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It’s almost impossible to talk about progress in cancer research without invoking metaphors and analogies. New discoveries ‘shed light’ on problems and ‘pave the way’ for new treatments, while researchers engage in a ‘fight’ or ‘war’ against the disease. The most recent of these to enter public consciousness is the ‘moonshot’ (of which more later).
But given that cancer research is often incremental – and occasionally serendipitous – perhaps a more appropriate analogy is of a fiendishly complex jigsaw puzzle: first, you build up a basic outline and define the puzzle’s edges. Then you start working on the individual parts of the central picture, painstakingly trying out new pieces to see what fits. And finally, you try to join everything up.
In cancer research, we’ve now got a good understanding of many of the individual challenges. We’re figuring out the key controls that help cells divide, how faults in their DNA are repaired – and how cancer corrupts these processes. We know how hormone levels, blood vessels and the immune system are involved, and we’re starting to understand how different patients respond to different treatments while others become resistant. And we’re learning the role different faulty genes play in all of this, and how these change as a cancer grows and divides.
And treatments spawned from this understanding have helped double survival in recent decades.
But, just as in solving a jigsaw, each of these elements has tended to be worked on in relative isolation. And to further improve survival, the challenge now is to start joining them together to resolve the bigger picture.
This has been difficult. Until recently, cancer metabolism experts didn’t often mix with, say, immunologists. Researchers studying how cells communicate often compared notes with each other, but less often with the cancer geneticists. And lab-based researchers were seldom heard from in clinical trials circles.
But if the dynamic at the American Association of Cancer Research (AACR)’s Annual Meeting – a mass gathering of some 19,000 delegates in New Orleans – is anything to go by, things seem to be entering a new phase. The different elements of the puzzle are starting to dovetail, as new links are emerging between them. The bigger picture is starting to become clear, while the size and shape of the remaining gaps are becoming ever more defined.
So, what new pieces of the puzzle were revealed at AACR 2016?
Immunotherapy has become the poster-boy for new cancer treatments in recent years. We’ve seen a torrent of headlines proclaiming new immune-targeting drugs, known as checkpoint inhibitors, as the ‘next big thing’ in the treatment of certain cancers – notably melanoma and lung cancer.
And several trial results presented at the conference, and covered widely by the media maintained this excitement. Head and neck cancers – urgently needing new treatments – and a rare skin cancer called Merkel cell carcinoma, have now joined the rapidly expanding list of cancer types where patients may benefit from these drugs.
But there’s still a crucial mystery to solve before the hype around these new drugs – which work by jumpstarting a patient’s immune system – can be fully justified. Most patients don’t respond to them. And we don’t know why.
But several researchers at the conference, from a range of disciplines, presented findings that suggest they’re on the cusp of answers to this part of the puzzle.
One answer seems to lie in the discovery that, as they kill cancer cell, conventional cancer treatments also seem to kick-start the immune system too. For example, a team from the US National Cancer Institute revealed promising signs that liver cancer patients pre-treated with a technique called radiofrequency ablation seem to be more susceptible to immunotherapy. Another US team focusing on bowel cancer found similar results – patients given a chemotherapy combo called FOLFOX seemed to have more active immune systems, rendering them more sensitive to subsequent immunotherapy.
And Cancer Research UK’s Professor Tim Illidge showed how using radiotherapy in combination with immunotherapy can – in mice at least – trigger an extremely rare but mysterious phenomenon called the abscopal effect. This is where a small dose of radiotherapy to a single tumour can trigger an immune reaction that wipes out a patient’s other tumours too – and has been spotted among patients given checkpoint drugs. Working out how to reliably harness this could reap big dividends for patients: “The goal is to turn radiotherapy into a systemic therapy, rather than a local one,” he told delegates.
But among the more surprising developments was research from Cancer Research UK’s Professor Gerard Evan. Far from studying the immune system, Evan has devoted much of his career to the study of the internal wiring of cells – in particular, a ‘master switch’ protein called MYC. This is frequently hyperactive in cancer cells, and responsible for a whole range of processes linked to cancer.
But a crucial question Evans’ team has sought to answer is exactly which of these processes is important in causing cancers to develop (and hence, which ones to try to block). His latest findings suggest that, once again, it’s the immune system that’s central (something other groups have spotted too). The overactive MYC inside cancer cells seems to set off signals that effectively banish immune cells from inside a tumour, allowing the cancer cells to grow unharmed. So future efforts to target MYC-driven cancers will likely centre on uncloaking them to immune attack. “We’re all immunologists now,” Evan quipped.
Back on target
Away from the excitement over immunotherapy, there were signs that another cancer treatment strategy – so-called targeted therapy – was also nudging its way back into the limelight after a tricky few years.
Unlike immunotherapies, targeted therapies are exquisitely designed to interfere with particular faulty proteins inside, or on the surface of, cancer cells. And like the latest immunotherapy drugs, they too were the subject of much hype, hope and promise a few years back. But recently this has died down after many of them failed to deliver long-term responses, with drug resistance kicking in after weeks or months in most patients.
But in cases where a patient’s cancer is uniquely driven by a small number of faulty genes, targeted drugs can be very effective indeed. And the initial results of the US STARTRK trials, presented at AACR2016, bore this out. The trial set out to test a drug called entrectenib, which targets cancers that carry DNA faults triggered by two genes fusing together inside the cells.
While these gene fusions are uncommon in cancers like bowel and lung cancers, they seem to be fundamental events in rare cancers such as mammary analogue secretory carcinomas, which affect the salivary glands. Preliminary data from patients on the STARTRK-2 trial show that patients whose cancers harbour these gene fusions often showed a profound and long-term response to entrectinib.
Another emerging crucial role for targeted therapies is not in curing the disease before it’s spread, but in shrinking it down to make subsequent surgery more successful (so-called neoadjuvant therapy). Results of another trial presented at AACR – I-SPY2 – showed that a combination of two new targeted therapies was twice as effective at shrinking tumours in women with breast cancer before surgery, compared with a combo of chemotherapy and Herceptin.
And we heard promising results of several new experimental drugs aimed at targeting some of the 400-odd proteins involved in cancer cells’ ability to repair its own DNA. AstraZeneca’s Dr Graeme Smith shared promising data on drugs targeting two key parts of the DNA repair process – ATR and ATM – while the Cancer Research UK Manchester Institute’s Dr Allan Jordan revealed the first compound able to target a key repair protein called PARG (we’ll be hearing more about this over the coming months and years).
As became abundantly clear over the course of the conference, there is still plenty of mileage in targeted therapies.
Fly me to the moon
With four solid days of presentations spread over scores of lecture halls, the above is only a snapshot of the huge volume of research presented at the AACR. We’ve run out of space to report on the fascinating results of a new breast cancer test that could spare women chemotherapy they don’t need (though you can read about it here), or how more precise imaging techniques and methods of tracking cancer’s development via blood tests are all showing promise. Or report how discussions around how changes in cancer cells’ metabolism may hold clues to treating it, or how cancer researchers are using cutting edge gene-editing techniques like CRISPR to speed up new discoveries.
But we do want to close by trading our jigsaw for a moon-rocket, and dwell for a moment on an inspirational closing speech from US Vice-President, Joe Biden.
Late last year, Biden was appointed by President Barack Obama as ‘mission control’ of an ambitious attempt to “end cancer as we know it” – dubbed the Moonshot Initiative.
In the aftermath of Obama’s announcement many sceptical articles were penned, especially from battle-weary cancer researchers recalling the hype and over-promise of President Nixon’s 1960s War on Cancer.
But as he sketched out his preliminary thoughts in the main conference hall, Biden – who lost his son to a brain tumour just a few years ago – seemed to fully grasp the challenges slowing progress in cancer, while having the personal drive and kudos to tackle them.
He told a packed final session how, as he’d spent months talking to cancer researchers of all levels and all countries, it became clear that rather than focusing on any particular treatment or technology, his job was to boost one single aspect: collaboration.
Listing several high-profile US cancer studies, he asked: “Why is all this being done separately? Why is so much money being spent when, if it’s aggregated, everyone acknowledges the answers will come more quickly?”
Which brings us back to the jigsaw. As anyone who’s ever tried to solve a 1000 piece puzzle knows – it’s much slower, and more frustrating, if you try to do it on your own. As we’ve made clear through our Research Strategy, the key to continued progress against cancer – and to helping the tens of thousands of people affected by the disease each year – is to bring different scientists together to fill in the remaining gaps in our knowledge, and – as Biden puts it, “end cancer as we know it”.
It’s not going to happen overnight, but as the US Vice President himself said, “The things that are just about to happen I believe we can make happen. I think it’s possible.”
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