Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘VEGF’

Video Report from 2012 European Association of Urology Congress in Paris

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

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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Update from AACR Molecular Targets 2011 #2 – Angiogenesis

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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Glioblastoma recurrence after VEGF therapy: lack of rebound vascularisation as a mode of escape

One of my favourite journals, Cancer Research, has a new paper available via open access (i.e. free to the public, thank you AACR), which you can obtain from the link in the Reference section below.

It caught my attention because there was a fascinating symposium on angiogenesis at ESMO this summer with some heavyweight debates from Robert Kerbel (accelerated metastasis) and Lee Ellis (normalisation of tumour vessels) taking different viewpoints on the pros and cons of VEGF inhibition.  I took a few photos of the slides for private study and reflection, as they were going too fast for me to keep up with the key points with unreadable chicken scratch notes, but sadly my iPhone went missing in the exhibit hall less than an hour afterwards before I could download the photos :(.  That said, both sides argued with very compelling data for their perspective that I’m not sure which way I roll on the issue.

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What's hot in molecular diagnostics and biomarkers? AACR #1

One of the biggest challenges with Vascular Endothelial Growth Factor (VEGF) therapy to date has been the singular lack of either predictive or prognostic biomarkers.

This means that we have no idea which patients are most likely to respond to therapy (ie predictive) when selecting either a monoclonal antibody (eg bevacizumab) or a small molecule tyrosine kinase (eg sorafenib, sunitinib or pazopanib), nor do we will know what their likely prognostic outcome might be in terms of survival.

In an ideal world, we would be able to predetermine and monitor therapy for specific subtypes, thereby avoiding exposing thousands of patients to the systemic effects (and costs) of a drug that may not work for them.

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Angiogenesis, angiopoeitin and Glioblastoma Multiforme (GBM)

Read and writing about malignant brain cancers, gliomas or glioblastoma multiforme (GBM) always makes me sad as life span from diagnosis is often only a year. Over the last decade we have seen many advances in surgery, radiation, chemotherapy and targeted therapies in many cancers, yet this one remains largely immune to significant progress.

Background

Angiogenesis inhibitors targeting the VEGF signaling pathway have been shown to be effective both in preclinical cancer models and in clinical trials. This has led to the approval of several agents targeting VEGF in cancer, including bevacizumab (Avastin), sorafenib (Nexavar) and sunitinib (Sutent). To date, bevacizumab, has been approved for the treatment of relapsed glioblastomas in the US, at a dose of 10 mg/kg IV every 2 weeks. The approval in GBM was based on objective response rate, not survival.

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New potential targets in ovarian cancer?

Treatment for ovarian cancer hasn't changed much in the last ten years, reflecting the lack of biomarkers and biochemical targets for the disease. Chemotherapy with a platinum (carboplatin or cisplatin) and a taxane (paclitaxel or docetaxel) has therefore formed the bedrock of therapy, along with other options such as gemcitabine or pemetrexed, as illustrated in the latest NCCN Guidelines.

The good news is that the use of paclitaxel-based combination chemotherapy has been shown to increase progression free survival (PFS) and overall survival (OS) in women with primary peritoneal or ovarian cancers.

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Exelixis and BMS part ways over XL184

It came as no big surprise this morning to hear that Exelixis and BMS have announced they are terminating their agreement over XL184.  The compound is being tested in medullary thyroid cancer, glioblastoma multiforme (GBM) and non-small cell lung cancer (NSCLC).  This is a small molecule that inhibits several targets, namely MET, RET and VEGFR2.

According to Exelixis, the CEO stated in their press release:

"We certainly understand BMS' need to make pipeline and prioritization decisions."

It looks as if they couldn't agree on the priorities for the clinical development, which would be a little odd given the $240M invested in XL184 and XL281 in 2008, with the same indications planned.

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Bench to Bedside: How can we speed up cancer drugs to the clinic?

After yesterday's post about the I-SPY trials in neoadjuvant therapy for breast cancer and how they may speed up the process of bringing new innovative cancer drugs to the clinic faster, I was reflecting on my own experiences with imatinib (Gleevec).   

The Philadelphia Chromosome was first identified in 1960 by Nowell and Hungerford. Gleevec was finally approved by the FDA in May 2001, 41 years later.   

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Afinitor extends life for renal cancer patients

A new drug in development, Afinitor (everolimus, RAD001) appears to extends life without tumour growth by almost 5 months compared to 1.9 months with placebo.  In addition, a quarter of the patients in the study remained progression free beyond 10 months of treatment.  This is the first therapy to show significant benefit after failure with initial tyrosine kinase therapy (Sutent or Nexavar).  It is currently being reviewed by the FDA for treatment of advanced kidney cancer after failure of initial therapy.

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