{"id":28539,"date":"2022-12-15T16:05:19","date_gmt":"2022-12-15T16:05:19","guid":{"rendered":"https:\/\/news.cancerresearchuk.org\/?p=25088"},"modified":"2024-11-03T15:13:10","modified_gmt":"2024-11-03T15:13:10","slug":"the-power-of-partnership-the-unique-alliance-taking-on-brain-cancer","status":"publish","type":"post","link":"https:\/\/ogkologos.com\/en\/the-power-of-partnership-the-unique-alliance-taking-on-brain-cancer\/","title":{"rendered":"The power of partnership \u2013 the unique alliance taking on brain cancer"},"content":{"rendered":"
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The Antibody Alliance Laboratory \u2013 a collaboration between Cancer Research UK and AstraZeneca \u2013 combines academic rigour with agile bioengineering to push forward antibody discovery projects. Here we explore how the partnership is enabling one researcher\u2019s career long mission to better the lives of childhood brain cancer patients\u2026 <\/em><\/p>\n<\/div>\n

<\/div>\n

The course of Richard Gilbertson\u2019s career was set in motion roughly thirty years ago. During his second week as a medical student, Gilbertson witnessed a young girl die of a brain tumour. And ever since, he has strived to understand the disease.<\/p>\n

At first, Gilbertson split his time between clinical practice and basic research. But in 2000 \u2013 moving from the UK to St. Jude Children\u2019s Research Hospital in Memphis \u2013 he dedicated himself entirely to research. This, he says, was how he thought he could have the greatest impact on the lives of children with cancer.<\/p>\n

Gilbertson wanted to better define the genetics of brain tumours. Initially, his work focused on the cancer that had killed that girl \u2013 medulloblastoma, the second most common paediatric brain tumour. But later, he started to also explore the third most common type: ependymomas. He has been instrumental in uncovering the multiplicity of existing medulloblastoma and ependymoma subtypes.<\/p>\n

Professor Richard Gilbertson is a paediatric oncology clinician scientist and is the Director of the Cancer Research UK Cambridge Centre.<\/p>

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Professor Richard Gilbertson is a paediatric oncology clinician scientist and Director of the Cancer Research UK Cambridge Centre.<\/p>\n<\/div>\n

\u201cWe recognised that ependymoma were born in stem cells that line the ventricles of the brain<\/a>,\u201d he says. \u201cThat was the first time that that had been shown. And so, we got interested in ependymoma \u2013 what causes it, where it comes from.\u201d<\/p>\n

That quest took a major step forward in 2014<\/a>, when Gilbertson\u2019s team at St. Jude described a mutation that was present in \u2013 and likely caused \u2013 around two-thirds of ependymomas occurring in the front most part of the brain.<\/p>\n

The mutation resulted from chromosome 11 splintering, then re-annealing in such a way that two genes were thrust together to generate a unique, carcinogenic fusion protein.<\/p>\n

Now \u2013 having moved back to the UK to become director of the CRUK Cancer Centre in Cambridge \u2013 Gilbertson hopes he is on the verge of introducing a brand-new diagnostic tool: an antibody that binds this fusion protein.<\/p>\n

If it passes through its final stages of development, the antibody could transform the clinical care of children and adults diagnosed with ependymomas. In addition, being able to easily distinguish fusion protein-negative and -positive ependymomas will facilitate clinical trials in patients with precisely defined subtypes of this cancer.<\/p>\n

\u201cThis project happened, because we had the opportunity to set up the CRUK Children\u2019s Brain Tumour Centre of Excellence,\u201d Gilbertson says, \u201cwhere we were always thinking about the diagnostic side.\u201d<\/p>\n

But when it came to the concrete process of actually making the antibody, it was another CRUK venture that took centre stage: The Antibody Alliance Laboratory.<\/p>\n

The AAL \u2013 which opened in September 2015, shortly after Gilbertson\u2019s move to Cambridge \u2013 was born of a unique collaboration between CRUK and AstraZeneca. Staffed jointly by CRUK- and AstraZeneca-scientists, the AAL was founded to run collaborative projects between academics and bioengineers who had at their disposal the full might of AstraZeneca\u2019s antibody discovery platform.<\/p>\n

\u201cThe academic community hold a vast knowledge around oncology biology and have novel insights into cancer targets,\u201d says Maria Groves, the lab\u2019s director. \u201cAs part of the AAL collaboration, they propose ideas for novel cancer targets and if that project is accepted into the Alliance, we work with them very closely.\u201d<\/p>\n

Groves recalls that when Gilbertson proposed targeting the ependymoma fusion protein, it wasn\u2019t just the robust scientific rationale for doing so that stood out. \u201cOne of the things that was really noted,\u201d she says, \u201cwas he was incredibly passionate about delivering this putative diagnostic.\u201d<\/p>\n

An in-fusion of data<\/h2>\n

Ependymomas are first classified according to where in the central nervous system they occur \u2013 the spinal cord, the rear of the brain (posterior fossa) or the frontmost part of the brain (supratentorial). While ependymomas affect both children and adults, the most aggressive ones develop most frequently in children under the age of ten.<\/p>\n

Despite being the third most common paediatric brain cancer, they remain relatively rare \u2013 about 50 cases are diagnosed annually in the UK and roughly 185 per year in the US. Such numbers make it difficult to run clinical trials deter pharma from investing heavily in the disease; and make gaining sufficient materials for doing research challenging.<\/p>\n

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\u201cGilbertson and his colleagues had found a gene that distinguished one class of supratentorial ependymomas from another\u201d<\/p>\n<\/blockquote>\n

No effective chemotherapy regimen has been developed for ependymoma. Instead, the current standard of care is maximal resection followed by radiotherapy. The survival rate following such treatment is around 60%. This number does vary according to where the tumour is growing \u2013 and successful treatment typically comes at a high cost.<\/p>\n

The course of radiation used is so intensive, it\u2019s referred to as \u2018devastating radiotherapy\u2019. \u201cOur conventional radiotherapy is very damaging for a child,\u201d says Gilbertson, \u201cthey don\u2019t form long-term relationships; they don\u2019t graduate from high school; they don\u2019t have long-term jobs; and they often remain dependent.\u201d<\/p>\n

Clearly, there is a need for new treatment options.<\/p>\n

Gilbertson\u2019s 2014 study built on work showing that, despite their shared histology, spinal, posterior fossa and supratentorial ependymomas had different gene expression profiles and different mutational loads.<\/p>\n

To dig deeper into this heterogeneity, his group examined dozens of supratentorial and posterior fossa tumours using whole genome sequencing and RNA sequencing. The standout finding was that in all nine supratentorial tumours that underwent whole genome sequencing, a region of chromosome 11 had undergone a catastrophic rearrangement. And in 8 of 9, this had made a little-known gene now termed ZFTA<\/em> abut the well-characterised gene RELA<\/em>.<\/p>\n

RNA-seq revealed a transcript \u2013 formed by splicing \u2013 that encoded a putative fusion protein. And in a larger sample, this transcript was absent from posterior fossa tumours and present in around two-thirds of supratentorial tumours.<\/p>\n

When Gilbertson\u2019s group expressed the ZFTA-RELA<\/em> fusion protein in neural stem cells, they became malignant. \u201cYou can make tumours using the fusion with nothing else, which is pretty remarkable,\u201d says, Gilbertson. \u201cTypically, the dogma is you need three or four mutations to make a cancer. In fact, you don\u2019t.\u201d<\/p>\n

These insights will inform novel strategies for tackling tumours that contain the ZFTA fusion protein. But back in 2014 what mattered was that Gilbertson and his colleagues had found a gene that distinguished one class of supratentorial ependymomas from another.<\/p>\n

Gilbertson\u2019s data suggested that these two types are caused by different mechanisms. But soon data from another group \u2013 with access to a larger number of patient samples \u2013 upped the ante by showing that the people whose cancers contained the fusion protein fared considerably worse than those whose cancers did not. People with fusion protein-negative tumours have about an 80% chance of surviving \u2013 people with positive cancers survive at a rate of around 20%.<\/p>\n

Finding a reliable way to distinguish the two tumour types immediately felt urgent. \u201cFirst of all,\u201d says Gilbertson, \u201cyou could tell patients who are fusion negative that they have maybe an 80% chance of being cured. At the moment, we can\u2019t do that, because we don\u2019t know which patient they are until we\u2019ve done the genomic testing.\u201d<\/p>\n

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\u201cThis is story of discovery and collaboration, with two different groups coming together that had completely different skills and knowledge to enable the discovery of something that has the potential to be very valuable.\u201d<\/p>\n<\/blockquote>\n

But as well as a diagnostic, Gilbertson says, distinguishing patients by tumour type will allow the respective groups to partake in targeted clinical trials.<\/p>\n

In particular, those with the fusion protein should be prioritised for tests of novel medicines. \u201cWe\u2019ve done a very large, high-throughput drug screen of about 1.2 million compounds \u2013 beginning at St. Jude, and now working with the Institute of Cancer Research through the CRUK Children\u2019s Brain Tumour Centre of Excellence \u2013 with the aim of making completely new therapeutics that target this disease,\u201d says Gilbertson. \u201cThese are the patients who we should be testing this in.\u201d<\/p>\n

Towards a diagnostic<\/h2>\n

For a diagnostic to have real impact, thinks Gilbertson, it must be reliable, straightforward to use and easily accessible.<\/p>\n

This, he says, ruled out relying on either whole genome sequencing or RNA sequencing, because \u201cthat automatically restricts that diagnostic capability to labs that currently have the ability to do that \u2013 which are a minority of labs around the world.\u201d The same applies to more recent, somewhat simpler, methods for staining DNA methylation.<\/p>\n

Therefore, Gilbertson decided the best tactic was to use the standard pathology technique of immunohistochemistry. That required developing an effective antibody \u2013 and thankfully as Gilbertson was deciding on this, CRUK and AstraZeneca were planning to open the AAL.<\/p>\n

Gilbertson learnt about this in 2015 when he met representatives of Cancer Research Horizons Together, they agreed that he should apply to work with the AAL. In January 2016, his proposal was greenlit, becoming one the lab\u2019s first projects.<\/p>\n

The cornerstone of the AAL\u2019s technical capabilities is AstraZeneca\u2019s proprietary phage display library, which contains around 100 billion fragments of human antibodies that can be screened for binding to a recombinant target protein.<\/p>\n

Dr Maria Grove, Head of CRUK-AstraZeneca Antibody Alliance Laboratory.<\/p>

” data-medium-file=”https:\/\/news.cancerresearchuk.org\/wp-content\/uploads\/2022\/12\/A.SMY_CRUKMedi0465-199×300.jpg” data-large-file=”https:\/\/news.cancerresearchuk.org\/wp-content\/uploads\/2022\/12\/A.SMY_CRUKMedi0465-680×1024.jpg” decoding=”async” loading=”lazy” class=”wp-image-25090 size-thumbnail” src=”https:\/\/news.cancerresearchuk.org\/wp-content\/uploads\/2022\/12\/A.SMY_CRUKMedi0465-150×150.jpg” alt width=”150″ height=”150″ srcset=”https:\/\/news.cancerresearchuk.org\/wp-content\/uploads\/2022\/12\/A.SMY_CRUKMedi0465-150×150.jpg 150w, https:\/\/news.cancerresearchuk.org\/wp-content\/uploads\/2022\/12\/A.SMY_CRUKMedi0465-96×96.jpg 96w” sizes=”(max-width: 150px) 100vw, 150px”><\/p>

Dr Maria Grove, Head of CRUK-AstraZeneca Antibody Alliance Laboratory.<\/p>\n<\/div>\n

A fusion protein was, however, a special challenge. \u201cThis was a unique fusion protein,\u201d says Groves. \u201cBut the un-fused proteins are also present within the cells, within the nucleus, so we wouldn\u2019t want our antibodies to cross react with the two proteins involved in the fusion.\u201d<\/p>\n

This meant that the team had to target the junction between RELA and ZFTA, the only exclusive sequence in the whole fusion protein. They managed, and having done just that, a panel of tens of antibodies was given to Gilbertson\u2019s lab for the next stage of testing.<\/p>\n

\u201cThey found some antibodies that looked quite promising. But the staining was quite weak,\u201d says Groves. Uncertain whether it was best to look for more candidates or to work on improving the performance of these initial hits, the team decided on the latter, taking the two best and working to better them.<\/p>\n

\u201cThat\u2019s when they got this fantastic data,\u201d says Groves. \u201cWhen Richard describes first seeing the results, he says he nearly fell off his chair! There was really strong nuclear staining with one particular antibody.\u201d<\/p>\n

\u201cThe AAL had refined our initial \u2018blush\u2019 of staining on tumour sections to absolutely striking and clear binding in sections of tumours that expressed the fusion protein,\u201d Gilbertson says. \u201cWe knew then we were in with a chance for this to work.\u201d<\/p>\n

Groves says: \u201cThis is story of discovery and collaboration, with two different groups coming together that had completely different skills and knowledge to enable the discovery of something that has the potential to be very valuable.\u201d<\/p>\n

The next phase<\/h2>\n

That confidence led to two patents being filed on the antibody, in 2019 and 2020. Now, the final hurdle is to confirm that the antibody works as well in human brain sections as it does in mouse.<\/p>\n

This relatively straightforward experiment is complicated by the rarity of supratentorial ependymomas and Gilbertson has had to seek tissue samples from international collaborators to complete the work. \u201cAlthough ependymomas are the third commonest brain tumour in children, they are still rare,\u201d says Gilbertson. \u201cAlso, the fusion is only seen in tumours that occur in the front of the brain. Most of the ones in children arise at the back. So, its rarest of rare. Finding enough tissue from those cases that we can test antibody on very precious samples is very hard.\u201d<\/p>\n

It is exactly this \u2013 rarity \u2013 which makes the development of this diagnostic antibody an excellent match for CRUK\u2019s mission to meet unmet clinical needs even when they only affect a small patient population.<\/p>\n

\u201cCRUK is a very special organisation,\u201d says Gilbertson. \u201cYou can pick up the phone and talk to the CEO of CRUK. It gives you this sense that you\u2019re partnering \u2013 and they\u2019re receptive and they\u2019re responsive. It makes them much more agile in the research space.\u201d<\/p>\n

Nothing is certain for ependymoma patients \u2013 all this will depend on careful trials and clinical exploration. But Gilbertson points to the evolution of medulloblastoma treatment as a cause for optimism. \u201cThe thing that brings me to tears as a paediatric oncologist is that over the last ten years, St. Jude has backed off on radiotherapy, and all those patients are disease-free. They\u2019re all cured, and they will have normal lives.\u201d<\/p>\n

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Explore the Antibody Alliance Laboratory<\/a><\/strong>
Today, the AAL is running nine projects, each at a different stage of development.<\/p>\n

The team work on very early-stage target discovery and validation, all the way through to preparing an antibody for clinical use. Using a range of technologies beside their phage display library, they are developing several different types of antibody applications, including immunotherapy, signalling cascade blocking and delivery of conjugated drugs to the inside of cancer cells.<\/p>\n<\/div>\n

Author:<\/em>
Liam Drew is a writer and journalist covering biology and medicine. In 2020, he received the Association of British Science Writers\u2019 Award for Best Engineering and Technology Reporting.<\/em><\/p>\n

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The Antibody Alliance Laboratory \u2013 a collaboration between Cancer Research UK and AstraZeneca \u2013 combines academic rigour with agile bioengineering to push forward antibody discovery projects. Here we explore how the partnership is enabling one researcher\u2019s career long mission to better the lives of childhood brain cancer patients\u2026 The course of Richard Gilbertson\u2019s career was […]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"footnotes":""},"categories":[5137],"tags":[],"class_list":["post-28539","post","type-post","status-publish","format-standard","hentry","category-world-news"],"_links":{"self":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/28539","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/comments?post=28539"}],"version-history":[{"count":1,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/28539\/revisions"}],"predecessor-version":[{"id":43113,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/28539\/revisions\/43113"}],"wp:attachment":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/media?parent=28539"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/categories?post=28539"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/tags?post=28539"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}