Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘Metastasis’

Understanding cancer metastasis – possible new therapeutic targets

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“Scientists at Dalhousie University in Nova Scotia have identified a key mechanism of metastasis that could lead to blocking tumor growth if their findings are confirmed.”

AACR press release

Loved this opening to an AACR press release about a key paper (freely available for anyone to download – see the reference session below) that was just published in Cancer Research by David Waisman’s group.

Now, before getting into the technical details, I was reflecting recently on both my recent awesome trip to the MD Anderson basic research campus at Smithville, Austin where a lot of research into tumorigenesis is conducted and pointed questions from patients about why their hasn’t been enough progress in treating and curing metastatic breast cancer.

GWAS and breast cancer metastases

Breast cancer isn’t a topic I cover very often on this blog, mainly because there is so much written about it elsewhere, but I confess to being fascinated by the ongoing work on cancer cell seeding and metastases from Joan Massague and Larry Norton at Memorial Sloan Kettering.   The reason for this is that the origins of metastases might have wider applicability to other cancers, so the studies as a body of work are important in the field.   For those of you looking for some background on this important topic, check out this previous post on cancer cell seeding first.

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On RANKL and denosumab in advanced cancer metastasis

In this week’s Nature, my eye was drawn to a Letter from Tan et al., (2011) discussing how inflammatory mechanisms influence tumorigenesis and metastatic progression, even in tumours that seemingly don’t involve pre-existing inflammation or infection such as breast and prostate cancers.

In advanced prostate cancer, metastasis is sadly inevitable.   So far as we know, lymphocytes infiltrate the tumour, causing upregulation of nuclear factor-KappaB (RANK) ligand (RANKL) and lymphotoxin (see Luo et al., 2007).

RANK signalling controls osteoclastogenesis and bone resorption and targeting it with denosumab has been shown to reduce the incidence of skeletal related events (SRE) but not overall survival in prostate cancer (see Fizzazi et al., 2011):

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Do stromal endothelial cells directly influence cancer progression?

Years ago, while doing my Ph.D research in respiratory medicine, I was fascinated by one of my friends chosen area of study.   She was looking at the role of endothelial cells and nitric oxide in controlling blood vessels.   At the time, it was particularly relevant to cardiovascular disease and most of the focus was in that area. However, at one of the University of London seminars where she was presenting, the conversation spilled into related areas such as where else the concepts could be applied.   One of the students was doing related area in cancer research and was interested in how the learnings were relevant to his research.  A fairly spirited debate ensued.

Can we predict when cancer will spread?

Early this morning I saw a headline float by my Twitter stream from yesterday with a link to an article or paper suggesting that yes, we can indeed predict metastasis. I can’t remember who shared it, or what was the exact news article but a quick Google search for latest news found some noise around a potential biomarker, CPE-ΔN. The paper (open access) in the references link below, is from the Journal of Clinical Investigation.

Role of Smads and WWP2 in potentially blocking some cancers

“Ubiquitin-dependent mechanisms have emerged as essential regulatory elements controlling cellular levels of Smads and TGFβ-dependent biological outputs such as epithelial–mesenchymal transition (EMT).

In this study, we identify a HECT E3 ubiquitin ligase known as WWP2 (Full-length WWP2-FL), together with two WWP2 isoforms (N-terminal, WWP2-N; C-terminal WWP2-C), as novel Smad-binding partners. We show that WWP2-FL interacts exclusively with Smad2, Smad3 and Smad7 in the TGFβ pathway.

Cancer Cell Seeding – a new hypothesis from Larry Norton

At the annual NY Chemotherapy Foundation symposium the other week, one of the highlights for me was listening to Larry Norton (MSKCC) give a 30 minute keynote entitled:

“Cancer Cell Seeding: a hypothesis with therapeutic implications”

He talked at length about what he described as some of the breast cancer mysteries, namely the puzzles associated with:

  1. Phenotypic consistency (hyperplasia, anaplasia, rapid growth, angiogenesis, large tumour size, invasion, metastases and latency)
  2. Disorderly order
  3. Unclear clear margins

Several main points were then raised from this quick synopsis:

  • The phenotypic elements are so inextricably linked that they must be related, but how?
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Cancer biology is becoming very complex #AACR

As we learn more about the biology of cancer, I’m finding that rather becoming simpler, it actually seems much more complex and sophisticated than we may have first realised.

Sometimes, we don’t know what we don’t know.

Take for example, the recent AACR meeting on the molecular origins of lung cancer that I attended and wrote a few summary posts on (with more to come!) 

Clinical trial results show Denosumab is superior to Zometa in breast cancer patients with bone metastases

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Amgen's recent announcement of phase III trial data showing that it's monoclonal antibody, denosumab was superior to Novartis' Zometa (zoledronic acid) for the treatment of breast cancer patients with bone mestastases is further news that scientifically driven drug development can yield exciting results. 

Denosumab is in essence a targeted therapy like Gleevec, Avastin or Herceptin.  It's development came about from basic research that discovered the cellular control of bone remodelling and regulation of bone density is reglated by the RANK Ligand pathway.

What does Tes mena?

Metastasis, or the the spread of cancer to other parts of the body, is common in many advanced cancers.  The cancer can break off and travel to form new invasive tumours.  

In the latest edition of Molecular Cell, UK scientists have reported on new research showing that they have potentially discovered a vital clue to stopping cancers spreading.
In the article, a protein called Tes is able to block a second protein, Mena, from helping cancer cells escape from the initial tumour.  It is possible that his knowledge may help in the design of new drug treatments to ensure that a tumour is kept in
one place, thereby preventing deadly metastasis from occurring. 44323005 breast cancer cell spl2 2 What does Tes mena?

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