Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘AKT’

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.

Can Merck make an impact in pancreatic cancer?

There were a number of interesting posters at the AACR-NCI-EORTC Molecular Targets meeting today. Specifically, two on metastatic pancreatic cancer caught my eye. You can read about the other one on Millennium/Takeda’s ADC MLN0264 here.

This is an area of high unmet medical need with the fourth highest number of cancer deaths in the US and a median survival of 10 months or less. Even with improvements in the standard of care, it still remains a miserable cancer to get.

Many of you will be aware that KRAS is mutated in 90% of pancreatic cancer cases. As Dr Barry Nelkin (Johns Hopkins) noted today,

What’s hot at ECCO 2013 – Preview of late breakers and PI3K abstracts

Next I’ll be off to the European Cancer Congress (ECC) in Amsterdam. This meeting alternates each year between ECCO and ESMO hosting the event at a different European city.

The last couple of years have seen some nice data that missed the ASCO deadline, other years can bring an update of the already familiar ASCO data. I suspect that this year will be one of those events, with updated PD-1 and PD-L1 data.

If you missed my colleague Pieter Droppert’s ECCO highlights yesterday, you can catch them here, including details of the iPad app and abstracts.

ASCO 2012 Preview – Highlights of key data emerging from Chicago

It’s that time of the year again where we cogitate and contemplate on what might be hot at the annual meeting of the American Society of Clinical Oncology (ASCO) before the abstracts are available (they’re released online tomorrow at 6pm ET).

This year, while interesting early data from up and coming small biotechs is likely to be eagerly presented in poster sessions, the focus is more likely going to be on big Pharma with various phase III and also late phase II trials that are due to report data.  Unfortunately, not all of these will produce overwhelmingly positive results though!

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Will combining custirsen and MDV3100 reduce resistance in advanced prostate cancer?

EAU 2012 View of Eiffel Tower 224x300 Will combining custirsen and MDV3100 reduce resistance in advanced prostate cancer?

Sights of 2012 EAU Congress

Greetings from the European Association of Urology (EAU) congress in Paris. Despite the grey drizzle typical of Europe in winter, this is actually quite an interesting meeting with lots of poster presentations.

One poster that caught my eye yesterday was from Martin Gleave’s group on clusterin knockdown synergising MDV3100 activity. Previously, we discussed on this blog how inhibiting clusterin with custirsen (OGX-011) potentiated docetaxel. At the AUA meeting last year, the issue of whether the same would happen with MDV3100 was suggested, as you can see in the short video blog.

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EGFR activates mTORC2 in glioblastoma – a potential role for new therapies

One of the great things about following the American Association for Cancer Research (AACR) on Twitter, is that they regularly share technical open access articles from their journals for scientists to read.  Of course, many will have access through their institution subscription, but there are also probably quite a few interested community oncologists and scientists like me that don’t. The idea of sharing some of their really important scientific research with the broader public is a great one – a little bit of goodwill goes a long way and furthers their cause too.

Update on EGFR resistance in lung cancer: new directions

This morning I was reading a fascinating paper on lung cancer and one of my favourite proteins, CRKL, from the group of prolific lung researchers at Mass General, Dana Farber, MIT and the Broad Institute in Boston:

“Over-expression of CRKL in immortalized human airway epithelial cells promoted anchorage-independent growth and tumorigenicity. Oncogenic CRKL activates the SOS1-RAS-RAF-ERK and SRC-C3G-RAP1 pathways. Suppression of CRKL in NSCLC cells that harbor CRKL amplifications induced cell death.”

Cheung et al., (2011)

We also know that one of the mechanisms of resistance to gefitinib is over-expression of CRKL in EGFR-mutant cells by activating ERK and AKT signaling.

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Update on MEK and AKT inhibition in RAS driven cancers

A couple of interesting developments have emerged over the last week with AKT and MEK inhibitors, specifically Merck’s MK-2206 and AstraZeneca/Array’s AZD6244, that are well worth discussing.

  1. At the ECCO/EMCC meeting in Stockholm last Tuesday, Johann De Bono discussed the combination data for MK-2206 and AZD6244 in KRAS driven colorectal cancer.
  2. Later the same week, Array Biopharma announced the initial results from a randomized phase II placebo-controlled study that compared the efficacy of selumetinib (AZD6244/ARRY-886) in combination with docetaxel compared to docetaxel alone in the second-line treatment of patients (n=87) with KRAS-mutant, locally advanced or metastatic non-small cell lung cancer (NSCLC).
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On mTOR and Tuberosis Sclerosis Complex (TSC)

It’s that time of year in the dog days of summer when many people in the industry are either incredibly busy, heads down, rolling out new things for the third quarter or else it’s a pleasant lull between the strategic and tactical phases and a good time to catch your breath.  Here in the Icarus office, we’re busy creating and writing a new series of syndicated reports in a variety of different tumour types and pathways.  I have hundreds of snippets and notes saved electronically from various cancer meetings this year, making it a great opportunity to collate and process them into broader insights. If you have any particular needs in this area, now is a good time to let us know, so do email me and your wishes may get added to the list.

New mechanisms of resistance to MET inhibition

A very apt quote from Jeff Engelman’s group caught my eye this week:

“Unfortunately, cancers invariably develop resistance, and overcoming or preventing resistance will ultimately be key to unleashing their full therapeutic potential.”

MET is the receptor tyrosine kinase for hepatocyte growth factors (HGF) and inhibition has been implicated in metastases and migration of cancer cells (Rong et al., (1994), Takayama et al., (1997)), but more recently, it has also been observed that some tumour types have MET oncogenic addiction, including gastric cancer (Smolen et al., 2006).

6603884f3 New mechanisms of resistance to MET inhibition

MET Inhibition - source: Ma et al., (2007) BJC