Identifying novel biomarkers and therapeutic targets for cancer treatment

Over the past decade or so, there has been a massive shift in cancer research toward discovering more targeted therapeutic alternatives to chemotherapy and radiation.

Subscribing to this approach, Professor Virna Leaner, head of the Division of Medical Biochemistry at UCT, and her group of researchers have dedicated their academic work to looking for novel cancer biomarkers that could serve as therapeutic targets.  
 

A lot of work, universally, is now focusing on treatments that are potentially less toxic and that can be used in combination with other drugs to minimise the side effects.

Their hypothesis is that if cancer cells express certain proteins abundantly, they should die if the protein in question is blocked effectively.

“When you have a therapeutic target, it means that you are able to inhibit or block the specific protein’s function, which will hopefully affect the cell where that protein is abundantly expressed,” explains Leaner.

Apart from the fact that directing treatment to diseased cells may be more effective than the more generalised therapies currently widely available, the hope is also that it would reduce the side effects on non-cancer cells.  

“Most of the standard therapies out there have a proven track record of being effective, but unfortunately they also have side effects. And these are often difficult to deal with,” she says. “A lot of work, universally, is now focusing on treatments that are potentially less toxic and that can be used in combination with other drugs to minimise the side effects.”

Identifying potential biomarkers

During a recent study focusing on a small cohort of cervical cancer patients at Groote Schuur Hospital, Leaner’s group identified a protein called Kpnb1 as a potential biomarker and therapeutic target for this kind of cancer.

“It’s a Greek word that means ‘to carry things’. So, its function is to carry things into the nucleus of the cell. Because it has this critical function, if you inhibit it in the cell, in theory, the cell should die,” explains Leaner.  

What makes the group’s work especially interesting, is the fact that they are using the structure of the protein to find chemical compounds with a close match.

“Our work in this field is to look for drugs – small molecules, chemical compounds – that specifically target proteins that are found to be highly expressed in cancer cells.”

Finding matching chemical compounds

Knowing the structure of the protein, Leaner and her group worked with Professor John Trent from the University of Louisville to scan in silico libraries for chemical compounds with structures that will match Kpnb1 in a lock-and-key manner.

The idea is that these drugs will attach to the protein and hopefully impede its function.
 

Their hypothesis is that if cancer cells express certain proteins abundantly, they should die if the protein in question is blocked effectively.

“If the function of the protein is affected, the entire cell loses one of its vital functions and – in cancer’s case – we hope that this will stunt the cell’s growth to such an extent that it will die.”

Based on the in silico work they’ve conducted, Leaner’s group have identified a number of promising compounds, which are now being tested in the laboratory.

Research Contracts & Innovation (RC&I) recently facilitated a review of the drug candidates by MRCt (now LifeArc) in the United Kingdom. This identified the need for a clear understanding of the actual mechanism involved to understand the manner in which the drug will impact non-target cells.

Thus, this has been the primary focus of Leaner’s group’s recent research work.

Series of tests

“What we want to see during these tests is, firstly, that these compounds kill cancer cells, because ultimately that’s what we want to do. Secondly, that they kill cancer cells based on these protein targets,” she explains.

Once they’ve proven that some of these drugs do interfere with the function of Kpbn1 and ultimately kill cancer cells, the next phase will be to test this drug in vivo. These animal model systems will be used to see if tumour formation can be blocked.

“We’ve actually taken three of these compounds into animal models already and shown that one seems to slow the growth of the tumours,” says Leaner.

Alongside this, the group is also busy with pharmacokinetic work to see how the organism affects a drug, instead of the other way around (which is the basis of in vitro and in vivo testing).

This will assist them in establishing whether the drug is non-toxic, the compound is effective and stable, and also, if the cell takes the compound up. This is all essential in proving that the drug is safe and effective and can be taken to market.
 

“When you have a therapeutic target, it means that you are able to inhibit or block the specific protein’s function, which will hopefully affect the cell where that protein is abundantly expressed,” explains Leaner.

RC&I assisted Learner in raising Seed Funding from the Technology Innovation Agency (TIA). The funding was used to perform the above mentioned preclinical tests and experiments. Conducting these tests and generating the accompanying data on the efficacy of the identified compounds enables external developmental and industry partners to see the potential value associated with the UCT technology. These technology development and maturing activities are crucial in enabling technology transfer from UCT to industry.

Currently RC&I is seeking a commercial firm to partner with or funding to take the drug through the necessary clinical trials and hopefully through to making it available to patients.

Combination treatments

Leaner and her team are also working to establish whether the drugs they identify can be used in combination with other existing drugs.

By doing this, doses could be minimised to reduce side effects even further and the treatment could be made altogether more affordable.
 

Read more about UCT Research Contracts & Innovation…