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A dual assault on multiple types of cancer may be possible with a new cancer therapy developed by researchers at Rigshospitalet, Denmark’s largest hospital. By targeting both the cancer cells and the connective tissue cells around them, the therapy delivers a more precise double-strike. 

Proverbially, a chain is only as strong as its weakest link. This is true of cancer, too. Inside a tumour, the malignant cells live side by side with connective tissue cells, benefiting from the support of these neighbouring cells. But the connective tissue cells are also a chink in the cancer ‘armour’ because they can be used to kill the cancer cells.

This is the premise for the development of a novel cancer therapy in a project led by Lars Henning Engelholm, MSc, at Rigshospitalet and the Biotech Research & Innovation Centre (BRIC), University of Copenhagen.

Engelholm, together with his research team and other researchers at the Finsen Laboratory, a basic cancer research department, have developed a therapy that targets both the cancer cells and the supportive connective tissue cells with cytotoxins capable of penetrating cell membranes and spreading to the neighbouring cells. 

“Sometimes, most of the tumour mass is connective tissue. The connective tissue cells are densely packed around the cancer cells deep inside the tumour, forming a physical barrier that is virtually impenetrable to cancer drugs,” Engelholm explains.

“So our hope is that we will achieve more effective tumour killing with this double strike.” 

The therapy is initially under development for pancreatic cancer, but the researchers are also planning to test it on other types of cancer.

Engelholm has just been awarded DKK 5 million under the Lundbeck Foundation’s Frontier Grants programme. 

“Rigshospitalet and the University of Copenhagen own the commercial rights to the project, but owing to the vast cost of drug development, the two institutions do not have the means to bring the therapy to clinical trial. So we’re thrilled to receive funding to mature the case to a level where it can attract commercial investors,” he says. 

Cheating cells with Trojan horses

The new cancer drug belongs to a class of cancer therapies called antibody drug conjugates (ADCs), which have attracted a great deal of interest in recent years. For about two decades, researchers worldwide have been working on ADCs, and there are currently 14 approved ADCs with more in the pipeline. 

The researchers at Rigshospitalet are among those who have pioneered ADC development. Engholm was involvedin readying a laboratory-stage ADC for commercial production with a company that will shortly be launching clinical trials of its therapy. 

“That drug candidate gave us the courage to tap into the insights we now have for targeting other forms of cancer. We know how an ADC has to act, and we have the expertise to work with it,” he says.

An ADC has two components: an antibody and a potent cell killer (cytotoxin).

The antibody is like a target-seeking missile and is linked (conjugated) to its cytotoxic ‘bomb’. This is achievable because ADCs target specific proteins – antigens – on the surface of the cancer cells, which the antibody is designed to recognise.

And as these antigens are seldom present in healthy cells but do occur in much higher concentrations in cancer cells, the therapy attacks fewer healthy cells. This means less side effects and a more potent therapy compared with conventional chemotherapy.

But the antibody is not only target-seeking; it also works like a key in a lock. Once it binds to the antigens, the ADC can enter the cell. And the therapy is designed to ensure that the cytotoxins are not activated until the ADC is inside the cell.

Engelholm calls the conjugates ‘Trojan horses’ because they are harmless while they are circulating in the bloodstream, but carry a lethal payload, which is released as soon as they are inside the cell.

Oncologists lack treatment

Some rapidly growing cancers produce large amounts of a specific antigen, a receptor, known as uPAR. This is the one Engelholm and his team are working on. 

“Many types of cancer upregulate this receptor, meaning they produce a lot of it,” says Engelholm.

The research team chose to develop their ADC for pancreatic cancer because this is the form of cancer in which uPAR is most upregulated, and because the patients have a poor prognosis. 

“I work at Rigshospitalet, and the oncologists are saying ‘bring it on, we need something for these patients’. Pancreatic cancer is the most fatal form of cancer there is, so we’re keen to focus on it.”

One particular benefit of uPAR is that the cancer cells cause the cells in connective tissue in and around a tumour to also produce large amounts of uPAR, giving the research team a means of targeting the cancer cells from two sides.

The efficacy of the conjugate was demonstrated by the researchers in trials on mice. They are now ready for the next step.

During the 18 months funded by Frontier Grants, they will be solving a number of tasks in order to be able to select the ideal drug candidate. 

The team will be selecting an antibody and adapting it for human use, since what they originally investigated came from mice. They also have to identify the most suitable cytotoxin and describe with which drugs and dosages the conjugate performance is optimal while causing the least side effects.

Another task is to map adverse reactions to the drug, and finally they will be investigating if the therapy could potentially treat more types of cancer. 

Although there is a way to go, and a good deal of funding yet to secure before this cancer treatment can be administered to patients by infusion or injection, the next 18 months represent an important step in that direction,” says Engelholm.

“Right now, we’re readying the therapy for investors, so within the foreseeable future we should be able to bring it to the patients, which is what we’ve set our sights on. That’s what drives us.”

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