Researchers from Peter Mac have developed a brand new approach to treating some aggressive blood cancers. This new advancement comes on the back of more than fifteen years of dedicated work by researchers at Peter Mac in collaboration with scientists at the John Curtin School of Medical Research.

In a small first-in-human clinical trial involving 16 patients with various forms of blood cancer, researchers found their new treatment, CX-5461, stalled disease progression in one third of patients whose cancer had not responded to previous forms of therapy. One patient with anaplastic large cell lymphoma showed a sustained partial response to the treatment for over one year.

The treatment was generally well tolerated with manageable side-effects.

This current study just published in the journal Cancer Discovery proves the feasibility of using CX-5461, including a safety profile allowing prolonged dosing, for the treatment of blood cancers in the future.

“Despite significant progress over the last 40 years in the treatment of blood cancers, including with chemotherapy, monoclonal antibodies and cellular therapies, there remain many patients who are not cured with existing therapies,” says A/Prof Simon Harrison, co-senior author on the study and Peter Mac consultant haematologist.

“New types of treatment for blood cancers are therefore needed.”

More than fifteen years ago researchers at Peter Mac started investigating the concept that cancer cells are addicted to the ability to make ribosomes – cellular factories that make the high levels of proteins required for their growth and survival.

First indications that targeting ribosome production may be a new and important approach for treating cancer came in 2003 and 2004 when Peter Mac researchers in the laboratories of Prof Rick Pearson, Prof Ross Hannan (now at the John Curtin School of Medical Research at Australian National University) and Prof Grant McArthur, published their ground-breaking studies on how a critical protein involved in making ribosomes called RNA polymerase (Pol) I is controlled by cancer-causing molecules.

“At the beginning, the established dogma was that ribosome production was a “housekeeping” process, required by all cells,” reflects Prof Rick Pearson.

“Our studies revealed that cancer cells are actually exquisitely reliant on the ability to make ribosomes and this reliance can be exploited to selectively kill them. This was a ground-breaking finding, identifying a totally new approach to treating cancer.”

They used these insights to design new ways of targeting Pol I, including working with a small American biotech company to develop the compound CX-5461, a brand new class of drug that interferes with ribosome production.

In the preclinical laboratory experiments that followed, researchers demonstrated the effectiveness of this approach in animal models of blood cancer. They found that CX-5461 effectively shut down the initial steps of ribosome biogenesis, at the same time switching on stress programs inside cells that caused the cancer cells to ultimately die.

These studies helped to establish an entirely new paradigm for the treatment of cancer and were the basis for the NHMRC funded clinical trial of CX-5461 in patients with refractory blood cancers at Peter Mac.

“We knew that CX-5461 showed great promise as a new anti-cancer therapy in preclinical studies in the lab. This phase I clinical trial builds on this work to prove that the approach can provide clinical benefit to patients while being well-tolerated” says Dr Gretchen Poortinga, co-senior author on the current study who has led the advancement of CX-5461 from the laboratory into the clinic.

The success of the trial reinforces the importance of basic laboratory research in driving advances to cancer treatments, and is a testament to many years of dedication by scientists and clinicians working to see their ideas become reality.

“To see efficacy in heavily pre-treated, refractory patients is a fantastic validation of our approach and the dedication and hard work of our staff”, says Prof Pearson.

Dr Amit Khot, co-first author and Peter Mac consultant haematologist who led the trial, believes that as a first-in-class drug, CX-5461 demonstrates the feasibility of targeting Pol I in patients and reinforces the importance of taking these medicines further in the clinic.

“The next steps for CX-5461 will be to trial it in specific diseases settings where clinical benefit was evident,”says Dr Khot.

“We will leverage the extensive preclinical data now available from our group and others to use CX-5461 in combination with other medicines already in the clinic. We hope that this will offer new treatment options not previously available to people with some hard-to-treat cancers.”