of T’s large pool of research talent and a growing cluster of venture capital investors on or near the university’s downtown campus. “Maybe some people from my lab will even go to work for the company.”

Read about his latest research findings for Parkinson's

Helping to seal the deal: a $1 million grant from CQDM’s Quantum Leap program. The grant, co-funded by the Brain Canada Foundation, targets research with “very high potential impact” within the biopharmaceutical industry. It’s only the second time the program has funded a Canadian researcher. The other was U of T’s Andrei Yudin, a professor of chemistry.

Stagljar’s research certainly qualifies as having a potentially big commercial impact.

With the help of his 17-person lab, he developed a new genetic technique that allows researchers to map the interactions between proteins in a cell’s membrane, a process previously made difficult because of the proteins’ fragile, transitory states. The interactions play a key role in determining whether a cell stays healthy or becomes diseased, and are therefore of huge interest to pharmaceutical companies seeking a new generation of precision drugs to cure deadly diseases like cancer.

“There’s about 500 proteins that we know of nested in the cellular membranes that are involved in the onset of various human diseases,” says Stagljar, citing cancer, Parkinson’s, Alzheimer’s, hypertension, diabetes, cardiovascular disease and even migraines. “There are approximately 500 diseases that can be tackled with this technology.”

But studying protein interactions in the lab is not the same as systematically evaluating them on a commercial scale. So Stagljar is in the process of retooling his laboratory at U of T’s Donnelly Centre for Cellular Biomolecular research, tapping a local Ontario company to design and build robotics that can handle hundreds of screens per day.

Everything should be up and running within the next 12 months. Stagljar’s focus at U of T will be on “druggable” membrane proteins related to three types of cancer: lung, breast and pancreatic. His company, meanwhile, will use similar technology and equipment to focus on other diseases in partnership with pharmaceutical partners.

“We’re already leading very serious talks with well-known drug companies,” Stagljar says. “Two out of the five biggest pharmaceutical companies are interested in our technology.”

How long until ProteinNetwork expects to see results?

“I think in the next two or three years, we will learn about new drug targets, which, when neutralized by drugs, would lead to cures for these cancers,” says Stagljar. “But before these drugs would appear in clinics is a long process, from nine to 12 years.

“Our focus right now is to build a high-throughput, high-grade technology for biomedical research.”

Learn more about entrepreneurships and startups at U of T

U of T study provides new hope for Parkinson’s as elusive proteins come to light

ullahnor — Thu, 16 Mar 2017 18:01:08 +0000

U of T study provides new hope for Parkinson’s as elusive proteins come to light

ullahnor Thu, 03/16/2017 - 14:01

Cutline

Research reveals a breadth of new drug targets for neurological conditions and opens the door to a greater understanding of the way in which common medications work

Jovana Drinjakovic

Author legacy

Jovana Drinjakovic

Topic

Ever take antihistamines? Or heartburn medication?

Along with drugs used for a variety of conditions like diabetes, high blood pressure and depression, these common household drugs work by targeting the same class of protein molecules in our cells. They are only the tip of the iceberg. A ��Ƶ study reveals a large swath of new therapeutic opportunities for these drugs, including ones that could lead to a better treatment for Parkinson’s disease.

Despite representing about a half of prescribed medications worldwide, these compounds target only a sliver of one of the largest – and most elusive – classes of human proteins, called G protein coupled receptors (GPCRs). Tapping into this vast unexplored therapeutic potential has been difficult because available tools weren’t up to the task of surveying the GPCRs on a large scale.

Enter Professor Igor Stagljar of U of T’s Donnelly Centre.

“Our cells are made of proteins, which also do most of the work in them. But no protein acts alone and that’s why we have to look at interactions between proteins to understand what’s going on in the cell,” says Stagljar, who is also a professor in the departments of molecular genetics and biochemistry.

Stagljar’s new study, which is on the cover of the March issue of Molecular Systems Biology, is based on technology developed in his lab, called MYTH.

The technology allows detection of membrane protein interactions as they occur in their natural setting – on the surface of cells. Using MYTH, Stagljar’s team was able to capture almost 1,000 interactions between more than 600 proteins for almost 50 clinically important GPCRs (see inset).

The largest survey of GPCRs to date, it revealed new associations among proteins involved in neurological disorders like motor neuron disease, schizophrenia and neurodegenerative disorders, as potential targets for new drugs.

One association that stood out involved a G protein coupled receptor targeted by Parkinson’s disease drugs, called ADORA2A. By binding to ADORA2A, the drugs stimulated the release of dopamine, which helped communication between nerve cells to ultimately reduce tremor in patients with Parkinson’s.

Stagljar’s team found that ADORA2A associates with another Parkinson’s disease associated receptor (GPR37), in a way that affects movement in a mouse model of disease, suggesting that a combination of drugs targeting both receptors may work better in patients.

The work on Parkinson’s was done in collaboration with Professor Francisco Ciruela’s team at the University of Barcelona in Spain, which will continue to investigate the clinical potential of the enhanced combination therapy involving ADORA2A and GPR37.

“High-throughput studies like ours are going to be major contributors in future drug development,” says Jamie Snider, a senior research associate in the lab and a lead author of the study. “You can look at the cell in the ways we could not do before. We can understand how proteins interconnect better to identify possible reasons why certain drug compounds might be causing side effects and also to predict which targets might potentially be valuable for treating disease.”

To appreciate just how pervasive the 800 or so human GPCRs are, you only need to take a deep breath and look at yourself: nestled inside the eye, these proteins detect light and help us see, those in the nose detect scents, while the ones in taste buds let us taste chocolate, sweets and bitter foods.

But these proteins also detect glucose and hormones in the blood, neurotransmitters, or chemicals that help our brain cells communicate, as well as hold cells together, ensuring that tissues don’t fall apart. It’s no surprise then, that when GPCRs go awry, this can lead to brain disorders, diabetes, cancer and a host of other diseases.

In the past, scientists would either focus on the GPCR parts that are easily accessible, such as those sticking out on either side of the cell.

Or, to study the GPCRs in entirety, they would remove the surrounding membrane, which changes the proteins’ properties. Either way, researchers weren’t getting the full picture of how these proteins work. Stagljar's technology has revolutionized the study of membrane proteins, attracting interest from the pharmaceutical industry.

Read here about Stagljar’s work on proteins playing a role in cancer

“Our previous limited knowledge of the GPCRs had already helped us to tremendously improve human health,” Stagljar says. “Think of what we might be able to do if we mapped all these proteins and their interactions and then understand the biological importance of those – this would be a huge step forward for biomedicine.”

U of T research unlocks new data for cancer drugs

ullahnor — Fri, 06 Jan 2017 21:50:10 +0000

U of T research unlocks new data for cancer drugs

ullahnor Fri, 01/06/2017 - 16:50

Cutline

U of T researchers have mapped out 300 drug targets in cancer (illustration by Leja Stagljar)

Jovana Drinjakovic

Author legacy

Jovana Drinjakovic

Topic

Research & Innovation

Igor Stagljar

��Ƶ scientists have uncovered more than 300 drug targets in cancer, attracting interest from the pharmaceutical industry looking to develop more precise treatments.

Led by Professor Igor Stagljar of U of T’s Donnelly Centre, the study maps interactions between receptor tyrosine kinases (RTKs) and protein tyrosine phosphatases (PTPs) in humans, which can lead to cancer when their functions are disrupted. The highly anticipated study will be featured on the cover of the journal Molecular Cell, available in print on Jan. 19.

Most cancer patients are treated with punishing chemotherapy drugs that have serious side-effects.

In the last 15 years, a new generation of "smart" cancer drugs has been developed such as Gleevec, which effectively cures some forms of leukemia. These drugs are designed to target cancer cells with needle-like precision to avoid harming tissue that’s healthy. They do this by blocking proteins called kinases, which include receptor tyrosine kinases (RTKs) that control cell growth. RTKs are often mutated in cancer. However, the existing drugs block only a fraction of RTKs because these proteins have features that have made them notoriously hard to study.

Senior research associate Zhong Yao was able to carry out the largest study of RTKs to date by mapping their physical interactions with PTPs using methods previously developed in Stagljar’s lab.

“We tested interactions between almost all 58 RTKs and 144 PTPs that exist in human cells. Our map reveals new and surprising ways in which these proteins work together. These insights will help us better understand what goes wrong in cancer in order to develop more effective treatments,” said Stagljar, who is also a professor in molecular genetics and biochemistry.

Lodged inside the cell’s outer envelope, or membrane, RTKs receive signals from the outside world – a hormone, for example – telling the cell to grow and divide. Normally, their activity is controlled by PTPs, which bind the RTKs and shut them down. This prevents sustained cell division that could lead to cancer.

The RTKs' place in the cell membrane is critical for their function, but it is also what has made them such a tough nut to crack. Traditional methods haven’t been able to capture the often short-lived physical interactions between RTKs and PTPs because the surrounding membrane has to be dissolved, which changes the proteins’ behaviour.

Stagljar bridged this gap by developing MYTH and MaMTH technologies designed precisely for measuring such fleeting interactions between membrane proteins in their natural setting.

The resulting map charts out more than 300 interactions between RTKs and PTPs in human cells, each a potential way to fight cancer. The findings have attracted attention of major pharmaceutical companies, including the pharma giant Genentech, which could lead to future collaborations in drug development.

Stagljar worked with two leading experts in PTP biology: Professor Anne-Claude Gingras of the Lunenfeld-Tanenbaum Research Institute and U of T’s department of molecular genetics and Professor Benjamin Neel of New York University, who was formerly with U of T and the University Health Network’s Princess Margaret Cancer Center.

“We wanted to show that these two assays we developed in our lab – MYTH and MaMTH – are suitable for studying these two important classes of proteins on such a large scale. The resulting wealth of important data can be used to develop new therapies against various types of cancer,” said Stagljar. “Ultimately, we want to build a map of interactions with all 3,000 or so human membrane proteins, of which at least 500 have direct roles in the onset of many human diseases. This will keep us busy.”

Croatian president visits U of T, tours lab and meets students

ullahnor — Tue, 22 Nov 2016 21:10:39 +0000

Croatian president visits U of T, tours lab and meets students

ullahnor Tue, 11/22/2016 - 16:10

Cutline

Photo of Croatian President Kolinda Grabar-Kitarović with Rose Tominac from U of T's Croatian Student Association (photos by Johnny Guatto)

Geoffrey Vendeville

Author legacy

Geoffrey Vendeville

Topic

Global Lens

Croatia

International partnerships

Global

Ted Sargent

international students. Donnelly Centre

Igor Stagljar

Croatia’s first female president toured the laboratory of a ��Ƶ molecular biologist Tuesday, making time to chat and snap selfies with local Croatian students.

Kolinda Grabar-Kitarović was shown around the lab of Professor Igor Stagljar, a renowned researcher and biochemist at U of T. The purpose of her visit was to foster partnerships with the University of Zagreb and other Croatian institutions – a mission Stagljar shares.

“I’m trying to really push the boundary of collaborations between these two universities so that we have a steady exchange of students and ideas that will lead to some cool discoveries one day,” Stagljar said.

Croatian President Kolinda Grabar-Kitarović talks with U of T's VP International Ted Sargent (left), philanthropist Terrence Donnelly (second from left) and Professor Igor Stagljar (right)

Grabar-Kitarović also met with philanthropist Terrence Donnelly after whom U of T's Donnelly Centre for Cellular and Biomolecular Research is named.

Stagljar, who graduated from the University of Zagreb and earned a PhD in Switzerland before joining U of T’s departments of biochemistry and molecular genetics in 2005, said he was flattered that his home country’s head of state wanted to visit his lab.

“How many times do you get the chance to welcome the president of a country in your lab? We’re thrilled, very happy. It means we’re also doing great research,” Stagjlar said

Watch a video with Mladen Vranic

At one point during the lab tour, Grabar-Kitarović donned a white coat and learned to stain a protein gel with the help of Stagljar.

U of T molecular biologist Igor Stagljar shows Croatian President Kolinda Grabar-Kitarović around his research lab

Afterward, she and her entourage – including the Croatian ambassador to Canada – went to Simcoe Hall, where they chatted with 20 Croatian students majoring in a variety of subjects, from architecture to international relations. In a candid talk about Croatia’s growing pains since independence and the challenges she faced in office, she said her country would benefit from closer ties with universities such as U of T.

“We need your knowledge, we need your experience, and I will hope you will consider how to forge closer connections with your peers in Croatia,” she said.

Her remarks hit home with Veronika Salamun, a third-year architecture student and the president of the U of T Croatian Student Association.

“You want to know that you could have potential to grow in Croatia,” she told U of T News. “It felt really amazing to meet with a female role model.”

Iva Dadic, a master’s student in civil engineering who came to U of T more than a year ago, said she was happy to come face-to-face with the president of her native country.

“I never met the president back home – I guess I had to go to Canada,” she joked.

Croatian President Kolinda Grabar-Kitarović speaks to U of T students

Igor Stagljar

U of T researcher launches startup to help find new smart drugs

Read more about his research

Read about his latest research findings for Parkinson's

Learn more about entrepreneurships and startups at U of T

U of T study provides new hope for Parkinson’s as elusive proteins come to light

Read here about Stagljar’s work on proteins playing a role in cancer

U of T research unlocks new data for cancer drugs

Croatian president visits U of T, tours lab and meets students

Read more about Igor Stagljar's research

Watch a video with Mladen Vranic

View the photo gallery of her visit