Biotech Strategy Blog

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

Posts tagged ‘HIF-2α’

The Nexus Frontier

Futuristic image created with WALL-E   Source: Blue Ice Publishing

The Nexus Frontier stands as a bold and groovy movement at the intersection of discovery and understanding, where complexity meets clarity.

It’s a frontier where scientific rigour and human relatability converge.

In other words, it’s time for a collaborative guest post from a physician CMO to learn about his perspectives and reactions to recently presented data.

What jumped out?

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On black holes and rising supernova stars in oncology

Hubble Space Telescope, Spitzer Space Telescope

Hubble Space Telescope, Spitzer Space Telescope – Image credit: NASA/ESA/P. Jeffries

With the latest Nobel Prize in Physics being awarded to three scientists (Roger Penrose, Reinhard Genzel, and Andrea Ghez) for their work on black holes in the galaxy, it occurred to me there are some handy analogies for cancer research and development too.

As NASA aptly put it:

“Every second a star somewhere out in the universe explodes as a supernova. But some extremely massive stars go out with a whimper instead of a bang. When they do, they can collapse under the crushing tug of gravity and vanish out of sight, only to leave behind a black hole.”

Almost every Pharma company with an oncology pipeline is faced with the same fundamental challenge at some point in its life cycle – which ones are the rising stars that could explode as a blockbuster versus which compounds are doomed to vanish and be sucked back into the black hole (aka the screening library)?

Can we always tell from the basis of what are usually relatively simple allcomer trials in phase 1 with dose escalation in advanced solid tumours?

It’s fairly straightforward to tell when something is too toxic for patients to tolerate, as the number of grade 3+ serious events will quickly indicate, but activity isn’t so easy to determine.  This begs an important question to be answered – what are researchers and new product professionals actually looking for and how do they interpret the data?  Are they looking from a similar lens or are there differences in perception, much as a kaleidoscope changes even with the same elements included.

Here we take an in-depth look at a couple of early compounds against targets, which have garnered some attention this year and explore reactions from both sponsor and KOL angles.  As anyone involved in clinical trials knows, not everyone sings from the same hymn sheet every time!

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ESMO20 Preview 2 – New Targets, New Opportunities

Sunset in Puerta del Sol, Madrid

Not in Madrido – In our latest ESMO20 Preview, we take a look at five emerging areas of cancer drug development involving early stage pipelines and highlight some important features and benefits to watch out for.

These topics won’t be on everyone’s radar, especially if the focus is on the big phase 3 trial readouts, yet they can teach us much about new combinations and future pipeline evolution.

Who’s actively moving novel approaches along and who’s sitting on their laurels?

After covering biomarkers to watch out for yesterday, we now take a dive into what’s looking interesting in terms of novel targets and the fresh new opportunities for the not faint of heart…

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Highlighting an under-rated clinical development at ASCO20

Embedded deep in any conference database of abstracts are often important findings, which tend to be overlooked by many observers in the rush to focus on the more obvious candidates.

Time to scale the cliff on a previously little known and undruggable target!

This preview and accompanying thought leader interview explores one such underrated avenue of research.

There is a lot to be said when we have clear signals from our knowledge of the underlying biology in front of us because they inform where therapeutic intervention should be both rational and fruitful.

Is this actually the case in practice?

We dug deeper to find out what’s really happening…

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New developments in Genitourinary cancers

San Francisco!

San Francisco – It’s time to switch horses for some the latest conference coverage and explore some important new findings emerging from the genitourinary world of bladder, prostate, and renal cell cancers at the ASCOGU specialist meeting held late last week.

Not that many years ago, much of this niche was dominated by numerous updates in prostate cancer, with little good cheer to write about on the other two cancers – how things have changed in such a short time!

This year there’s plenty going on in all three categories, I’m pleased to say.

Here we focus on several important trials or targets and explain why they matter and what’s significant about the findings…

Some of the agents or trials selected here are likely to receive more attention going forward as more data become available, so it behooves us to set the scene now.

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Hypoxia and Inflammation: is HIF-1 a target for drug development?

I have a long-standing interest in hypoxia (lack of oxygen). Many years ago while completing my Masters degree in human physiology, I undertook research at the RAF Institute of Aviation Medicine at Farnborough on the effects of mild hypoxia on pilot performance.

So I was interested to read an article in the February 17, 2011 issue of the New England Journal of Medicine (NEJM) on hypoxia and inflammation, and how this influences disease.  Inflammation is one of my blog themes for 2011, and in a previous post, I wrote about how its ubiquitous role has been characterized as one of the “Insights of the Decade”.

In the NEJM article on mechanisms of disease, the authors Holger Eltzschig and Peter Carmeliet discuss the cross-talk between hypoxia and inflammation, and how this is implicated in cancer, infections and inflammatory bowel disease.

A lack of oxygen (hypoxia) is something that humans are acutely aware of.  We are all familiar with the flight/fight response that is designed to increase oxygen delivery to the brain and muscles.  Hypoxia can also lead to an inflammatory response.  The flip side is also true, where there is inflammation there is often local tissue hypoxia. An example of this is in solid tumors where the level of oxygen is considerably lower than in normal tissue.

The link between hypoxia and inflammation is regulated by the hypoxia-inducible transcription factor (HIF) that is activated by hypoxia. HIF has two subunits HIF-α (consisting of HIF-1α and HIF-2α) and HIF-β. The article goes into detail (beyond the scope of this blog post) about the interaction between HIF and the nuclear factor kappa-B (NF-κB ) transcription factor that regulates inflammation.

Elevated levels of HIF-1α and HIF-2α correlate with cancer deaths.  HIF-1 overexpression is associated with tumor growth, vascularization and metastasis. This has led to HIF-1 being evaluated as a target for anti-cancer drugs.

EZN-2968, a novel HIF-1α antagonist is in phase I clinical trials.  It is a joint development of two biopharmaceutical companies, Enzon in New Jersey and Santaris pharma in Denmark.

It will be interesting to see whether targeting hypoxia dependent signaling pathways will enable a clinically significant reduction in the inflammatory response.

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