Biotech Strategy Blog

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

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Posts by MaverickNY

AACR21 Preview 5 Promising new developments in the PARP field and beyond

Imagine the DDR pathway as a mass of many different notes and targets all interconnected…

We’re on our fifth AACR Preview already this year and there’s plenty more science and clinical topics to cover yet as we go through the emerging topics up on deck.

In this latest update we take a look at the growing field of DNA damage repair – not just old targets, but a raft of emerging ones too, some of which are still in early preclinical development while others are in early phase 1 trials.

We also have some expert commentary on some of these new targets – what stands out, what’s validated and just as importantly, what’s not?

It’s time to get to the centre of things in PARP-land…

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AACR21 Preview 3 Novel and cool approaches emerging in oncology pipelines

Who, and importantly, what is in the spotlight at AACR21?

In our third Preview of the AACR21 annual meeting series, it’s time to highlight some early or promising new categories, some of which involve some elegant or cool science concepts.

Here we selected our Top 8 emerging areas of innovative research in targeted therapies.  The immunotherapy developments will be covered separately.

So what ideas should you be looking over your shoulders at and which ones might make you shudder in horror?

After all, oncology R&D is very much a game of Yin and Yang – for every great new idea that comes along there’s always something in the category which makes you go, “Huh?!”

Hurry along and see what’s in the spotlight this year…

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Novel combination strategies to enhance KRAS inhibitors

A modular approach to bolting on different combination partners might be useful

In this second AACR 2021 Preview, we take a broad and deep look at the KRAS niche, with respect to both molecular glues (SHP2) and covalent inhibitors (G12C, RAS::SOS1 etc).

There’s a lot to cover here in terms of basic and translational science, as well as clinical learnings and also plenty of intricate interactions coming to the fore.

Where are we going – and just as importantly – shouldn’t be going with combinations? Not all of them will work out and not all combination partners are the same, which certainly adds to the spice and interest!  There’s the additional issue of which strategies might be useful yet haven’t been considered by the KRAS players.

Every time we look at this rapidly growing niche there is something new or important to discuss…

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The King of Kings

A bold move?

Over the last couple of years we have been quietly interviewing the various biotech and pharma players in the protein degradation niche and exploring their numerous approaches and pipelines.

In the latest company interview, we take look at C4 Therapeutics (C4T), who are a relatively young company with preclinical data at AACR next month, plus their first clinical trial opening imminently, both excellent achievements in a relatively short space of time.

So what are C4T about and where do they seem themselves positioned? What are their goals and what should we be expecting to see/hear from them?  Do they have a shot at achieving their lofty aims?

To find out drop in and catch up on our latest CSO interview…

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AACR21 Preview 1 Emerging targets for protein degradation and molecular glues

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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The broad and deep protein degradation landscape

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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Using bacteria as a trojan horse to target oncogenes

Colon cancer cells Source: NCI Center for Cancer Research

We have covered a tremendous array of different modalities here at BSB from chemotherapies, targeted therapies, immunotherapies, encompassing cytotoxics, small molecules, antibodies, bispecifics, various conjugates, and even viral therapy approaches, but what about the potential for bacterial approaches having an impact in cancer research?

This is isn’t something we come across every day week and thus it piqued our interest.

If we want to start thinking about creative ways to hit hard to target oncogenes then maybe we need to think outside the box a bit with some bold ideas…

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The potential for a novel chemotherapy approach

Earlier this week we highlighted how click chemistry technology has enabled the development of a protodrug platform with inert polymers for more targeted delivery of chemotherapeutic drugs.

Similarly, another related approach we can consider to reduce unwanted adverse events is the prodrug concept. In this situation, a potent chemotherapy is activated in the tumour where it is most needed thereby reducing the toxic effects on normal cells and improving tolerability for people receiving the therapy.

Can prodrug technology deliver potent alkylator chemotherapy in a much more targeted fashion in the tumour?

One of the well known challenges and limitations associated with standard alkylating chemotherapies has always been the indiscriminate toxicities resulting from systemic administration – they impact both cancer cells and normal cells with impunity.

What if we could develop a more targeted chemotherapy approach?

This might be useful for some people with advanced cancer where a modicum of disease control is needed, so how would we go about achieving this aim?

Here’s one way to potentially accomplish the task…

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How innovation in chemistry can transform anticancer therapy

One of the inevitable aspects of a new year is a fresh start and spring cleaning attitude to almost everything. This is also true of oncology R&D too – there are also a lot of cool ideas out there, which can get lost in the noise and hullabaloo of life, especially when the political climate is attracting much attention or distraction.

Shining a light on protodrugs

In our latest mini-series we have been chatting with a variety of academic and company executives about their perspectives on emerging novel and innovative technological approaches in cancer therapeutics.

The examples chosen for this series encompass a wide variety of different approaches from chemotherapies and targeted therapies all the way to cell and gene therapies. I can tell you now that some of them are so out-of-the-box they may have an real element of surprise and aura about them.

It’s time to shine a light and lift up new ideas challenging old dogma.

Perhaps surprisingly, some of these cool approaches may also have the potential for intersection and overlap with each other, as today’s intriguing example illustrates…

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La Coupe de Feu

Fans of Harry Potter, will no doubt be familiar with the Goblet of Fire (“La Coupe de Feu” in the French version) and how it was used to select the champions from three schools of magic who would compete against each other in a tournament.

The metaphor of fire is very apt when it comes to cancer immunotherapy, as we’re often seeking to either create or optimally target an inflamed tumour microenvironment.

In this post were looking at how prior research and an understanding of science can sometimes lead to an unexpected contender in the “Goblet of Fire” that is early stage cancer drug development. Could the contender end up as the new champion AKA standard of care?

As in the Harry Potter story, there are trials that have to be conducted and overcome along the way, and until the data reads out there is uncertainty as to how the story will end.

Intrigued? Do read on…

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