On adaptive mechanisms of crizotinib resistance in ALK-positive lung cancer

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One of the biggest challenges facing cancer research was aptly summarised by Levi Garraway and Pasi Jänne in this month’s Cancer Discovery journal:

“All successful cancer therapies are limited by the development of drug resistance. The increase in the understanding of the molecular and biochemical bases of drug efficacy has also facilitated studies elucidating the mechanism(s) of drug resistance.”

It will therefore come as no surprise to PSB readers that resistance occurs with two drugs approved by the FDA only last year; vemurafenib (BRAFV600E melanoma) and crizotinib (ALK+ lung cancer). We’ve discussed the development of resistance in melanoma here via several potential mechanisms in the past and potential strategies for overcoming them (eg MEK inhibitors), but what about lung cancer?

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J&J unblind Zytiga phase 3 trial in pre-chemotherapy castrate-resistant prostate cancer

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The big cancer news that hit the news wires this morning was not entirely surprising:

“Janssen Research & Development, LLC today announced that it has unblinded the Phase 3 study of ZYTIGA (abiraterone acetate) plus prednisone for the treatment of asymptomatic or mildly symptomatic patients with metastatic castration-resistant prostate cancer (CRPC) who have not received chemotherapy.”

Source: Press Release

Given the accelerated approval of abiraterone in the post-chemotherapy setting last year, the results in the pre-chemotherapy setting were widely expected to:

  1. Be even better in earlier stage than the 3.9 months OS advantage already seen
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The importance of metabolism in cancer research

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Cancer metabolism is fast becoming an area to watch out for in R&D.  Last month I tweeted that I was attending a one day meeting at NY Academy of Sciences on Cancer Metabolism with keynote speakers Drs Lou Cantley and Craig Thompson. Jonathan Mandelbaum (@biotechbaumer) responded saying it looked like a dress rehearsal of another related meeting he was attending the following week. That was too good an opportunity to miss, so I invited Jonathan to consider guest posting a summary of the Keystone event he attended here on Pharma Strategy. I’m delighted to say he kindly took me up on the offer and what follows is Jonathan’s synopsis, including some references he chose to illustrate the key points, most of which are open access.

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nab-Paclitaxel and its potential role in pancreatic cancer

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Back in 2009 at the American Association for Cancer Research (AACR) Molecular Targets meeting, a researcher (Anirban Maitra) from Boston had a most interesting poster about the use of nanotechnology to deliver nab-paclitaxel (Abraxane) to pancreatic adenocarcinomas in a more targeted fashion.  You can read about it in more detail from the meeting coverage at that time.

Essentially, one of the things that stops chemotherapy being more effective in advanced pancreatic cancer is that the stromal layer forms a physical, almost impenetrable layer, that slows drugs from getting through to the tumour.

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Video Report from 2012 European Association of Urology Congress in Paris

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Amazingly, it’s been a year since I started doing conference highlight videos, with the first one rolling out at EAU meeting in Vienna last March. They’ve proven to be much more popular than expected! The good news is that the video recording, production and presentation skills have improved along the way.

Unlike last year, the 2012 EAU Congress wasn’t lit up with excitement about new data (abiraterone and MDV3100 dominated last year).  Instead, there were more reflective discussions about how to consider sequencing and combinations in a more crowded castrate resistant prostate cancer market going forward as well as some mention of new up and coming targets outside the androgen receptor (AR) such as ERG and Src.

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We the People…

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I don’t do this very often, but here’s a worthy cause for scientists and cancer researchers to rally around – Dr Steven Meltzer at Johns Hopkins established an online petition to the White House to increase funding to the NIH – the current proposal is to maintain the budget at a flat $30.7 billion.

Supporting the petition taught me something interesting – NIH funding created 350,000 jobs and contributed $50 Billion to the national economy in 2007 alone.

The problem, though, with flat budgets is that every 7 years the value of money halves, so the NIH budget has essentially been decimated over the last decade. This is sad for science, for progress and also for patients.

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The challenge of prostate cancer drug approval versus reimbursement

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IMG 7619 300x224 The challenge of prostate cancer drug approval versus reimbursement

Scenes from EAU - Arc de Triomphe

Here at the European Association of Urology (EAU) congress in Paris, there are some interesting debates amongst delegates attending the meeting regarding new therapies either recently – or about to be approved – for castrate-resistant prostate cancer (CRPC).

For example:

  1. How should abiraterone and MDV3100 be sequenced pre or post chemotherapy?
  2. Would combining the two drugs post chemo be a better strategy that leads to superior outcomes?
  3. Where does chemotherapy fit into this emerging paradigm?  Do we need chemotherapy in an new era of oral therapies?  If yes, which patients should be considered eligible?
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Will combining custirsen and MDV3100 reduce resistance in advanced prostate cancer?

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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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Combined VEGF and MET inhibition in some cancers may be better than either alone

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A couple of recent controversies in the field of angiogenesis have fascinated scientists and clinicians alike, namely:

  • Does VEGF inhibition lead to more aggressive tumours?
  • What drives metastases and invasion?
  • What is the role of tumour hypoxia in this process?

Data was originally presented in glioblastoma by Rubenstein et al., (2000), showing that anti-VEGF antibody treatment prolonged survival, but resulted in increased vascularity caused quite a stir.  Several other groups subsequently demonstrated in preclinical models that VEGF signaling shrinks tumours, but also results in increased invasion and metastases (see Casanovas et al., (2005), Ebos et al., (2009), Paez-Ribes et al., (2009), for examples).

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Cancer Clinical Trials: Companion Diagnostics or Gene Sequencing?

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Last year saw some interesting developments from MD Anderson Cancer Center in early phase clinical trials that may have a far-reaching impact on the future of cancer research as we know it:

  1. At ASCO in June, Dr Tsimberidou presented the initial results from a phase I study run by the MD Anderson Department of Investigational Cancer Therapeutics group. Instead of testing patients with a given cancer (eg lung) for individual mutations eg ALK or EGFR and then offering patients a targted drug as we normally do, they ran a broad diagnostic panel across a multitude of patients with different cancers to determine what the tumour was telling them about the aberrations and selected appropriate targeted therapies. While the study was small in size, the results were better than random selection.
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