[suzierose]

VEGF inhibitor agents increase tumor metastasis..i.e. IMID's

by suzierose on Mon Mar 19, 2012 1:25 pm

Dear ALL,


Again, I have to give thanks to Dr Trent Stephens @ Idaho State for his most impressive and elegant research regarding thalidomide. Without it, I would have had no clue as to where to search for possible causes of SPM with IMID's.

This post is about the SPM that have resulted in the labelling changes for lenalidomide which is a VEGF (vascular endothelial growth factor) inhibitor along with thalidomide and pomalidomide.
VEGF promotes blood vessel formation needed for tumor growth..called angiogenesis. VEGF inhibitors were developed to stop growth..they did...however..

The sad part is the outcome of VEGF inhibition where the tumor shrinks but there is increased tumor invasion and metastasis has been known for sometime as it was demonstrated by Casanavos, et al (2005), Ebos,et al (2009) & Piaz-Ribes, et.al (2009). Yet, we have had to listen to folks quibble about this as a 'controversy' with IMID therapy used in multiple myeloma?...sigh
( thalidomide was authorized for multiple myeloma use in Oct 2006)

There is hope however:


"These findings document that invasion and metastasis are promoted by selective inhibition of VEGF signaling and can be reduced by the concurrent inhibition of c-Met."

http://cancerdiscovery.aacrjournals.org/content/2/3/270

Targeting tumors simultaneously with c-MET overcomes the limitations of VEGF inhibitor alone resulting in tumor shrinking without increased invasion and metastasis:

http://www.chemotherapyadvisor.com/dual-vegf-and-c-met-inhibition-synergistically-reduces-tumor-invasion-and-metastasis/article/229374/

http://www.exelixis.com/resources/articles/186
http://www.exelixis.com/cabozantinib


MET inhibitors have been used to treat bone metastasis from other cancers, i.e. prostate, ovarian, breast. The former tumors exhibited upregulation of MET when treated with anti VEGF agents.

" In their latest research, Barbara Sennino, PhD, with other investigators in his group set out to determine whether c-MET drove tumor aggressiveness during anti-VEGF therapy. What their paper shows is that blocking c-MET and VEGF together in mice is more powerful than blocking either alone because it not only slows tumor growth but also reduces invasion and metastasis.

They tested two inhibitors of VEGF—a neutralizing antibody and sunitinib—and three inhibitors of c-MET—crizotinib, PF-04217903, and cabozantinib (XL184). Unlike the other agents, cabozantinib simultaneously inhibits both c-MET and VEGF. Inhibition of c-MET and VEGF together with a drug combination or with cabozantinib had more profound effects on tumors than any of the agents that blocked only one of the targets."
http://www.news-medical.net/news/20120227/Two-target-approach-may-effectively-stop-pancreatic-cancer-metastasis.aspx



A little background history from 2007:


"Mutations and amplifications of Met may be relatively rare in many cancers, noted Dr. Lutterbach. But for patients whose tumors depend on Met signaling, blocking these signals will be necessary to treat the disease.

The Met protein, which sits on the surface of cells, is a tyrosine kinase receptor. Other members of this family include the targets of gefitinib (Iressa) and imatinib (Gleevec).

Over the last 20 years Met has been a tool for understanding how kinase receptors can be deregulated, said Dr. Morag Park of McGill University, who discovered the gene while working with Dr. Vande Woude at NCI. "
http://www.cancer.gov/aboutnci/ncicancerbulletin/archive/2007/061207/page6


So I suppose the question to ponder is whether those SPM seen following lenalidomide therapy in multiple myeloma patients have upregulated MET and if so...perhaps there is hope and agents already on the market that can help those patients.

Bevacizumab, sunitinib and critzonib are presently approved MET inhibitors, with indications for other cancers.

[suzierose]

Re: VEGF inhibitor agents increase tumor metastasis..i.e. IM

by suzierose on Mon Mar 19, 2012 4:46 pm

"In the study, 402 patients received four 28-day courses of Rd as an induction therapy. Patients were then randomised to receive either six 28-day courses of MPR or two courses of autologous stem cell transplant (MEL200). Upon completion of this regimen, patients will again be randomised to either continuous Revlimid or no continuous therapy until relapse.

After the Rd induction phase, 84% of patients achieved at least a partial response (PR) and 41% achieved at least a very good partial response (VGPR). Patients were then randomised and those who then received 3 cycles of MPR>

At a median follow-up of 12 months, the primary endpoint, progression free survival rate, was 91% for both the MPR and autologous stem cell transplant (MEL200) arms.

In the study, the most common Grade 3 or 4 adverse events were neutropaenia (46% and 86% for MPR and MEL200, respectively) and thrombocytopaenia (MPR 9%, MEL200 87%), infection (MPR 1%, MEL200 15%) and gastrointestinal events (MPR 1%, MEL200 23%)."
................

This trial was prior to approval of lenalidomide for newly diagnosed multiple myeloma patients.

It would be interesting to see follow-up data on this study for SPM...we know now that the combo of melphan/lenalidomide is showing a higher incidence of SPM than lenalidomide alone....We would have a combo arm and a lenalidomide maintenance arm to compare as well for SPM.

I wonder if this was one of the three trials presented at ASH 2010 when the link between lenalidomide and SPM first began to emerge.

Follow up, follow up...we need it.

[Nancy Shamanna]

Re: VEGF inhibitor agents increase tumor metastasis..i.e. IM

by Nancy Shamanna on Mon Mar 19, 2012 9:51 pm

Hi Suzierose...when was the initial study with the 402 patients done? The initial follow up with the two arms (Rev. alone, or Rev./Malphalan) after one year, could be reviewed later after the next year or later. That seems like very clear cut science, and the sample size is really large compared to most studies in this area, I think. Could be quite informative! Of course one hopes that there are not very many secondary cancers detected, and that most of the patients are still doing well, but it doesn't hurt to check!