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Avastin Regrowth (Rebound)
By gdpawel at 2010-12-10 04:32
Avastin Regrowth (Rebound)

A study published in the Journal of Clinical Investigation (Volume 116, Number 10) tested human serum, derived from colon cancer patients who had either been treated with chemotherapyterm alone or with chemotherapy + Avastinterm. Serum from Avastin treated patients actually support endothelial cell growth in cell culture better than serum from control patients, without Avastin treatment.

The serum from patients treated with Avastin supported more rapid re-growth of endothelial cells than did serum from patients who weren't treated with Avastin. This implies that the body is, indeed, cranking out more endothelial cell survival/growth factors in Avastin-treated patients. When you get rid of VEGFterm with Avastin, the body cranks out other types of blood vessel growth (survival) factors.

One aspect of a functional tumor cell profiling assay is that microvascular viability can measure dead microvascular cells in tissue, fluid and peripheral blood specimens to identify potential responders to anti-angiogenic drugs (Avastin, Nexavartermterm, Sutenttermterm) and to assess direct and potentiating anti-angiogenic effects of tyrosine kinase targeted therapy drugs (Tarceva, Iressa).

Endothelial cells are present in tumor microclusters and drug effect upon these cells can be assessed in the microvascular viability assay. The "target" is not the cells themselves but rather a hormone (VEGF) secreted by the tumor cells. Anti-angiogenesis drugs complexes with free VEGF and blocks its action.

VEGF-receptor tyrosine kinases are expressed preferentially by endothelial cells of the growing neovasculature of a tumor and VEGF is a key survival (anti-apoptic) factor for the endothelial cells of newly formed vessels. There are several signalling pathways and molecular mechanisms by which VEGF can inhibit apoptosis (cell death) in endothelial cells.

Given the current state of the art, in vitro drug sensitivity testing with functional profiling could be of significant clinical value. If in vitro drug resistance can be demonstrated in the presence of cancer cells that are resistant to a drug, then it is rational to use alternative therapy. If in vitro drug sensitivity has the ability to demonstrate which drug would be synergistic to cell death in all cancer cells present, then it is rational to use the drugs indicated in the test.

What may limit the effectiveness of Avastin is that there are multiple ways by which tumors can evolve that are independent of VEGF. There are other proangiogenic factors that can affect whether Avastin works or not, FGF, PDGF, ephrin A1, angioprotein 1, IL8, etc. You need to attack these other targets as well. That is why we need combination anti-angioRX. If you can achieve this, then you don't really need the other drugs, which don't get into the tumor so well. Angiogenic attack provides true selective toxicity, something which is sorely lacking with all of the other treatments.

It could be vastly more important to measure the net effect of all processes (systems) instead of just individual molecular targets (like VEGF). The cell is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyze the systems' response to drug treatments, not just one or a few targets or pathways.

There are many pathways to the altered cellular (forest) function, hence all the different "trees" which correlate in different situations. Improvement can be made by measuring what happens at the end (the effects on the forest), rather than the status of the indiviudal trees.

VEGF-targeted drugs are poorly-predicted by measuring the preferred target VEGFR. They can be well-predicted by measuring the effect of the drug on the function of live cells.

Many of these fine drugs (and Avastin is a miracle drug for the few) cry out for validated clinical biomarkers as pharmacodynamic endpoints and with the ability to measure multiple parameters in cellular screens to help set dosage and select people likely to respond. Many molecular diagnostics approved often have been mostly or totally ineffective at identifying clinical responders to various therapies.

Literature Citation:
Eur J Clin Invest 37 (suppl. 1):60, 2007
Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 17117

It is going to take combination antivascular therapy to make a difference, as Weisenthal, et al had shown at the 2008 ASCO Breast Cancer Symposium.

5 comments | 3535 reads

by gdpawel on Sun, 2010-12-12 23:14
Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant Metastasis

Marta P*ez-Ribes, Elizabeth Allen, James Hudock, Takaaki Takeda, Hiroaki Okuyama, Francesc Viñals, Masahiro Inoue, Gabriele Bergers, Douglas Hanahan and Oriol Casanovas.


Multiple angiogenesis inhibitors have been therapeutically validated in preclinical cancer models, and several in clinical trials. Here we report that angiogenesis inhibitors targeting the VEGF pathway demonstrate antitumor effects in mouse models of pancreatic neuroendocrine carcinoma and glioblastoma but concomitantly elicit tumor adaptation and progression to stages of greater malignancy, with heightened invasiveness and in some cases increased lymphatic and distant metastasis. Increased invasiveness is also seen by genetic ablation of the Vegf-A gene in both models, substantiating the results of the pharmacological inhibitors. The realization that potent angiogenesis inhibition can alter the natural history of tumors by increasing invasion and metastasis warrants clinical investigation, as the prospect has important implications for the development of enduring antiangiogenic therapies.


Angiogenesis inhibitors targeting the VEGF signaling pathway have proven to be efficacious in preclinical cancer models and in clinical trials. While antitumoral effects and survival benefit are often evident, relapse to progressive tumor growth typically ensues, reflecting multiple mechanisms of adaptation to antiangiogenic therapies. Our findings further implicate angiogenesis inhibition as a driving force in tumor progression to stages of greater malignancy, reflected in heightened invasion into surrounding tissue and in some cases increased lymphatic and distant metastasis. Thus, antiangiogenic therapy that effectively inhibits neovascularization and produces antitumor effects and survival benefit can additionally alter the phenotype of tumors by increasing invasion and metastasis. This realization motivates clinical studies to confirm and potentially target this insidious consequence of antiangiogenic therapies.

Source: Cancer Cell, Volume 15, Issue 3, 220-231, 3 March 2009


by gdpawel on Wed, 2011-07-06 01:58
Genentech's clinical experience with antiangiogenesis therapy from clinical trials have prompted their investigators to evaluate tumor rebound following antiangiogenic therapy. So it maybe any antiangiogenic therapy, not just Avastin.

Observations were made in a Phase II study (J Clin Oncol 2008;26: 1810-1816) in patients with metastatic breast cancer (MBC) treated with a TKI. Investigators observed in several patients with superficial cutaneous or nodal lesions that appeared to respond clinically during periods of treatment, but then grew during a two week period off treatment.

Prior to this observation, investigators of a randomized Phase III trial of Avastin with paclitaxel in patients with MBC discussed the lack of an OS benefit in light of a significant and clinically meaningful improvement in PFS (N Engl J Med 207;357:2666-2676).

The authors noted the possibility of accelerated tumor regrowth (tumor rebound) compared with
chemotherapy alone. It was speculated whether increases in VEGF levels upon discontinuation of Avastin might have resulted in more aggressive disease.

What clinical scientists involved with cell culture assays seem to have found that serum from Avastin treated patients actually support endothelial cell growth in cell culture better than serum from control patients, without Avastin treatment. When you get rid of VEGF with Avastin, the body cranks out other types of blood vessel growth (survival) factors.

A study by Japanese researchers suggests a better antiangiogenic way to block tumor growth and prevent rebound (Journal of Experimental Medicine, May 11, 2009). They found (in mice) that blocking a different molecule (M-CSF) suppressed tumor growth even after treatment was stopped.

Three weeks of anti-VEGF treatment suppressed tumor growth, but the tumors bounced back when the drug treatment was curtailed. Tumor growth on a similar regiment of an M-CSF inhibitor remained suppressed in the absence of the drug.

Blocking VEGF can prevent dangerous vessels from growing such as those that feed tumors, but it also stops beneficial vessels from growing, such as those that help injured tissues heal. But it seems that blocking M-CSF only impeds bad vessel growth.

Most likely, the anti-M-CSF treatment had a lasting effect because it resulted in damage to the scaffolding that surrounds cancerous vessels, robbing the tumors of the structural support they need to grow. Meanwhile, the scaffold of mice treated with anti-VEGF remained intact.

M-CSF levels soar in patients with osteosarcoma (a malignant bone cancer), breast cancer and prostate cancer, making these cancers potentially the most responsive to M-CSF-blocking drugs Whether or not other types of cancer rely more on M-CSF than on VEGF for their blood supply remains unknown. Imatinib Mesylate (Gleevec) is an anti-M-CSF agent.

Source: The Rockeffeller University

It would be interesting to see if Gleevec (M-CSF inhibitor) + Avastin would damage the scaffolding that surrounds cancerous vessels, robbing the tumors of the structual support they need to grow. If the serum from Avastin + Gleevec does not support endothelial cell growth in cell culture? Cell function analyses have already shown that Tykerb enhances the antivascular activity of Avastin.


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