Stopping cancer’s clock

Cancer Scientists at Harry Perkins Institute of Medical Research in Western Australia, the Children’s Medical Research Institute in Sydney and the Max Planck Institute for Biology of Ageing in Cologne, Germany, have developed a way to wrap artificial proteins around the ends of chromosomes to effectively block the uncontrolled growth that occurs with most cancers.

Associate Professor Oliver Rackham’s team at the Perkins has engineered proteins that effectively clamp tightly around the end of the single stranded DNA in the chromosome.

“These proteins lock down the DNA so telomerase can’t touch it.”

Professor Rackham says that about 90% of cancer cells have the telomerase enzyme, when they shouldn’t and that cancer cells grow uncontrollably whereas normal cells limit their growth.

“A normal cell grows for just the right amount of time that is required for us to develop and maintain our bodies.”

“They control their growth with a molecular counting mechanism that tells the cell how old it is. This occurs on the ends of our chromosomes which have little caps on them. Each time the cell divides a little bit at the cap of the chromosome disappears. Once the caps shrink to a certain length the cell knows that it has divided too many times and it will then stop growing or die.

“However, cancer cells subvert the counting mechanism that shrinks the ends of our chromosomes so cancer cells keep replicating indefinitely.”

“The way cancer cells avoid this control mechanism is by producing an enzyme called telomerase which we need when we are babies and growing very fast but which we stop producing when we stop rapidly growing,” he said.

The enzyme extends the ends of the single strands of the DNA, or the caps in cancer cells, which effectively sends the message ‘we’re going to live forever’. So the chromosome thinks it’s a brand new chromosome.

New proteins to target DNA

“Our laboratory designed proteins that, for the first time, can actually recognise the single stranded DNA and bind it. We can basically program these proteins to target them.

“Previously scientists haven’t been able to target the single stranded DNA. The beauty of this new technology is that we have developed proteins that can actually recognise the DNA and bind to it.”

The research has been published in the journal Nature Communications.

The Australian Cancer Research Foundation has supported cancer research at Harry Perkins Institute of Medical Research by providing $5.3 million and the Children’s Medical Research Institute  by $15.2 million towards cutting edge research technology.

Roland’s story – in honour of Men’s Cancer Month

“When I was 34 years old, I thought I was invincible. I was a new dad to two young daughters, Jade and Amber. From the minute they were born, I was totally in love with my babies. I wanted to spend every moment with them, but I was also determined to provide for their future.

I burnt the candle at both ends.

It was 1988 and I had started my first bakery business. It became an immediate success, and after the first year I had twenty employees and working 18-hour days was typical. I was living on coffee and adrenaline.

For a few months, I had been ignoring the pain in my stomach. Then, one day I was rushed to hospital with a large swelling beneath my ribcage. I vividly remember the moment the doctors told me they had discovered a 20cm tumour wrapped around my intestines.

It was Burkitts Lymphoma, and I was told I had less than three months to live.

I remember looking at Jade and Amber’s uncomprehending faces at the end of the hospital bed and in that moment I decided there was no way that I wasn’t going to be around to raise my girls.

At first, I was offered very limited hope so I desperately sought a second opinion. I met with a young oncologist who was a big believer in cancer research. He suggested I try a chemo regime called MACOP-B that was very new at the time. It gave immediate results and I went through further treatment which included radiation and an autologous bone marrow transplant.

Amber and Jade were a huge part of my recovery – they were my life force

Twenty-nine years after I was first diagnosed with cancer, I can look back and count my blessings.

I recall there were times when frightening thoughts would cross my mind. In the wake of such a grim cancer diagnosis and treatment, I worried that I would miss my daughters’ precious childhood moments, and that I would never get to walk them down the aisle. Through the toughest times, the thought of another man stepping in to take my place as their father if I wasn’t around, was always a reliable motivator!

Six months later, my treatment was officially over. Shortly after I was told I had a high chance of leukaemia due to the high doses of chemo, and for the first few years I lived in the shadow of a relapse.

There has always been a 5cm mass present in my stomach, which is likely to be just scar tissue. I think of it as my talisman – it’s there to remind me to value each day, and keep me balanced in my approach to life and business. I am thankful that the only side effect of the innovative treatment was that my hair never grew back after the chemo. At least I didn’t have to go grey and I saved on shampoo!

I have been given this time to raise Jade and Amber, and their little sister Ava. Every day that I get to watch them fly is a miracle to me. I know that I am one of the truly lucky ones. Stories like mine are often too few and far between.

Everyday men are lost to cancer, and many others must live with the debilitating effects of painful treatment

This is why it is so important to continue to support cancer research into improved ways to prevent, detect and treat cancer.

When Jade told me she was taking action to support the Australian Cancer Research Foundation, I was so proud of her. I was thankful to be at her side as she shaved her head. A flood of memories poured in and I took the opportunity to phone and thank the doctor who helped me all those years ago.

ACRF supporters like you make life-saving discoveries possible. I know this because cancer research saved my life, and it will continue to save others, now and in the future.

Since my diagnosis, I have been in awe of all those new, more targeted treatments that provide better outcomes for all types of cancer.

And, there is still so much more we can do.

Cancer is smart, but when we join together, we are smarter

Each day I marvel at my extraordinary good fortune to have survived. When you donate to ACRF, you give more Australian men like me a better chance at survival.

Please make a donation this Men’s Cancer Month as an investment in the health of those you hold dear. Families like mine can’t thank you enough for your support of cancer research.”

Sincerely, Roland
Jade’s dad, cancer survivor and ACRF supporter

 

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Team behind new cancer treatment wins Clunies Ross Award

A team of cancer researchers at the Walter and Eliza Hall Institute (WEHI) has been recognised for their role in the development of a new anti-cancer medicine. The team received the 2018 Clunies Ross Knowledge Commercialisation Award from the Australian Academy of Technology and Engineering (ATSE).

Professors David Huang and Andrew Roberts and Associate Professors Peter Czabotar, Guillaume Lessene received the award for their roles in the development of the anti-cancer agent venetoclax, which involved a collaboration with the companies Genentech, a member of the Roche Group, and AbbVie.

Venetoclax (marketed as VENCLEXTA® and VENCLYXTO®) is a medicine that is now approved for clinical use in Australia, North America and Europe for the treatment of people with certain advanced forms of chronic lymphocytic leukaemia (CLL). CLL the most common type of leukaemia diagnosed in Australia.

Translating research discoveries to a treatment

The development of venetoclax has its foundation in a research discovery at the Institute in the 1980s, that a protein called BCL-2 can make cancer cells immortal by preventing a form of programmed cell death called apoptosis.

Professor David Huang, whose research has investigated cell death since the 1990s, said the team had a long-term goal of developing a new anti-cancer treatment that killed cancer cells by inhibiting BCL-2.

“Venetoclax was the first drug of this kind to be approved for regular use in the clinic,” he said.

“It has been thrilling to work with our team and our industry partners to see the translation of our laboratory research to clinical benefit. We are honoured to receive the Clunies Ross Award from ATSE.”

Clinical trials of venetoclax demonstrated its benefit as a treatment for people with certain forms of CLL who had no other treatment options, said Professor Andrew Roberts, who is the Head of Clinical Translation at WEHI, a clinical haematologist at the Royal Melbourne Hospital and the Peter Mac, and also holds theMetcalf Chair of Leukaemia Research at the University of Melbourne and Victorian Comprehensive Cancer Centre.

“It was exciting and rewarding to be part of the journey that saw a fundamental research discovery developed to benefit patients,” Professor Roberts said.

“The initial clinical trials of venetoclax took place at sites including the Royal Melbourne Hospital and the Peter Mac, which meant that Australian patients were the first in the world to benefit from Australian innovation.”

The power of collaboration

The research fields of structural biology and medicinal chemistry were crucial for the development of venetoclax. Associate Professor Peter Czabotar led research that revealed three-dimensional structures of target proteins. These provided ‘blue-prints’ for developing venetoclax through the team’s collaboration with AbbVie and Genentech.

“Our research benefited from the depth of structural biology expertise in the Institute, and from our access to the Australian Synchrotron,” Associate Professor Czabotar said.

“By visualising detailed structures of BCL-2 family proteins, we could see how medicines could be developed that were highly specific for BCL-2.”

The early work to develop drug-like molecules that specifically blocked BCL-2 family proteins was led by Associate Professor Guillaume Lessene.

“These proteins presented technical challenges that needed to be overcome in our quest for inhibitory molecules,” Associate Professor Lessene said.

“The depth of expertise in medicinal chemistry at the Institute was critical for the project to reach the point at which we could secure industry collaborations to progress the research further.”

Walter and Eliza Hall Institute director Professor Doug Hilton AO said the story of venetoclax was an important example of Australian science having a global impact.

“Venetoclax is a great demonstration of the power of collaboration,” he said. “David, Andrew, Peter and Guillaume led the team that brought together skills in cancer research, structural biology, medicinal chemistry and clinical translation that, when combined with the strengths of our commercial partners AbbVie and Genentech, enabled us to see a laboratory discovery translated into a new medicine.”

“I hope the recognition the Clunies Ross Knowledge Commercialisation Award provides to this team will inspire other Australian researchers to pursue similar journeys.”

The Walter and Eliza Hall Institute acknowledges the contributions of its funding partners to its cell death research, including the Australian Cancer Research Foundation, the Australian Government, Cancer Council Victoria, the Leukaemia Foundation of Australia, the Leukaemia and Lymphoma Society, and the Victorian Government.

This story was originally posted on the WEHI website.

ACRF has supported WEHI Institute by providing three grants, totalling AUD 5.5 million towards cutting-edge cancer research equipment and technology.

The strength of a mother’s love: Tax time campaign 2018

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“You always knew exactly where my mum was. Before you even saw her – you heard her big, infectious laugh. It was her trademark.

Last year, I watched helplessly as cancer took her away from us. Within weeks of her liver cancer diagnosis, she was gone.

Losing her has been the single most devastating event that I have ever experienced. I couldn’t stand by and let cancer continue to affect our loved ones in such a cruel way.

Remembering my mother lost to cancer

My mum saw the good in people and gave her love freely and openly, and that has left a lasting impression upon all who knew her.

No matter who you were, my mum was always there with a heartfelt smile and her unique way of making the worries of your day disappear.

She had so much zest for life, and it makes me so proud to know that’s how she is remembered, warm and bright.

I was fortunate to have known my mum very well. I’m an only child, and throughout my 39 years, I shared a wonderful relationship with both of my parents. The three of us supported each other through everything. My parents sacrificed so much for me, especially Mum, who was undoubtedly the most selfless person you would ever meet.

As a reminder of my mother’s legacy of happiness, joy and love I had the soundwave of her trademark laugh tattooed on my inner bicep to represent strength. It is my first and only tattoo and is my way of keeping her close to my heart, and under my wing.

How Scott supported cancer research

Soon after Mum passed away, I decided to take action to help Australian researchers find better ways to prevent, detect and treat all cancers. I’m determined to do everything I can, to stop others from feeling the unbearable pain and heartache caused by cancer.

My mum loved me like no other, but she wasn’t that keen on my long beard – she said it hid my face. I decided that I would shave it off for cancer research. With the help of my friends and family we raised over $12,000.

I was blown away by the result – it showed me that, “a snowflake is frail, but if enough of them stick together, they can stop traffic”.

To honour my mum, I hope that I can help others live a long and fulfilling life. Cancer affects us all but I know that together we will outsmart it.”
– Scott, ACRF supporter

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Prostate cancer patients to benefit from targeted radiation delivery

Some men with aggressive prostate cancer will benefit from targeted radiation therapy. The new therapy, utilising radioactive material sourced from Australia’s Lucas Heights nuclear reactor, has produced dramatic responses in some men with aggressive prostate cancer and who have failed current therapies.

The treatment, LuPSMA (Lutetium-177 PSMA-617), involves a radioactive molecule that is purpose made to bind to prostate cancer cells, enabling the targeted delivery of radiation to kill these tumours.

LuPSMA was also seen to reduce bone pain and improve quality of life in the proof-of-concept clinical trial which involved 30 patients – a world-first on this scale. Results of the Peter Mac-sponsored Phase II, single-arm study have been published online by Lancet Oncology.

Professor Michael Hofman, who led the trial at Peter Mac, said the responses were remarkable and supported starting a larger, randomised and multi-site trial of LuPSMA.

“Our small proof-of-concept trial shows that LuPSMA is highly active in men with aggressive prostate cancers, and it can trigger striking responses in some men,” said Prof Hofman.

“That LuPSMA was able to achieve this in men who have exhausted conventional treatment options is remarkable, and we now look forward with great interest and optimism to results of our Australia-wide TheraP trial now underway.”

The TheraP trial (ANZUP 1603) – which commenced once the positive results of Peter Mac’s proof-of-concept trial were known – is a partnership between ANZUP Cancer Trials Group Limited (ANZUP) and Prostate Cancer Foundation of Australia (PCFA).

The primary goal of Peter Mac’s proof-of-concept trial was whether LuPSMA could reduce PSA (Prostate Specific Antigen) levels by more than 50%. PSA is a blood biomarker for prostate cancer, so lowering PSA levels in men with advanced disease indicates a reduction in cancer activity.

After LuPSMA, all but one of the men saw a decline in PSA levels. More than half (57%, 17 of 30) showed at least a halving of their PSA levels – meeting the goal. Notably, in six of the men (20%) exceptional responses were seen with PSA levels becoming close to undetectable. Full body scans also confirmed dramatic changes in men before and after receiving LuPSMA (see below).

“Some men also reported LuPSMA gave them rapid relief from otherwise severe bone pain and they had more energy for daily tasks and to enjoy their family time,” Prof Hofman said, noting the treatment was well tolerated with no immediate adverse effects and no treatment-related deaths.

LuPSMA is a personalised treatment using a concept called “theranostics”. This combines a diagnostic test and targeted therapy. First patients undergo a PSMA PET scan to see if the tumours “light up” reflecting adequate expression of the target. Only if suitable do they proceed with treatment. Peter Mac has a long history of expertise in theranostic therapies which enabled the team to perform this world-first study.

Recruitment for the larger ANZUP/PCFA TheraP trial (ANZUP 1603) is underway with trial sites now open in Victoria, NSW and Queensland and soon to open in WA and SA.

ANZUP Chair, Professor Ian Davis, says ANZUP was delighted to work with Prof Hofman to launch this important study in partnership with PCFA and: “Clinical trials like this are the only way we can find out how well new treatments work, whether they are safe, and whether they should become the new gold standard for treatment in the future.”

The news was first published on the Peter Mac Website. Image courtesy of Peter Mac, from left to right: Shaun Jenkinson (ANSTO), AProf Anthony Lowe (PCFA), AProf Michael Hofman (Study Chair) and Marg McJannett (ANZUP) at the Lucas Heights reactor.

The Australian Cancer Research Foundation has supported Peter MacCallum Cancer Centre by providing four grants, totalling AUD $7million, towards cutting edge cancer research equipment and technology.

Two clinical trials demonstrate effectiveness of venetoclax

Venetoclax, a breakthrough cancer treatment, is driving a major shift in the management of a range of blood cancers, with two new clinical trials of chemotherapy-free combinations demonstrating dramatic benefits for patients with hard-to-treat leukaemia and lymphomas.

Results of two new venetoclax trials – the MURANO Study involving patients with Chronic Lymphocytic Leukaemia (CLL) and AIM Study in Mantle-Cell Lymphoma (MCL) – were recently published in the New England Journal of Medicine.

Both trials, involving patients whose blood cancer had relapsed or was resistant to conventional treatment, used venetoclax in combination with another targeted drug. These treatment combinations resulted in high rates of patients with no detectable cancer.

“That venetoclax is able to produce such dramatic results in this hard-to-treat patient group is remarkable, and has led to much excitement among blood cancer clinicians globally and the research community particularly in Melbourne where this drug was pioneered,” said Professor John Seymour, Director of Haematology at Peter Mac and RMH.

“The data shows venetoclax should replace chemotherapy altogether in patients with advanced forms of CLL – a practice-changing result which will rapidly translate into the standard of care globally.”

The MURANO study, led by Prof Seymour, involved 389 patients across 109 international trial sites and compared venetoclax plus rituximab to standard immuno-chemotherapy (bendamustine plus rituximab).

Venetoclax treatment was found to more than double the likelihood that CLL patients would live for two years without their cancer recurring (84.9% vs 36.3%), and the proportion of patients who had very few or no detectable leukemia cells in their blood was 83.5%, compared with 23.1% of patients who received standard immune-chemotherapy treatment.

The AIM study, led by Peter Mac’s A/Professor Constantine Tam and trialled at both Peter Mac and RMH, involved 24 patients with MCL. They were treated with venetoclax plus ibrutinib – two drugs expected to have an improved synergistic effect. This was the first ever trial of this scientifically-designed chemotherapy-free combination. Most (71%) patients went on to show no detectable cancer, and 78% of these patients remained cancer free for at least 15 months.

“This was in patients who we expected to have a poor outcome on conventional therapy, and in which treatment with either ibrutinib or venetoclax alone was expected to see only 21% of patients show a complete response,” said A/Prof Tam.

“These very promising results have triggered additional and larger studies to better understand the synergistic benefits of the venetoclax-ibrutinib treatment combination in MCL patients.”
CLL is the most common form of leukaemia in Australia, with around 1000 people diagnosed with the cancer every year. MCL is an uncommon sub-type of lymphoma which is considered incurable in most patients with conventional chemotherapy treatments.

“The development of venetoclax – from basic science through to international clinical trials with practice-changing results – provides a strong example of how Australian cancer researchers and clinicians can lead the world,” said Professor Andrew Roberts, a clinical haematologist at RMH and Peter Mac, researcher at the Walter and Eliza Hall Institute and University of Melbourne, and co-designer of the AIM study.

“Venetoclax selectively targets BCL-2, essentially causing cancerous cells to simply melt away, in many instances.”
The rapidity of this “melting away” can also be problematic for patients leading to the side-effect of tumour lysis syndrome. This affected six patients in the MURANO Study and two in the AIM Study, but was managed safely in all cases.

Venetoclax is a targeted drug in tablet form that was developed based on scientific discoveries made at the Walter and Eliza Hall Institute of Medical Research. Thanks to the generosity of ACRF supporters, ACRF contributed significantly to the success of the early phases of research into venotoclax.

This news was first posted on the Peter Mac website. Image of Professor Seymour provided by Peter Mac.