Finding new treatments for B-cell lymphomas is the goal of a Leukaemia Foundation co-funded* and collaborative** research project led by Professor Ricky  Johnstone  at the Peter  MacCallum  Cancer Centre (Melbourne).   

An urgent clinical need underlies this research, as around 40% of people with B-cell lymphomas either don’t respond to the standard treatment (they’re refractory to the chemotherapy-immunotherapy regimen) or they respond, then the lymphoma comes back (they relapse).

“We need to find better treatments,” says Dr Pilar Dominguez, who moved to Australia last year to join Prof. Johnstone’s lab.

“I want to broaden my knowledge and have more impact by doing work that is more translational, so a step closer to the clinic,” said Pilar.

After completing her PhD in molecular biology, followed by a post-doctoral degree in immunology, in Spain, Pilar went to the U.S. to further her post-doctoral work in lymphoma with Professor Ari Melnick at Weill Cornell Medicine in New York (U.S.).

Now based in Melbourne, Dr Dominguez heads this three-year project titled, Targeting deregulated epigenetic mechanisms in B-cell lymphomas, which involves pre-clinical studies in diffuse large B-cell lymphoma (DLBCL). DLBCL is a lymphoma that develops from the B-cells in the lymphatic system, and makes up one third of all patients newly diagnosed with non-Hodgkin lymphoma.

Prof. Johnstone and Prof. Melnick are co-principal investigators on this research project that follows on from preliminary data published in late-2018 in Cancer Discovery – one of the world’s leading cancer journals.

Dr Dominguez was first author on the paper that described the genetic basis of this disease and showed the gene, TET2, was mutated in DLBCLs.

“That publication set the scene for this project,” said Prof. Johnstone, “and gave us the confidence that the gene we were looking at – TET2 – was indeed an important gene in DLBCLs.

“This allowed us to form hypotheses about how we might be able to treat these lymphomas with some new world-first compounds.

“We think this is world leading research that will have enormous impact internationally,” said Prof. Johnstone.

Dr Dominguez said that trying to understand how normal cells transition to become cancer cells “is a major focus of Prof. Johnstone’s lab”.

“Our goal is to find new biomarkers for B-cell lymphomas and develop new therapeutic approaches,” she said.

“This involves screening patients who don’t respond to standard treatment to find out what’s wrong with those cells, then selecting the right treatment for those patients.

“The advantage of these therapies is they will be personalised  to the patients who are going to benefit the most,” explained Dr Dominguez.

“There are two angles to this project – to test new treatments in pre-clinical models of DLBCL using human lymphoma cells, and to find out what defects are in these cells at the DNA level that lead to normal cells becoming lymphoma cells.

“And, there are two clinically relevant sides to this research – prevention and therapy,” said Dr Dominguez.

“For patients in whom current standard therapy doesn’t work and those newly diagnosed in the future, we can use precision medicine to change the way we diagnose lymphoma, then select those patients who are going to benefit from more specific, targeted treatments.

“This is a relatively new field that looks not only at the DNA level, where cells receive instructions, but at another level, the epigenetic level, where proteins control how genes are expressed at any time.

“It’s difficult to explain epigenetic power in simple terms – the mechanism is very technical,” said Dr Dominguez.

“Each cell contains the same genetic information, but each cell has a different function and that depends on epigenetic changes. These epigenetic proteins control and regulate which genes are turned ‘on’ and ‘off’ at any time.

“If the proteins that control epigenetics don’t work properly, genes may be are turned ‘on’ and ‘off’ when they shouldn’t be, and the cell becomes altered. In some cases, this leads to cancer.

“When the epigenetic proteins or systems are not working, tumour cells use that to their advantage, to keep growing.

“But the good thing about the epigenetic system is that those processes are in most instances reversible, so once you know how this process goes wrong, you can try to reverse it.

“The therapies we are developing are designed to convert cancer cells in which the epigenetic processes have become abnormal back to normal cells.

“TET2 is a protein that is highly mutated in 10-15% of patients with DLBCL. In these lymphoma patients, TET2 doesn’t work and the tumour uses this to its advantage,” said Dr Dominguez.

She has demonstrated that TET2 is a tumour suppressor in DLBCL by showing that when TET2 is mutated, the progression of lymphoma is accelerated.

“That’s why we’re focusing on TET2. We’re studying its function in cancers compared to normal cells. We want to know how it works in normal cells to prevent cancer formation, and understand the consequences when this molecule is not working.

“We think patients with the TET2 mutation will benefit most from a targeted, precision medicine approach, where we plan to combine two epigenetic therapies that block two different chemical modifications in the DNA.”

One of the drugs is azacitidine, which is already used in the clinic for other blood cancers – myeloproliferative neoplasms, myelodysplastic syndrome and acute myeloid leukaemia – and is in clinical trials as a monotherapy for B-cell lymphomas. Azacitidine will reverse the epigenetic changes caused by TET2 mutation.

The other compound – an HDAC3 inhibitor – doesn’t yet have a commercial name because it is still in development by a small biotech company in the U.S.

“This research will test this drug combination in human cells and we will perform pre-clinical studies so we have some proof that it works and that this new therapeutic approach can be effective and safe,” said Dr Dominguez.

“This will potentially change how lymphoma is treated. It will be very different to chemotherapy, which is non-selective in that it kills tumour cells and normal [healthy] cells.

“At the end of this project, we hope to have enough data [results] for the next step; establishing a clinical trial. That would be the final goal for this project,” she said.

After the completion of this study, to prove this epigenetic drug combination is a new option for patients with this form of DLBCL with these genetic lesions, Prof. Johnstone hopes to run a clinical trial at two sites – at Peter MacCallum Cancer Centre and at Monash Medical Centre with associate investigator on the project, Dr Gareth Gregory.

“This project is significant on two levels – the science and the strong collaborative opportunities – and we’re thankful to the funding agencies for giving us the opportunity to test our hypotheses,” said Prof. Johnstone.

“It’s a unique and innovative way to fund research; bringing together Leukaemia Foundation, Snowdome Foundation and the Leukemia & Lymphoma Society in the U.S.

“I love the collaborative nature of it. It’s not just one group working in isolation, it’s a global effort,” he said.

 

*This project is funded under the Leukaemia & Lymphoma Society – Snowdome Foundation – Leukaemia Foundation Translational Research Program. (US$600,000 over three years)

* Collaborating institutions: Monash University, Melbourne; Weill Cornell Medicine, New York, U.S.; University of Miami, Florida, U.S.; The Jackson Laboratory Cancer Centre, Conneticut, U.S. Further support is critical to ensure all Australian can reap the benefits of scientific advancements. If you would like to invest in blood cancer research, contact us on 1800 620 420 today to find out how.  

Further support is critical to ensure all Australians can reap the benefits of scientific advancements. If you would like to invest in blood cancer research, contact us 1800 620 420 today to find out how.