Biotech Strategy Blog

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

Posts tagged ‘PI3K’

If you had told me several weeks ago that we would write over 28 posts on #AACR16 and become very interested in mouse models, then most likely I would have laughed out loud and told you not to be so ridiculous!  Here we are with the 29th one and, another, on the bromododomain landscape yet to go.  Such was the vast richness of data and concepts being discussed or presented in New Orleans for those who chose to look.

Today, I want to start the segue from AACR to ASCO coverage.

Nawlins MGRAS FIOne way to do that is through the second part of the Gems from the Post Hall series. This latest one looks at a range of intriguing new targeted therapies and novel targets that are emerging, including a pharma company with a particularly interesting early pipeline.

Several pharma companies presented interesting data on their very early compounds currently in development, plus I noticed a trend for a new class of targeted therapies to emerge, MNK inhibitors, which we will also discuss.

Companies mentioned: Bayer, Orion Pharma, Lilly, Novartis, Pfizer, Agios.

Targets mentioned: PI3K, CDK, Akt, TWEAK, FGFR, BUB1, IDH1, SMYD2, MNK

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EBCC10

EBCC-10 Cancer Conference

Amsterdam: The 2016 European Breast Cancer Conference organised by the European CanCer Organization (ECCO) is underway (Twitter: #EBCC10 – it’s the 10th official one they have organised).

We thought it would be a good opportunity to take a break from our coverage of #BMTTandem16 to look at some of the posters that are of interest at the meeting.

As regular readers know, we spend a lot of time reading posters – it’s where we pick up new trends and early data. Most go unnoticed or unpublicised in press releases.

For this post, I’ve highlighted four posters that I’m quite interested in and that merit further discussion.

They range from basic and translational research to clinical new product development. By chance, they are evenly split between immunotherapy (PD-L1 and TILs) and acquired drug resistance to different targeted therapies.

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Over the last few years we have seen new therapies emerge for the treatment of advanced prostate cancer from immunotherapy to chemotherapy and second generation hormone therapies. Each of these has increased survival and outcomes. Along the way though, a host of other agents have fallen by the wayside with a raft of negative phase III trials that did not live up to their phase II promise. These include atrensentan, dasatinib, ipilimumab, lenalidomide and more recently, custirsen.

Much of the focus has, however, been on the hormonal drugs, abiraterone (Zytiga) and enzalutamide (Xtandi) in both the pre and post chemotherapy settings. One thing has become clear though – over time the responses attentuate as resistance sets in. This is very common with oral therapies.

Some big questions to consider here are:

  • What causes it?
  • How can we overcome adaptive resistance?
  • Would combination approaches produce synergistic results?
  • Or should we consider new targets with a different mechanism of action (MOA)?

The answers to these questions are now being eagerly explored through basic, translational and clinical research. I was very impressed with the quality of research and breadth of fresh ideas and approaches emerging from the SBUR, SUO and UOR sessions at AUA this year, including new combination trials already in the planning phase.

In the past, Bertrand Tombal (Belgium) talked about the Grand Cru year for clinical research in CRPC. In the future we may well look back at 2014 as a similar Grand Cru year for basic research for prostate cancer, if the findings translate to clinic. The bench-to-bedside process is very much alive and well in urologic research.

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“Nothing lasts forever, because nothing ever has.”

James Shelley, The Caesura Letters

This year’s annual AACR meeting was so good, we could probably write another 50 posts and still not be done! With ASCO fast approaching, however, it’s almost time to draw it to a close and the final post conference note will be published on Monday.

Today is the penultimate report and focuses on the key highlights that caught my attention in immuno-oncology, which covers the gamut from checkpoint inhibitors, co-stimulants, innate immunotherapy and CAR T cell therapy to bispecific antibody TCRs.

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We hope that everyone had a relaxing holiday break and now it’s time to get back to work.  Tomorrow I will review some more of my thoughts in the immuno-oncology space, since that area had a tremendous amount of progress in San Diego with lots of new ideas to process and summarise.

In the meantime, a few people have written in and asked about what was happening with overcoming resistance in various tumour types, was there anything new to say in that space that was in addition to the the detailed previews we covered before the conference?

Actually, there was a quite a few posters and presentations that caught my eye, so I thought this would be a good idea to review them here:

Lung Cancer: HER2, VEGF, T790M, EGFR, erlotinib, gefitinib, trastuzumab, bevacizumab, CO-1686, AZD9291

Prostate Cancer: mTOR, PI3K, Androgen Receptor, enzalutamide, abiraterone, CC214–2, ARN–509, BET Bromodomian inhibition, ODM–201, GDC–0980, GDC-0068, PF–04691502, BKM120, BEZ235

“You may say I’m a dreamer

But I’m not the only one.”

John Lennon, Imagine

As part of our ongoing series on the AACR Previews, today I want to take a closer look at some interesting scientific and clinical data in triple negative breast cancer (TNBC).  One reason for this is that we need to remember that the disease, as currently defined, is essentially what’s left after taking out the ER+, HER2+ and inflammatory breast cancer subsets. In other words, it’s a very heterogeneous catch-all population, making clinical trials rather challenging at best. It also means that the chances of success in general all-comer trials is rather low.

It is my hope that as we learn more about the biology of this disease, we may see further subsets be defined by molecular peculiarities, much in the same way that gastrointestinal stromal tumours (GIST) were defined by KIT expression and CD117. Once we have more homogenous subsets, it will be easier to conduct trials just looking at those specific patients, thereby improving the chances of clinical success with therapeutic intervention.

There’s been a lot of work focused on this area over the last few years, so it seems a good point to find out where the progress has got to.

Without much further ado, what can we learn about the biology of TNBC from AACR this year and which potential new targets might emerge?

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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 – to learn more about some stunning new genomic approaches to research and the lessons we can learn for future drug development, sign in or sign up below.

Following on from yesterday’s post about learnings from the Boston AACR-NCI-EORTC conference in immuno-oncology, today’s post focuses on learnings from non-immune R&D, namely monoclonal antibodies and TKIs.

We know that cancer is a very complex topic and that adaptive resistance is increasingly a huge focus, but where are the new developments in this area and what can we learn from them in order to improve outcomes?

Another key area to consider is therapeutic index, that is are we shutting down enough of an oncogenic target’s activity in order to ensure efficacy? We’ve seen this in the anti-angiogenesis field, for example, where many VEGF inhibitors failed before bevacizumab (Avastin) finally cracked the nut in colorectal cancer and shifted the needle in terms of improving overall survival. We are now seeing this happen in other areas too, which will be covered below.

Some interesting early drugs in development were presented in a packed session this morning, across a wide variety of targets and tumour types. The four that stood out from the pack to me were:

1) MEDI4736 (anti-PD-L1)

2) GDC-0980 (dual PI3K/mTOR)

3) BKM120 (buparlisib) + GSK112 (trametinib) (PI3K + MEK)

4) alectinib (ALK)

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