Category Archives: Biomarkers

Highlights of AACR 2012 – Part 2

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Yesterday, I mentioned that some of the best bits of this year’s American Association for Cancer Research (AACR) meeting were the numerous gems in the poster sessions.

Reuben Sierra AACR e1334766105891 224x300 Highlights of AACR 2012 Part 2

Reuben Sierra, Ming Tsao's Lab (with permission)

One of the coolest such posters I came across was from Ming Tsao’s group.

Specifically, Rafael Sierra (see photo right) was hosting an excellent piece of research entitled: “Overcoming resistance to EGFR-tyrosine kinase inhibitor therapy in non-small cell lung cancer.”

This is an area of much needed research and breakthroughs.

Why?

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Highlights of AACR 2012 – Part 1

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The 2012 American Association for Cancer Research (AACR) meeting in Chicago was interesting for several reasons.  While there were no truly ground breaking data such as in previous years as with, for example:

  • vemurafenib in BRAFV600E melanoma
  • vismodegib in basal cell carcinoma (BCC)
  • crizotinib in ALK+ lung cancer

there were a lot of encouraging signs for the future.

What made the meeting exciting for me was the sheer number of new compounds emerging from late preclinical to early phase I – clearly companies are looking to restock their pipelines with the threat of major patent cliffs imminent.  Not everyone is chasing new compounds to license in!  The sheer breadth and depth of the pathways targeted by the new compounds took me a little by surprise.

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American Association for Cancer Research Meeting 2012

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Today marks the kick off for one of my favourite conferences on the oncology-hematology calendar, with the annual meeting of the American Association for Cancer Research (AACR) being held in Chicago.  It’s all about the science and basic research here, although there are clinical sessions, usually on strategy and early emerging phase I/II data.

Wifi is usually pretty good at the AACR annual meeting, although it can be more variable at the smaller meetings.  Like many attendees, wifi permitting, I’ll be tweeting from the conference and blogging some of the interesting highlights over the next few days.

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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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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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Raised platelets reduce survival in ovarian cancer

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During my years in Pharmaland, I often sat in waiting rooms waiting to see the Principal Investigator (PI) for one of the studies we were doing.  I would generally see them at the end of the clinic, preferring to arrive early and chat with some of the patients to learn of their experiences, the trials and tribulations of cancer therapy.  This keeps your feet on the ground – drug development is not an academic exercise, there are real people involved after all.

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On KRAS, NF-kB activation and pancreatic cancer

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Pancreatic cancer as many readers know, is one of those cancers that is generally diagnosed later than most in stage IV and as a result, has a poor prognosis, often only a year or so from diagnosis.

It has been known for a decade that constitutive Kras and NF-kB activation is one of the signature changes in the disease in the majority (80-95% ) of patients. Kras is a particularly important gene because it is often involved with on-off signaling of other genes. In addition, mutational inactivation of a key tumour suppressor gene (Ink4a/Arf) also occurs in over half (50-75%) of pancreatic adenocarcinomas. What is not known, however, is what are the key signaling pathways downstream of Kras and how they relate to pancreatic cancer.

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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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