What do T cells want?
In the third post in our summer mini-series on immunometabolism, we’re continuing our journey by taking a look at glutamine as a target, and in particular, the potential of glutaminase inhibitors.
Cancer cells compete with immune cells for glucose and glutamine in the tumor microenvironment, and if the cancer cell wins then immuno-surveillance and anti-tumour immune response can be diminished. Of interest, glutamine addiction is commonly seen in cultured cancer cells.
This begs a critical question – can we target glutamine therapeutically in patients, and if so, what happens?
In this article we highlight an expert interview with Dr Jeffrey Rathmell, who is Professor of Pathology, Microbiology and Immunology at Vanderbilt, where he directs the Vanderbilt Center for Immunobiology.
Dr Rathmell is at the forefront of research into T cell fuels such as glutamine and has published preclinical work on early compounds in this niche, including Calithera’s glutaminase inhibitor, CB-839, for example.
He kindly spoke to BSB after the AACR20 virtual annual meeting where he chaired a session on Metabolism and the Tumor Microenvironment.
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It’s the dog days of summer and time for some meaty controversy to read!
For the longest time there have been several cancer types which have been incredibly difficult to treat therapeutically.
Metastatic melanoma and non-small cell lung cancer (NSCLC) both used to be in this category, as did glioblastoma and advanced pancreatic ductal adenocarcinoma (PDAC).
We have made great strides in changing the face (and more importantly outcomes!) for people with both metastatic melanoma and lung cancer, so what’s happening on the pancreatic cancer front?
The last two years gave certainly thrown up a series of disappointing clinical trial readouts such as RESOLVE, HALO–301, CanStemIIIP, and SEQUIOA, for example, where in each and every case the findings favoured the control arm of gemcitabine plus nab-paclitaxel over the experimental arm in terms of improving survival. Not one of them was able to raise the bar and show a significant improvement over standard therapy, which is pretty disappointing.
So what can be done to change the face of PDAC?
If we want to improve further then we need to go back to basics and enhance not only our understanding of the funadamental biological mechansisms and processes, but also the models we use to interrogate the systems involved.
In this post, we look at six key new areas of research in PDAC and explain what we’ve learned and why they matter if we are to see new therapeutic developments arise from the ashes of the past…
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A graceful white swan serving as an antidote the current COVID19 pandemic (black swan event)
In our the third of our AACR 2020 Preview series, we turn to the KRAS pathway to look at some new aspects, whether they be new targets, novel agents in development or even twists on the biology of the disease.
There’s quite a bit to discuss here, certainly more than I was expecting considering it was expected to be a down year by some after all the excitement of last year’s revelations and developments in the clinic!
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Attention on small molecule inhibitors – after being in the doldrums for a while – seem to be making a comeback over the last year with much attention focused on a few companies developing new selective agents in specialised niches.
Time for a KRAS spring clean!
One such space is KRAS inhibition. Not just in terms of direct or indirect inhibition, but also with regards to tackling acquired resistance mechanisms such as SHP2. While there has been quite the frenzy over what Amgen, Mirati, Revolution Medicine and a few others are all doing, other companies are quietly getting on with the business of producing some nice work and will soon be ready for the off.
In our latest review we explore some of the factors involved, which companies will need to be concerned about going forward, especially in the context of future combination strategies.
In solid tumours, with targeted therapies the winners are not always the ones who reached the market first, but rather the crafty ones who optimise the combination strategies and become ingrained in protocols across multiple situations.
Here we look at one of the hidden gems in the KRAS space and explore what it does, why it’s important and how it might fit in. We also include a company interview with a scientist who gets the broader implications…
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The calm before the storm as the KRAS competition heats up and also gets more complex in the process
I was very tempted to tease everyone and say something along the lines of… ‘while you were all partying, there was some new KRAS clinical data being presented somewhere in the world’ but that would be rather naughty, I suspect.
Instead, I’ll simply point out that it’s time to take a look at the latest phase 1 data in the KRAS niche.
What more clinical data already?!
Yes there is and what’s more it doesn’t belong to the either of the leading two in the early race to market, aka Amgen and Mirati. There’s a whole bigger world out there for those interested in following the broader slate runners and riders. It pays to pay attention because this is not a race about single agent therapies, rather it’s about who figures out the optimal combinations and is able to finesse that better than their competitors. Like real horse races, an unexpected runner can surprise a few folks by making a strong push on the rails or a bounding leap round the outside like Lester Piggott was famous for doing.
This highly specialised field is moving much faster than the BRAFV600E arena was a decade ago and there’s also more players involved too, plus multiple different approaches and targets to consider, which I expect we will be covering quite a few times during 2020.
Are you ready?
Get set, GO!
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As we head into the AACR-NCI-EORTC Triple meeting in Boston this weekend, excitement is growing around a suite of RAS inhibitors in lung, colon and other cancers.
Charles River, Boston in October
Over the last couple of weeks we’ve received a bunch of questions from readers on several topics relating to this niche that I thought would be useful to spend some time on to set the scene ahead of the data dump expected on Monday and Tuesday.
Some people do like to try and simplify things thinking that it’s just a matter of adding in a checkpoint blocker or something else and boom! off we go… Except that we know from past experience with similar agents against different related targets that this won’t necessarily be the case and we look at some of the reasons why.
Yes I know folks are likely expecting too much in terms of efficacy, but we can put some framework and structure around the issues on which to build on, which are actually more than many may realise plus it could also be tumour and even patient dependent.
So here we go with a joint KRAS mailbag, together with a short expert interview with a view to highlighting some crucial roadblocks that are likely heading our way…
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Old Post Office in Barcelona
Barcelona – After the torrential rains that hit here earlier in the month at WCLC, it’s glorious weather in Barcelona for the 2019 Congress of the European Society for Medical Oncology (#ESMO19).
Each day we’ll be providing highlights from the Congress with news, commentary and analysis from various presentations we’ve attended and thought leaders we’ve spoken to.
This ESMO Congress is a really exciting meeting, perhaps one of the busiest we’ve seen in recent years with multiple sessions in parallel to choose from. There are no shortage of data to discuss and review. In distant years past, ESMO used to be known as the metaphorical dumping ground for negative trials that undoubtedly got lost in hurly burly – no longer! That changed after they started appearing in the Presidential Symposia and having the spotlight shone on the data. It’s now a much more vibrant meeting for clinical development, with an increasing translational focus thrown in too to explain the why and not just the what. That’s good news for all of us.
To kick off our daily live ESMO coverage, we begin with sharing some useful insights gleaned from what we’ve heard so far plus more will be added throughout the day as we hear from the educational sessions later…
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Chariots of Fire in Barcelona?
Barcelona – Gosh, what a weekend chock full of lung cancer data at the World Congress on Lung Cancer hosted by the IASLC!
There’s nothing like a bit of controversy to get riled up or crash with disappointed hopes under the weight of expectation, but if we go under the hood and look carefully, what do we find?
There was a lot of topics that we’re going to cover the important highlights and learnings in a two parter series – today we focus on KRAS with targeted therapy, while tomorrow we look at other topics of interest, both targeted and immunologic.
Without much ado, let’s roll with the Amgen update as there are many subtleties and nuances to consider…
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Yesterday we posted the first part of an extended interview with Professor Gerard Evan (Cambridge), where we discussed the oncogene MYC and what we have learned from his and others work in this emerging field.
It hard not to be in Cambridge and think of biology as anything but an seriously intellectual pursuit, and yet there are many lessons to be gained from a better understanding of why things do what they do – in both health and disease – if we are to even think about going about manipulating them therapeutically.
The river Cam in Cambridge earlier this year
Without much ado, here’s the second part of the interview with Prof Evan, where we channel our inner Socrates and focus on a lot of whys rather than hows.
We turn to discussing the biological principles around how MYC and KRAS behave in concert, what we do and don’t know about p53 as a tumour suppressor, plus a few other related topics of interest, including what happens to immune cells in their lung and pancreas cancer models. There’s also the little secret of what Prof Evan describes as the ‘dark matter of cancer biology.’
I highly recommend reading the previous post before moving on to digesting this portion of our enlightening discussion…
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River Rhine, Mainz
Mainz, Germany: We’re back for Day 2 highlights from the 2019 Association for Cancer Immunotherapy (CIMT) annual meeting with a look at some insights emerging from some academic and industry talks, as well as gems emerging from the poster halls.
Much attention is focused on cancer immunotherapy clinical data, yet it’s also important to watch out for new developments.
These can take many different forms such as what are companies doing to meet those challenges with novel therapeutics, as well as understanding more detail about immune mechanisms, including evasion and escape as well as defining phenotypes based on different immune cell populations.
As we head into ASCO, let’s not forget that there’s some important learnings to be had elsewhere in the world before we get there…
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