Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts from the ‘Genomics’ category

Under the hood – a look at important new cancer research

One of the challenges of the short whirlwind period between AACR and ASCO is that many new research papers get published and largely missed or forgotten about in the data tsunami that drops as people eagerly (and almost exclusively) focus on the new abstracts that are available.

This is a real shame since there were many really good pieces of research that were rich in knowledge that were published around then.  My reading pile heading into AACR was much larger than usual, and after wading through it all, it built up rapidly again heading into ASCO, never mind over 20,000 abstracts to consider between those two meetings!

Contemplating new data…

With this in mind, it’s time for a new Journal Club post – these are surprisingly popular on BSB, although on reflection the selections have tended to highlight either new targets and areas of therapeutic potential or offer explanations for some of the phenomena that we are seeing.

New developments often (but not aways) allow us to step back and see results from clinical trials with greater clarity.

With this in mind, here are our latest selections for the BSB Journal Club, all of which should prove to be a useful read…

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Can STING agonists promote cancer metastasis?

Can STING (stimulator of interferon genes) agonists promote cancer metastasis in some patients?

That’s the intriguing question posed by research published recently in the journal Nature by Dr Samuel Bakhoum @Samuel_Bakhoum and colleagues. (doi:10.1038/nature25432) who found that, “chromosomal unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs.”

Samuel F. Bakhoum, MD PhD is a Holman research fellow at Weill Cornell Medicine and a senior resident in radiation oncology at Memorial Sloan Kettering Cancer Center in New York. The joint first author of the Nature article is Bryan Ngo, a student in the Weill Cornell Graduate School of Medical Sciences. It’s impressive work from two early career researchers.

The paper raises several important questions that drug developers – several of whom already have STING agonists in the clinic – may need to carefully think about.  It is, however, important to point out that this data is preclinical, so we don’t yet know what may or may not happen in cancer patients.

We first heard about the data published in Bakhoum, Ngo et al’s Nature article, “Chromosomal instability drives metastasis through a cytosolic DNA response,” at last October’s excellent AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics meeting in Philadelphia.

What we learnt at #Targets17 was that chromosomal instability is linked to tumour metastasis through the STING pathway.

Readers of BSB will know that we’ve been covering activation of innate immunity through the STING pathway for several years now (See posts: “What we learnt at AACR about Aduro ADU-S100” and “Tom Gajewski takes the STING out of Cancer,” to name but a few.

So how do we reconcile the positive and encouraging data that has led to development of multiple STING agonists, several of which are now in the clinic, with the potential that there might be a harmful aspect to them?

There are some important subtleties and nuances around this critical issue and that is the essence of this post and what we sought to gain more insight into, beyond the obvious superficial answer that there could be harmful effects involved.

The Roman god Janus is depicted as having two faces – one looking to the future and the other to the past.

There are also two faces to cancer immunotherapy: It can be a force for good, we can harness our immune system in a way that results in a positive outcome – people with cancer live longer, some are even cured.  Alternatively, if we harness the immune system in a negative way it can also be a force for harm. 

We heard on the recent Novel Targets Podcast episode that while combination cancer immunotherapies can be effective in a subset of people, they can also lead to rip-roaring toxicities as well as unwanted auto-immune side effects, and in some cases, these can be fatal.  With multiple inhibitory and activating forces at place, cancer immunotherapy can tread a fine line balancing these out.

Dr Bakhoum kindly spoke to BSB about the translational and clinical implications of this latest research.

Given the potential impact of this research, we also sought additional commentary from experts active in STING research such as Jason Luke, MD FACP (@JasonLukeMD). He’s an Assistant Professor in the Department of Medicine at the University of Chicago and a Principal Investigator for early immunotherapy trials, including those with STING agonists.

BSB readers may recall we did an in-depth interview with him at AACR17 (See post: Overcoming Immunotherapy Resistance). This time around, he shared his perspective on Dr Bakhoum’s research and looked at the potential clinical implications.

Like Janus, does the STING pathway really have two faces to it?

Should companies with STING agonists be concerned or not?

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What can genomics and tumours teach us about cancer drug development?

Non-small cell lung cancer (NSCLC) is big news this morning with the announcement from Genentech/Roche that the IMpower150 trial exploring whether adding atezolizumab to the standard of care Avastin plus chemotherapy hit it’s first co-primary endpoint of PFS. The data will be presented at European Society for Medical Oncology (ESMO) Immuno Oncology Congress in Geneva, Switzerland next month. The other co-primary endpoint, overall survival, is expected in a couple of months.

I’m delighted that this trial hit a positive note, especially after a few folks were surprised at our emphatic positive prediction for both the PFS and OS outcomes in reviews this year when we looked at it in the summer and again in the fall – see: predictions in 1L NSCLC trials followed by red and green flags.

In the meantime, recently there was some very important news in the lung cancer niche relating to the field of genomics and our understanding of how tumours develop and evolve.

It’s easy for many folks to forget that even in a tumour type that is considered to be a hot/inflamed one due to the high tumour mutation burden (TMB), not all patients respond to checkpoint therapy upfront and not all will achieve lasting durable responses that go out five years. Resistance (primary and acquired), as well as immune escape, will inevitably have a large impact on many patients.

Understanding the underlying biology of the disease will not only help us figure out the causes of non-response and relapse, but also explore rational combination approaches that might improve outcomes.

Just as the triplet of atezo/bevacizumab/chemo has now been show to be superior to the control doublet, we may well see other approaches evolve in the near to medium term future.

The Dynamic Duo at #TARGETS17

Up on deck today is a timely yet rare joint interview that explores the science behind how cancers (including lung cancers) evolve and adapt to try and evade not only detection, but also being destroyed, by anti-cancer therapeutics.

Professor Charles Swanton (Crick and UCL) and Dr James Gulley (NCI) make for a thoughtful and compelling double act.

It was an absolute delight and a privilege to conduct our latest BSB fireside chat with them together. What they had to say was fascinating.

Often we have jested about putting researchers in the BSB hotseat, but frankly when it comes to people of this calibre, the tables are usually turned and the interviewer is the one in the hotseat with some selective pressure to keep up and maintain a flow of intelligent questions!

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EACR17 Cancer Genomics Day 3

Churchill College, Cambridge: Yesterday heralded the 4th and final day of the EACR Cancer Genomics conference with some invited speakers and proffered papers based on research from several groups and labs.

Churchill College, Cambridge

We got to see through the keyhole on several important areas of research that highlight both challenges and opportunities faced by the field.

The good news is that the opportunities provide insights into how we can learn from ongoing and optimise future clinical trials.

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EACR Cancer Genomics Day 2

Churchill College, Cambridge:  Yesterday, the main focus at the EACR Cancer Genomics conference was on immunology-related topics as they pertain to genomics.

A rainy day in the Fens for #CG17

Unfortunately, however, the Great British summer ended as almost as soon as it started – I can confirm that it started on a Wednesday this year and fizzled out by the following Tuesday!

Consider that on the first two days of the conference it was gloriously sunny and those wooden benches were full of scientists sitting outside eagerly discussing their research or various collaborations afoot.

A mere 24 hours later, the heavens opened and steadfastly drizzled all day long, much to the chagrin of the attendees.

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EACR Cancer Genomics Day 1 Update #CG17

Cambridge: the third annual European Association for Cancer Research (EACR) conference on cancer genomics is underway at Churchill College in the UK. (Official Twitter hashtag: #CG17).

Churchill College, founded by the former Prime Minister, Sir Winston Churchill, is a short 15 minutes walk from the historic city centre and has an edgy modernist field to it, with thought provoking sculptures scattered throughout the grounds. It’s a far cry from the more romantic and dreamy spires of Oxford portrayed in the TV detective series, Morse and Lewis.

Despite all the interest in cancer immunotherapy and immuno-oncology, it’s important to remember that cancer remains a disease of the genome, which is why we decided to cover this meeting for the first time. It has an impressive line-up of keynote speakers, as well as researchers presenting posters.

All too often now on the cancer immunotherapy conference circuit, it’s the same thought leaders giving a repeat of their ‘party piece’ standard “keynote” talk so it’s refreshing to hear new voices who are at the leading edge of cancer research, albeit in a slightly different niche.

What we are starting to see is the convergence of cancer immunotherapy with genomics, and that was very evident in the posters that are directional of where the field is going. More on that later.

This is the first of three daily blogs that summarise some of the insights and take-home messages from the EACR Cancer Genomics conference at Churchill College, Cambridge.

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What can we learn from exceptional responders in cancer trials?

Following on from yesterday’s post on the potential for small basket trials in ER+ breast cancer with the ESR1 mutation, I wanted to highlight another area where these type of highly focused and rational studies appear to be not only useful but also potentially produce stunning responses.

Some of you will recall the fascinating and widely told story of a single bladder cancer patient at Memorial Sloan Kettering who was resistant to multiple lines of therapies. The team sequenced the genome and found a rare TSC1 mutation. Importantly, this is known from pediatric astrocytoma studies, to be sensitive to an mTOR inhibitor, everolimus (Afinitor). The refractory patient was given the drug and responded well. The rest is history, as they say.

Can we learn more from these type of appraches, i.e. genomic sequencing of patients who have relapsed after initial therapy?

Can we also learn more from the few exceptional responders in clinical trials – what was unique about their response that elicited such a stunning effect?

The short answer is a resounding yes.

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MBCC: Will NGS change the way we treat metastatic breast cancer?

Following on from yesterday’s update on how proteomics and genomics can help us make better decisions in breast cancer at the Miami Breast Cancer Conference (#MBCC14) organised by PER, today also looks at the complexity of genomics, but from a different lens – can genomics impact the way we actually treat patients?

Interestingly, last week there was a rumour (unconfirmed) that Dr Debu Tripathy (UCLA) was heading to MD Anderson to head up the breast cancer division following Gabriel Hortobaygi’s retirement. That move was confirmed yesterday, with a tweet from Dr Naoto Ueno, who is part of the group:

His talk on the increasing role of genomics in breast cancer on Friday was engaging, thoughtful and well delivered.

It also made me (and several others) stop and think.

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AACR 2012: the automation of preclinical drug discovery will be a driver of innovation

There was so much good science on display at the recent 2012 annual meeting of the American Association for Cancer Research (AACR) in Chicago that any blog posts are but a personal snapshot or postcard.

Bill Sellers VP Global Head Oncology Novartis Institutes for BioMedical ResearchOne enduring image I have from the plenary presentation on “The Genetic Basis for Cancer Therapy” by Bill Sellers, VP/Global Head Oncology at Novartis Institutes for BioMedical Research was the video he showed of the robots that are used for automated cell profiling.

Imagine the advertisements that show robots being used to build cars, but now the robots are undertaking automated laboratory work in pursuit of new cancer compounds. Wow!

During his presentation, Sellers described how Novartis have built a robust preclinical translational infrastructure.

He went on to say that, “many experiments we have done in the past, and even many molecules that were put in the human, really were only profiled against a limited number of preclinical models such as one cell line.”

In order to make preclinical data more reproducible, Novartis had the goal to move from testing against one cell line to testing against an encyclopedia of cell lines.

This has now become a reality with the launch of the Cancer Cell Line Encyclopedia (CCLE) in collaboration with the Broad Institute. The CCLE was recently announced by Novartis in a media release, and details were published online on March 28, 2012 in a letter to “Nature” (doi:10.1038/nature11003).

The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity

As described in “Nature”:The Cancer Cell Line Encyclopedia (CCLE) is a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines.

When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity.”

Sellers noted in his AACR plenary presentation that the key to using the CCLE is for profiling and to:

“identify subsets of cancer cell lines that are sensitive to a given therapeutic versus those that are not. And then better yet to identify the markers of sensitivity that are differentially expressed or present in the sensitive versus insensitive cell lines.”

Novartis Institute for Biomedical Research Automated Robotic Drug DiscoveryTo do this, Sellers described how Novartis have built a robotic system that e.g. automates cell profiling.  In approx 3 months with this system we can profile 600 cell lines for about 1500 compounds, he said.

This type of preclinical automation is speeding up cancer drug discovery through the ability to more rapidly identify those compounds that are associated with and have activity against different mutations.

In my view, this will drive innovation through the effective and efficient screening of potential new cancer compounds, with the result that only those compounds with demonstrable promise progress.

AACR have made Bill Sellers plenary presentation available as a free webcast from the 2012 annual meeting (along with several others).  I encourage anyone interested in how cancer biology is driving cancer drug development to watch this.

What’s hot at ARVO 2011?

By on April 27, 2011

This weekend I will be at the annual meeting of The Association for Research in Vision and Ophthalmology (ARVO) in Fort Lauderdale.

I’m excited about attending because earlier in my career I worked at Alcon Laboratories on European IDE clinical trials for three novel intra-ocular lenses.

ARVO is the ophthalmology equivalent of AACR and is where scientists involved in drug, device research meet to discuss new findings and early stage research.

The title of meeting is “Visionary Genomics.”  After listening to the plenary session at the recent AACR annual meeting by Lynda Chin on how insights from cancer genomics are translating into personalized medicine, I’m looking forward to seeing the impact of genomics on vision research.

Sunday’s ARVO/Alcon keynote presentation is from Roderick McInnes who is the Canada Research Chair in Neurogenetics at McGill University in Montreal.

A presentation that is already generating some advance interest is Sunday’s presentation of the results from the Comparison of Age Related Macular Degeneration Treatments Trials (CATT).

Age related macular degeneration (AMD) is the leading cause of vision loss in those over 65 in the United States, with over 7 million people estimated to be at risk.  Once you have AMD in one eye, you have a 43% risk of developing it in the other eye over a  five year period, a scary statistic!

The first CATT clinical trial is between bevacizumab (Avastin®) and ranibizumab (Lucentis®), both similar anti-VEGF inhibitors that are derived from the same monoclonal antibody.  It will be interesting to see whether the data supports the current practice of off-label use of bevacizumab given its lower cost compared to ranibizumab.

The findings from this data will also potentially impact aflibercept (VEGF-Trap) that is being co-developed by Bayer and Regeneron.  In February, Regeneron submitted a biologics license application (BLA) to the FDA for the use of VEGF-Trap in wet AMD.

The initial results from the aflibercept phase III AMD trial announced late last year showed a non-inferiority to ranibizumab.  If aflibercept is approved and comes to market in 2012, depending on the CATT results, it may have to compete on price against off-label bevacizumab in AMD.  Whether a more convenient injection once every two months for VEGF-Trap (compared to monthly for Lucentis) is sufficient to justify a price premium, it will be interesting to watch the market dynamics in this space.

You can find more about the meeting on the ARVO conference website and they have also put up a blog for the meeting.   The theme of my blog posts over the next few days will be ophthalmology related, and I expect to be live tweeting from ARVO 2011 on Sunday and Monday.  I’ll also be aggregating tweets from the meeting (hashtag #ARVO11) on this blog.

 

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