Saw this arrangement in a local orchid garden, which reminded me of the blobs used to illustrate E3 ligase – protein complexes
In the first of our new season AACR Preview series, we continue to explore what’s happening in the protein degradation and molecular glue niche.
Yes, it’s still early days and there’s much we don’t know but it should be useful to follow the developments and see what can be learned.
Perhaps a few observers might be surprised at the sheer range of targets being evaluated in R&D pipelines since some of these are definitely not of the every day kitchen sink kind of variety. There is no doubt in my mind some will be easier or much harder than others, but what is intriguing is the depth of the details which are starting to emerge of late.
So what’s in store and which abstracts stood out this year in this niche?
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It’s a good time to take stock of an early but important niche where the basic concept is the hijacking of the natural ubiquitin-proteasome (waste disposal) system for protein degradation therapeutics.
Traditional targeted therapies involve a small molecule or an antibody (in monoclonal or bispecific format) to inhibit an oncogenic target thereby shutting down the activity of the tumour, at least for a while.
Getting to the centre of things
What if we could find a way to biologically destroy oncogenic proteins instead – especially those which are hard to reach in normal circumstances such as protein-protein interactions?
The inherent potential for this concept would extend what we could do in terms of the proteome, but can it be done in people?
We have, after all, seen the selective estrogen receptor degraders (SERDs) evolve with one drug approved and several companies developing third generation versions in early stage clinical trials, so why not other targets too?
The simple truth of the matter is this elegant idea – while simple in theory – is technically quite challenging involving quite different obstacles from what we have seen with TKIs and antibodies.
Nevertheless, the difficulty has not fazed companies from trying and in looking at the broad landscape, we found 24 companies actively involved in protein degradation research in a multitude of targets and cancers. These span publicly traded biotechs, privately held companies, and of course, big Pharma.
Who are they and what can we learn from them in order to anticipate some of the issues to be addressed?
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In the last post from SABCS, we looked at what’s new on the translational front with the MYC oncogene in terms of breast cancer.
This time around we turn our attention to other targets and subsets of interest, which don’t involve immunotherapy – more on the latter in a separate article.
Today’s featured image is inspired by my dear friend Jody Schoger and Lisa Adams, who inspired us to find a little beauty in the world each day, no matter how hard it might seem. 2015 was very bad year for losing wonderful BioTwitter chums in the breast cancer community – they may be gone, but never forgotten 🙁
In particular, we highlight new developments in four key areas of interest, with some intriguing observations to discuss…
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It’s time for another landscape review of a particular class of drugs in early development.
Here we take an in-depth look at the emerging SERD landscape in ER+ metastatic breast cancer. There’s a lot going on the ER+HER2- niche these days after a bit of a lull once we saw the CDK4/6 inhibitors approved so it’s a good opportunity for some extended colour commentary on what could become a hot area in oncology over the next couple of years.
Overcoming or delaying the onset of therapeutic resistance is going to be important, but how do we go about achieving this?
Historically we have seen some success in inhibiting the activity of the estrogen receptor (ER) as a driver of oncogenic activity, but what if we could degrade the aberrant protein instead? Would this approach yield some further benefits for people with advanced breast cancer?
There are quite a few companies, big and small, involved in this space so there’s still much to play for, especially in terms of figuring out what the ideal drug should look like and which combinations might be most useful. We also highlight key upcoming conference presentations to watch out for – hint: there’s quite a lot of them!
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Every once in a while a completely new modality comes along, which turns things on their head and changes how we think about cancer drug development.
The first chemotherapy, the first TKI, the first monoclonal antibody or bispecific antibody… the list goes on.
Each one creates a new race and bunch of companies and molecules quickly follow the trendsetter.
How about the first protein degrader to show initial evidence of clinical activity in men with a particular type of cancer?
This is exactly what Arvinas have done with their novel PROTAC molecule, ARV–110, in men with advanced metastatic castration-resistant prostate cancer who have received prior hormonal therapy.
What can we learn from the data due to be presented at ASCO and from what lens of the kaleidoscope should we be really be looking at? To find out more, I spoke to an expert in this niche, the scientist who developed the technology, Dr Craig Crews.
What he had to say and how he got there is well worth listening to. I doubt doubt he quietened a few sceptical researchers along the way who likely thought it wasn’t possible to do in patients having heard a few of them in Q&A sessions at various conferences over the last five years. One of them (who will remain nameless) when asked what he thought of the idea actually scoffed at me in a coffee break, “It’s a preposterous idea – it’s fine in mice I suppose, but it’ll never be done in patients, mark my words!”
During my convivial chat with Dr Crews, I was remembering the moment from the past and wondering what he might be thinking now… to the brave and creative scientists go the spoils of victory.
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The BET Bromodomain market is a meaty epigenetics topic we have followed for several years now, including a look at the space back in 2013 on the old Pharma Strategy Blog (Link). The last update on this was ironically at AACR last year when we discussed MYC and bromodomains (Link).
In a remarkable tale of two cities in real life, two companies we discussed in those posts – Constellation Pharma and Tensha Therapeutics – have had markedly different fortunes since then. Roche decided to end their collaboration with the former and went on to acquire the latter instead.
Since we first wrote about bromodomains and BET inhibitors, the niche has exploded in a wildly stunning way… More drugs in the pipeline, more tumour targets being explored, and even novel combinations being evaluated preclinically for synergistic or additive effects. Even I was surprised by how competitive this niche has become based on the offerings at AACR this year.
With all the wealth of new data at the AACR annual meeting and also some other recent presentations I’ve attended elsewhere, it’s time for a more in-depth look at the BET/Bromodomain landscape.
Who are the new players, which tumour targets are now being evaluated, which combinations might be useful?
A word to the wise – this is neither a nerdy science post nor a comprehensive literature review – instead we take a look at the emerging landscape from a new product development perspective.
Science has been absolutely critical to success in all of the cancer therapeutics from targeted therapies to immunotherapies that have emerged in the last decade.
It really doesn’t matter whether you come from a marketing and commercial organisation or the investment community – if you want to make great decisions, you need to understand the basics of the science underpinning the R&D, where the strengths and weaknesses are. The alternative is play Roulette and put everything on Black 11 as a euphemism for whichever company/product/target you have an interest in.
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