[suzierose]

Hallmarks of Cancer, towards Targeted Therapies

by suzierose on Wed Apr 18, 2012 8:16 am

Hi All,
This is a very good background article in terms of what scientists know about how cancer pathogenesis occurs. It also elucidates specific targeted pathways for targeted therapies.


http://www.onclive.com/publications/Oncology-live/2012/january-2012/What-Turns-a-Good-Cell-Bad-Exploiting-the-Hallmarks-of-Cancerous-Cells

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One of the actions of IMIDs is inhibition VEGF thus,

Of particular interest to me is the connection between VEGF and MET...as lenalidomide has been demonstrated to cause secondary primary maliganicies,(SPM) resulting in it's labelling change.

While, VEGF inhibition or anti-angiogenesis has been identified as the route for secondary malignancies, the article below tells how and why this occurs and why MET in combination with VEGF inhibitors does not result in SPM.



"In response to therapy, cancer cells may also reduce their dependence on a particular hallmark capability, becoming more dependent on another; this represents a quite different form of acquired drug resistance.

This concept is exemplified by recent discoveries of unexpected responses to antiangiogenic therapies. Some have anticipated that effective inhibition of angiogenesis would render tumors dormant and might even lead to their dissolution (Folkman and Kalluri, 2004). Instead, the clinical responses to antiangiogenic therapies have been found to be transitory (Azam et al., 2010,Ebos et al., 2009,Bergers and Hanahan, 2008).

In certain preclinical models, where potent angiogenesis inhibitors succeed in suppressing this hallmark capability, tumors adapt and shift from a dependence upon continuing angiogenesis to heightening the activity of another instead—invasiveness and metastasis (Azam et al., 2010: Ebos et al., 2009,Bergers and Hanahan, 2008). By invading nearby tissues, initially hypoxic cancer cells evidently gain access to normal, preexisting tissue vasculature. Initial clinical validation of this adaptive/evasive resistance is apparent in the increased invasion and local metastasis seen when human glioblastomas are treated with antiangiogenic therapies (Ellis and Reardon, 2009,Norden et al., 2009,Verhoeff et al., 2009). "

http://www.cell.com/abstract/S0092-8674(11)00127-9#MainText




Which makes Cabozantinatib an exciting new agent. It has significant impact on bone and is being using for many cancers ( prostate, ovarian, melanoma) which have bone metastasis. It is also a dual inhibitor of MET and VEGF.

http://www.youtube.com/watch?v=gIqvn-cerZg

[Eric Hofacket]

Re: Hallmarks of Cancer, towards Targeted Therapies

by Eric Hofacket on Sat Apr 21, 2012 2:41 pm

The more I read about cancer, the more it amazes me all the complex things that have to go wrong for cancer to develop. How can this ever happen? It is because with the billions, if not trillions of cells that we have that statistically eventually all these complex events will eventually happen in a cell? Another interesting thing I have read about cancer is that it seems to be a process that reverses all the evolutionary adaptations our cells have made to live together to make a multi-cellular organism and reverts back to a single cellular organism biology where it is the survival of the individual cell that is paramount.