Category Archives: Colorectal Cancer

A new opportunity for vemurafenib in BRAFV600E colon cancer

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There’s been quite a flurry of commercial news on the Pharma front this morning, with Amgen buying Micromet (whose leading product is blinatumumab in ALL) and Celgene announcing their acquisition of Avila Therapeutics who have a Bruton Kinase Inhibitor (BTK) AVL-292 in phase IB development for lymphomas, which was all the rage at the recent American Society of Hematology (ASH) meeting last month.

The big news for me today, though, wasn’t the commercial acquisitions but a gem of a paper relating to science and its significance for future cancer treatment.

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Unravelling early colorectal cancer: the links between ROS, DNA methylation and inflammatory responses

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During yesterday’s discussion with Dr Ray DuBois (MD Anderson Cancer Center) about inflammation and methylation, the topic of CpG island methylator phenotype (CIMP) in colorectal cancer (CRC) came up as you can see from the brief audio clip below:

Steve Baylin’s paper sounded most interesting, so I tracked it down – see O’Hagan et al., (2011) in the References below for the direct link.

CIMP is interesting to look at because it can occur in some 30% of colorectal cancer cases and has been previously shown to be an independent predictor of survival with 5FU in early or adjuvant CRC (van Rijnsoever, 2003). It is, therefore, a potentially useful molecular marker in this disease.

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New research demonstrates the link between inflammation and early development of colon cancer

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Recently, epigenetics has been very much to the forefront with promising new human data in lung and breast cancers.

homecover New research demonstrates the link between inflammation and early development of colon cancer

Nature Medicine

This morning I was therefore thrilled to see some exciting work just published in Nature Medicine Online First from Ray DuBois’s lab at MD Anderson Cancer Center, on the potential role of inflammation and silencing of tumour suppressor genes in early colorectal cancer. Previously, the group looked at the role of COX-2 in intestinal inflammation and colorectal cancer and observed that:

“A large body of evidence indicates that genetic mutations, epigenetic changes, chronic inflammation, diet and lifestyle are the risk factors for CRC.”

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Gene mutation and resistance to chemotherapy in colorectal cancer

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This week’s New England Journal of Medicine (NEJM) contained a fascinating article on how a specific gene mutation known as Transcription factor AP-2 epsilon, TFAP2E–DKK4, appears to be responsible for inducing at least some of the resistance to chemotherapy that occurs during treatment of colon cancer.

At first sight, I wasn’t sure from the abstract if they were referring to either adaptive resistance to therapy or whether genetic changes already present limited the effectivenes of the treatment.

Further reading of the full article more specifically pointed to the latter:

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Update from AACR Molecular Targets 2011 #2 – Angiogenesis

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Angiogenesis inhibitors have seen a long and rather chequered history since Judah Folkman first propounded the concept that tumours grow by adding new blood vessels. Many of these inhibitors have ended up in the dog heaven scrap heap, so to speak, while others (some monoclonals, some small molecule inhibitors) have made it to market in some indications, but failed miserably in others.  All in all, it’s been a bit of a crapshoot at best for manufacturers trying to crack this particularly difficult nut.

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The elusive mystery of KRAS and EGFR inhibitors in colorectal cancer

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The other week during a conversation with Dr Gordon Mills (MDACC) at the European Multidisciplinary Meeting (EMCC) in Stockholm, he mentioned the conundrum of variable responses to EGFR inhibitors in colorectal cancers and the impact of RAS.  Originally, it was thought that patients who had wild type, but not mutated, KRAS were more likely to respond (see Allegra et al., 2009 in the references below).

The reality, however, is that variable responses to therapy have actually been reported by several groups with cetuximab and panitumumab. De Roock et al., (2010) reported better outcomes with cetuximab in patients with p.G13D-mutated tumours than with other KRAS-mutated tumours, contrary to the US and EU Guidelines, so the situation is clearly more complex than first thought.

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Making a Difference: an interview with Dr Gordon Mills

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Earlier this year, I announced that there were two people I was hoping to interview next as part of the ongoing Making a Difference series, where thought leaders share their ideas and vision on emerging and important topics in cancer research. Previous discussants have included the following:

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Update on MEK and AKT inhibition in RAS driven cancers

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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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What's hot at ECCO, ESMO, EMCC in Stockholm 2011?

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After a wild day yesterday once we realised Continental had mysteriously and unaccountably changed our flights to Stockholm from Weds to Weds to Thurs to Tues, it seems that Cinderella will be going to the ball after all.

European Multidisciplinary Cancer Conference (EMCC) here we come, whew!

There are a couple of sessions I’m particularly looking forward to this year:

  1. Presidential Symposium on Sat 25th with talks from some of the leading lights in translational research:

    • Tak Mak (U Toronto) on metabolism and cancer
    • Jose Baselga (MGH) on the challenges of personalised medicine
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Lapatinib boosts effects of apoptosis-inducing drugs in colorectal cancer

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I’m a subscriber to Science Translational Medicine and one of the things I really like about it is finding little gems like this – shared by Science Magazine on Twitter:

Breast cancer drug lapatinib boosts effects of apoptosis-inducing drugs in colorectal cancer

On clicking the link, I was delighted to see it was from Dr Wafik El Deiry’s group at Penn State, Hersey – you can find him as @weldeiry on Twitter – he tweets interesting snippets from various cancer conferences that he attends, including ones in GI cancers.

Here’s the essence of the paper that caught my eye:

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