A new approach to molecular drug design involving researchers in Trinity College Dublin (TCD) has produced a highly promising drug candidate for the treatment of bladder cancer.

Bladder cancer affects around 490 people in Ireland every year and is the fifth most commonly diagnosed cancer in Europe.

More than 80% of patients will experience a recurrence after the complete surgical removal of the first tumour. Furthermore, lifetime treatment costs per patient are higher than for any other type of cancer.

This latest research yielded a promising drug, which induced rapid shedding of tumour cells, resulting in a major reduction in tumour size when used in clinical trials.

These effects were seen in patients with non-muscle invasive bladder cancer (NMIBC). Over the last 30 years, few drugs have been approved for NMIBC. Furthermore, access to these drugs is limited by insufficient supply, including BCG immuno-therapy and common chemotherapeutics, such as Mitomycin and Epirubicin. 

This new drug candidate was found to be safe, as no drug-related side-effects were observed.

The new approach by researchers involved designing a drug candidate using the “intrinsically disordered proteins” (IDP) concept, which relates to the recent understanding that a large segment of proteins in the body do not have a fixed 3D structure. Instead, they each typically take shape in a variety of ways/structures that change depending on a range of factors.

This contrasts with the more common direction that is currently taken, which is based on the “lock and key” concept. This relates to the idea that proteins have fixed, well-organised 3D structures, allowing drugs to be designed to target very specific regions. 

A team from TCD worked collaboratively with researchers in Lund University in Sweden, and Charles University and Motol Hospital in Prague, as well as the start-up company, Hamlet Pharma.

Their new approach involved the use of an IDP complex known as HAMLET, which is a component of human milk. They found that when partially unfolded, HAMLET possesses tremendous cancer-killing abilities.

Dr Ken H Mok is an associate professor in TCD’s School of Biochemistry and Immunology and the Trinity Biomedical Sciences Institute. He led the structural element of the work and pointed out that while targeted cancer therapies have made big advances in recent years, “the lack of tumour specificity remains a significant concern”.

“Few current therapies kill cancer cells without harming healthy tissues, and severe side-effects have become accepted as a necessary price to pay for survival or cure. This research is therefore exciting as the clinical trials show great impact in reducing tumour size in people with this form of bladder cancer without any side-effects,” he explained.

He said it was “extremely exciting” to have been involved in this new approach to molecular drug design.

“IDPs compose over 50% of the human proteome and their malleability to adapt towards binding a variety of surfaces may, in some cases such as this, result in a gain of function. One motif may have a ‘targetable weakness’ that others don’t have,” he noted.

He said that this concept may help people to understand why drugs that are designed using “lock and key” principles “often fail in clinical trials if they encounter different structural forms of the protein they were made to attack”.

“Once the blueprints change, a promising drug may not have the desired impact,” he added.

Details of this research are published in the journal, Nature Communications, and can be viewed here.