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Posts from the ‘Basic Research’ category

Developing a predictive biomarker for PARP inhibition

Today’s Science Friday post looks at the identification of a potential new biomarker and possible strategies for expanding use of PARP inhibitors in patients most likely to respond to them as a way to validate the the approach prospectively.  This has important implications for future clinical trial designs with this class of drugs.

205606714 92ecf3f428 m Developing a predictive biomarker for PARP inhibition

Photo Credit: Ben Sutherland via flickr

Regular readers will be very familiar at my rants against broad catch-all studies and phase III trials with targeted agents that do not have a biomarker or even a logical well defined subset of patients because it’s akin to blindfolding an archer, turning him around 360 degrees and then asking him to hit a bullseye 50 or 100 yards hence.

Update on RAF resistance in metastatic melanoma

“RAF inhibitors (vemurafenib and dabrafenib) have profound clinical activity in patients with BRAF-mutant melanoma, but their therapeutic effects are limited by the emergence of drug resistance.”

Solit and Rosen (2014)

For today’s post on Science Fridays, I wanted to take a look at an overview paper, published in Cancer Discovery, from two researchers in the metastatic melanoma field who have been looking at multiple mechanisms of resistance.  It’s an important topic because while we have seen incremental improvements in outcomes for this disease, the 5-year survival rate is still rather poor with only 10–20% of metastatic patients still alive by then.  This is not to disparage the efforts of scientists, clinicians or companies working in this space, far from it, but there is is clearly a need for new therapies, strategies and combinations, given the high unmet medical need that exists.

Will intermittent dosing transform TKI therapy in cancer research?

At AACR last year, one of the most revealing presentations was on metastatic melanoma, specifically, some elegant research by Meghna Das Thakur (NIBR) demonstrating that intermittent pulsing of vemurafenib (a BRAF V600E inhibitor) led to less resistance than inhibiting the target 24/7.

Many of us wondered whether such a pulsing approach would be useful for other tyrosine kinase inhibitors (TKIs).

Fast forward to this week.

CD current Jan 2014 226x300 Will intermittent dosing transform TKI therapy in cancer research?Neal Rosen’s lab at MSKCC has an interesting new paper out looking at the effects of pulse dosing with PI3K and ERK inhibition, since targeting both has long been suspected to be key in overcoming cross-resistance.

Removing the PD-1 brake enhances the effect on adoptive CAR T cells

Someone in my Twitter stream kindly shared a link to an article this morning on how removing the PD-1 brake enhances the effect of chimeric antigen receptor (CAR) T cells in solid tumour models.

Whoa!  Read that again and digest the implications.

We already know that the current leading immunotherapies, blocking PD-1/PD-L1 and adoptive therapy with CART, are rather effective in some cancers, but I’m willing to bet that few would have expected this effect, even though it makes a lot of sense when you actually sit down and think about it.

Certainly it gave me goosebumps reading the articles.

Transformative antibody technology in cancer research

Recently, I came across an exciting new development in a Nature publication and couldn’t resist teasing my Twitter followers with this terse statement:

Naturally, this mischievous tweet set off a lot of folks frantically trying to guess what I was referring to and the @replies came in thick and fast.

The National Science Foundation defines transformative as:

ASCO 2013 Highlights Part 2

It’s that time of the year when the annual meeting of the American Society of Clinical Oncology (ASCO) hurtles around with alarming speed out of nowhere and everyone in Pharmaland goes, “ASCO, what already? Is it really June?!” Suddenly the month becomes the focus for many frantic hives of activity.

Immunotherapy

The last two years have seen some unprecedented changes in new therapies emerging to treat several different tumour types, both liquid and solid.  One of the new trends that has begun to emerge is the new class of immunotherapy agents called checkpoint regulator inhibitors.  These include:

  • CTLA-4 (ipilimumab)
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Overcoming drug resistance in lung cancer

On the final day of the annual 2013 meeting of the American Association for Cancer Research (AACR) in Washington DC, Jeffrey Engelman (MGH) hosted an excellent plenary session on “Cancer Evolution and Resistance” with a series of superb talks not only from himself, but also Neal Rosen (MSKCC), Todd Golub (Broad Institute) and René Bernards (Netherlands CI).

If this session is included in the webcast, I would highly recommend watching the whole thing several times, as it was one of the meeting highlights for me. Despite being on the very last day, the large hall was pretty packed and well worth waiting for. You can check availability of the AACR 2013 webcast talks here.

Overcoming resistance to vemurafenib in metastatic melanoma

One of the interesting themes for that emerged for me at AACR this year was the amount of effort that is being expended on strategies to overcome drug resistance. This was particularly noticeable in metastatic melanoma and non-small cell lung cancer (NSCLC).  More on lung cancer in another post, as today I want to focus on melanoma.

In the advanced melanoma, vemurafenib is given to patients with the BRAFV600E mutation, which occurs in approximately 50% of patients. This oncogene drives activity of the tumour, but inhibition with vemurafenib (Zelboraf) has shown some remarkable effects, as the stunning before and after photos from Levi Garraway’s group demonstrate.

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AACR 2013 – some initial thoughts on the emerging trends

This year’s American Association for Cancer Research (AACR) annual meeting grew by 8% to approximately 18,000 attendees with 25% from 75 foreign countries, it is truly becoming a more global event for cancer researchers.

Over the next few days I plan to cover some of my highlights (basic, translational and clinical) in depth here on the blog and also with additional notes for email subscribers.  If you haven’t signed up for the PSB email alerts, there’s still time before the AACR notes go out.

Bromodomain Inhibitors – an exciting new target in cancer research?

One of the interesting things about basic cancer research is that new targets emerge all the time, offering fresh opportunities for developing novel therapeutics in the quest for clinical improvement. While you see many companies chasing the same well established targets, often generating me-toos, sometimes serendipity favours the bold and the brave, as we recently saw with Pfizer’s development of crizotinib for ALK+ lung cancer.

So what’s new on the R&D front?

Bromodomain inhibition is a novel cancer target and one that I am looking forward to learning more about at forthcoming annual meeting of the American Association for Cancer Research (AACR) in Washington DC.

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