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Precision Targeting of Elusive Cancer Oncogenes

Sunset over Boston Commons

Cancer remains one of the most intractable diseases, with certain types and subtypes continuing to evade effective treatment. While great progress has been made with immunotherapies and molecularly targeted drugs, cancers driven by notorious oncogenes like KRAS, MYC, and p53 remain challenging to drug.

These key transcriptional and signalling proteins play vital roles in normal cell physiology, meaning inhibiting them often causes toxicity. However, the allure of tackling cancers addicted to these oncoproteins keeps researchers striving for more precise, selective ways to target them.

One emerging approach is to inhibit a key transcriptional kinase involved in regulating MYC and other cancer-promoting genes. Several inhibitors of this kinase have been tested clinically, but most were either insufficiently selective or too toxic.

A new compound profiled in the post below shows early signs of being a more optimised inhibitor. It displays high selectivity and a long half-life, enabling sustained target inhibition without excessive toxicity. Early data from a phase 1 trial in solid tumours has demonstrated clinical activity, including exceptional responses in MYC-driven sarcomas.

These promising results highlight the potential of this new wave of inhibitors to tackle MYC-dependent cancers, including aggressive lymphomas. Other companies are advancing selective inhibitors of this kinase into clinical trials for hematologic malignancies.

Overall, these precision inhibitors represent an exciting targeted strategy against transcriptional addictions in cancer. The initial clinical success offers hope for making meaningful advances against once intractable oncogenes…

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How to Knock Out Cancer’s Backup Plan

Boston Commons in the Fall

Cancer’s got moves… sneaky moves to ensure its survival when you throw targeted therapies its way.

Monotherapy whacks just one piece of the beast. Crafty tumour cells can simply switch on alternate pathways to drive growth again. It’s like a hydraulic game of Whac-A-Mole.

But what if you could outsmart cancer’s backup systems? Shut down its escape route for a while longer?

New preclinical data reveal a smart 1-2 punch that can trap tumours in a corner. The sweet science of vertical and cross pathway inhibition.

This new technique tags both early and late players in pathways like MAPK and PI3K/mTOR. When this happens, cancer’s got no fallback. Nowhere to run, nowhere to hide.

Tumours take a sustained beating with every line of therapy thrown at them. Signalling disrupted. Proliferation caged. Apoptosis triggered. TKO.

Combinations tested in NSCLC, RCC, CRC and pancreatic cancer. Impressive, durable regressions. Researchers now poised to take this clever combo into the human ring.

Want the insider details? A ringside seat to the science? Step this way and we’ll walk you through the preclinical data blow-by-blow…

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The Next Frontier

Boston in the Fall

One of the joys of small specialist meetings is you can find early data from emerging biotechs or largely hidden abstracts from established companies seeking to avoid too much attention.

In great years, the AACR-NCI-EORTC molecular targets meeting doesn’t disappoint, offering unique insights on gems from the poster halls.

This meeting is also where we first cut our teeth reporting on promising targeted therapies before they became mainstream in 2009 and as such, I still have a soft spot for TARGETS or TRIPLE (when in the US) or EORTC (when in Europe).

The two things I was excited enough to write about that year were Dr Anirban Maitra’s fascinating nanobots as a stealth trojan horse strategy in pancreatic cancer (he was then an assistant professor at MGH) and Dr Mark O’Connor (KuDos) thoughtfully explaining synthetic lethality and PARP inhibition in the drafty poster halls using a three-legged stool analogy… you never forget either concept once you grasp them.

Who knew a little known small molecule then subsequently would go on to become a blockbuster for AstraZeneca as olaparib (Lynparza) and appear in multiple plenary sessions?!

This is ultimately why we love this meeting – who’s the next KuDos-in-waiting and what are the cool next generation developments, which could potentially be disruptive in their field?

In today’s post, we highlight another small, young biotech very much like KuDos were in 2009, only here we are looking at a very different approach to tackling KRAS, NRAS, and BRAF.

How far they will eventually go remains to be determined, but part of the excitement lies in finding engaging scientists who seek to do things differently from everyone else and win in the long run…

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What to watch out for at TARGETS23 – Part 2

Charles River, Boston in October for the TRIPLE/TARGETS meeting

With the AACR-NCI-EORTC molecular targets meeting (aka TARGETS for short) kicking off later today with a couple of education sessions and keynote talks, it’s time to put up our final preview on this conference.

Sometimes what starts out intending to be a short review ends up a much longer one because you discover there are an unexpected number of more intriguing compounds coming through biotech pipelines than you anticipated.

This is a good thing given today’s hostile market where raising money has become much more challenging of late. The health of the industry is very much driven by innovation from small, nimble biotechs producing intriguing products and new ways of doing things.

I’m delighted to say we found quite a few of these examples this year that break the cycle of the humdrum same old, same old trend.

In the first review we highlighted a number of key topics relating to KRAS, HRAS, and other areas.

In this latest version we explore and discuss over a dozen topics relating to DNA damage response (DDR), epigenetics, synthetic lethality and others.

In fact, I will go as far as to say a few of the class of 2023 may well stand out for years to come if all goes to plan in the clinic, although they are unlikely to be the more obvious examples I’ve seen touted lately…

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Ever Decreasing Circles

Fall Colors in Boston

The Fall cancer conference season is in full swing with the TARGETS and ESMO23 meetings both coming up this month.

Here we take a look at what to watch out for in both small and ‘large’ small molecules these include various epigenetic targets, KRAS, and SHP2.

The headline for today’s post was inspired by a British TV sitcom from the 1980s, which kind of reminds me of how perception of many of these targets has changed over time… as in time went on, in ever decreasing circles, the hype wore off and despair sets in.

Of course, there’s always redemption down the road in some form or other, as illustrated by the Fall and Rise of Reginald Perrin.

In this case, as the lustre fades on some of the frontrunners there’s now a rising tide of different – yet related – targets, as well as new compounds and combinations coming through – what’s not to like?

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ESMO Preview 2 – Making sense of controversy

Plaza de Cibeles, Madrid

In our latest ESMO preview series, we selected a modality to focus on and explore the potential opportunities and challenges many will face in the clinic.

There are a number of issues to address in this space:

Will new developments in technical design features help us see more agents over the finish line or are they doomed to repeat the mistakes of past?
As we see a much broader range of targets being evaluated, will this help or hinder the process?
What factors need to see improvement if we want to increase the number of Health Authority approvals?

There is no doubt the face of oncology R&D is changing – will recent successes help others over the line as well? To find out, we looked a large number of abstracts and selected some for discussion.

Here are our insights on the current state of play…

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ESMO23 Preview 1 – Hype over Hope?

Are you ready for ESMO23 in Madrido?!

It’s time to kick off our latest meeting previews highlighting some of the research being presented at the upcoming ESMO23 cancer conference in Madrid.

In the first of the series we take a critical look at some of the verbiage being used in the abstract titles and examine whether or not they hold up under the microscope.

We found some of the research doesn’t appear to actually represent major scientific advances, despite being labelled as such.

The key takeaway here is claims should be carefully scrutinised when evaluating early stage cancer research. Hard data and rigour are still essential to determine if something represents a real therapeutic advance versus hype.

The provocative question we address for readers is which abstracts fall into which category?

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Early stage oncology data of interest in TARGETS23 preview

Out with the old, in with the new

We’re reaching a turning point in oncology R&D.

More companies are looking to switch attention from classic, well established targets where there is so much competition it’s hard to differentiate to difficult, even intractable targets with significantly less competition.

To achieve this switch we need to find not only new targets, but also different modalities.

One way to go about bridging this switch is to develop molecular glues.

The magic of chemical induced proximity with this approach means there’s no linkerology involved, simplifying the design somewhat.

Here we look at what some companies are doing in this niche from targets to platforms and collaborations through to exploring what’s coming at the TARGETS meeting in Boston next month. There’s an added bonus included with some unexpected developments…

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Gunning for new targets, new approaches

Gunning for new targets, new modalities, and fresh directions

As we look at various emerging early stage oncology pipelines and think about future rising stars, there are a few which stand out for their sheer depth and breadth.

There are some intriguing similarities between them in they have forged multiple collaborations with selective young biotechs over the last few years rather than rely solely on in-house production.

In our latest review, we look at one of these companies and discuss how the various pillars they have chosen to focus on not only fit together, but also lend themselves to cross modality fusion.

The end result is a vibrant pipeline capable of fueling their life cycle management portfolio for quite a few years to come…

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What science tells us about future directions in lung cancer

The World Conference on Lung Cancers (WCLC) annual meeting in Singapore showcased important scientific findings illuminating new directions against these deadly diseases.

While some clinical presentations fell a little short of expectations, smaller sessions revealed some important gems illustrating the intricacies of lung cancer biology where art and science intersect.

In the end lung cancer remains complex, heterogeneous, often aggressive, and evolving. Emerging translational research undoubtedly brings hope towards guiding more targeted therapeutic strategies.

The art is in creatively leveraging emerging science to tackle these lethal diseases from every angle.

Here we highlight seven areas where we ought to be paying attention to when considering future directions in lung cancer…

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