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Old 12-09-2010, 04:32 PM
gdpawel gdpawel is offline
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Default 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 chemotherapy alone or with chemotherapy + Avastin. 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 VEGF with Avastin, the body cranks out other types of blood vessel growth (survival) factors.

One aspect of a functional cytometric 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, Nexavar, Sutent) 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. [url]http://cancerfocus.org/forum/showthread.php?t=3152

[url]http://www.jci.org/articles/view/24612
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Last edited by gdpawel : 05-15-2012 at 07:39 PM. Reason: post full article
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Old 12-12-2010, 11:14 AM
gdpawel gdpawel is offline
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Default Removal of antiangiogenic effect leads to rebound increase in proangiogenic signaling

Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant Metastasis

Marta Pez-Ribes, Elizabeth Allen, James Hudock, Takaaki Takeda, Hiroaki Okuyama, Francesc Vials, Masahiro Inoue, Gabriele Bergers, Douglas Hanahan and Oriol Casanovas.

Summary

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.

Significance

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

[url]http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874829/
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Old 07-05-2011, 02:58 PM
gdpawel gdpawel is offline
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Default A better antiangiogenic way to block tumor growth and prevent rebound?

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.

[url]http://cancerfocus.org/forum/showthread.php?t=3152
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Last edited by gdpawel : 01-21-2012 at 07:43 PM. Reason: correct url address
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Old 09-06-2011, 10:49 AM
gdpawel gdpawel is offline
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Default Tykerb enhances the antivascular activity of Avastin

Tykerb (lapatinib) enhances the antivascular activity of Avastin (bevacizumab) and has superior antivascular acitivity compared to Nexavar (sorafenib). The was a slide presentation at the American Society of Clinical Oncology (ASCO) Breast Cancer Symposium on September 5, 2008.

Antivascular activity of lapatinib and bevacizumab in primary microcluster cultures of breast cancer and other human neoplasms

Sub-category: New Systemic Agents - New drugs and targets (includes anti-angiogenics) - Other

Category: Treatment

Meeting: 2008 Breast Cancer Symposium

Session Type and Session Title: General Poster Session A

Abstract No: 166

Author(s): L. Weisenthal, D. J. Lee, N. Patel

Abstract:

Background: The following tyrosine kinase inhibitors (TKI) have been shown to have antivascular (AV) activity: sunitinib (Su), sorafenib (So), gefitinib (G), erlotinib (E), and imatinib (I). To date, AV activity has not been reported for lapatinib (LAP).

Methods: We studied the ability of TKI to induce tumor cell death (TCD) and also endothelial cell death (ECD) in primary human tumor cultures, using a novel functional profiling assay system, which detects TCD vs ECD in floating cell microclusters derived with > 90% success rate from fresh human tumor biopsies (Weisenthal, 2007 ASCO GI Symposium Abst 439; Weisenthal, et al. J Intern Med, In Press).

Results: LAP (15 g/ml) induced significantly greater tumor cell death (TCD) in breast cancer biopsy specimens (n=25) than in specimens from cancers other than breast (n=42). However, there was no average difference between the degree of LAP-induced endothelial cell death (ECD) in breast cancer specimens vs. non-breast cancer specimens. At drug concentrations which were equitoxic to tumor cells, LAP induced significantly greater ECD than did sorafenib (So). At concentrations (2.5 and 1.25 mg/ml) of bevacizumab (BEV) which reduced VEGF in the culture media supernatant to levels below detection by commercial ELISA assay, BEV-induced ECD was not significantly enhanced by So, Su, G, E, or I; however, BEV-induced ECD was significantly enhanced by LAP.

Conclusions: 1. LAP has AV activity superior to that of sorafenib. 2. BEV + LAP may be the first clinically-exploitable AV drug combination. 3. Our functional profiling assay system may be used to individualize AV therapy. 4. High dose, intermittent 'bolus' schedules of LAP to coincide with BEV administration may be clinically advantageous, even in HER2-negative tumors.

Abstract Disclosures

Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy and are designated with a caret symbol (^) here and in the print version.

[url]http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=58&abstr actID=40418

Note: connect the r and a in abstractID

Slide Presentation (large download 25.65 MB):[url]http://weisenthal.org/Weisenthal_ASCO.pdf
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Last edited by gdpawel : 01-21-2012 at 07:44 PM. Reason: correct url address
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Old 09-06-2011, 10:51 AM
gdpawel gdpawel is offline
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Default Microaggregates including endothelial cells

Microaggregates (microscopic collection of platelets, leukocytes or fibrin particles that occurs in blood) which mimic the native environment of cells contained in biopsied tissue are used to assess and predict the effects of various treatments on the viability of cell types contained in the microaggregate.

There is a need for improved methods to predict the activity of treatments which target the microvasculature of tumors. Avastin is an anti-cancer drug which targets the microvasculature of tumors. The wholesale cost of Avastin is more than $40,000 for ten months of treatment for a relatively small percentage of patient that can derive substantial benefit from it.

The most commonly used in vitro methods involve isolating and culturing endothelial cells. Once the cells have been cultured, the effect of drugs are studied using cell death endpoints.

Normally, Avastin is administered to a patient on a trial basis and then early treatment effects are assessed by means of external diagnositc scanning (MRI) and/or post-treatment tumor biopsies, with histopathologic evaluation of treatment effects. This approach has many disadvantages, including expense of treatment, exposure of patient to potential toxicity of ultimately ineffective therapy, and the expense of diagnostic studies (MRI). Such studies also lack the ability to test multiple different treatments simultaneously without risk to the patient as is possible with in vitro methods.

In vitro methods are able to detect and/or quantify viability changes in the microvasculature of microaggregates of cells isolated from biopsied neoplastic tissues in response to treatments. The observed microvascular and other cellular changes serve as tests to predict the in vivo activity of the tested treatments, while able to detect specific effects on endothelial cells, and also permit the observation of effects of the same or concomitantly administered treatment on the surrounding cells (a particular drug may affect both endothelial cells and the surrounding cells).
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Old 09-06-2011, 10:52 AM
gdpawel gdpawel is offline
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Default How does Avastin work?

Anti-vascular drug Avastin is a large molecule (monoclonal antibody) angiogenesis inhibitor. Angiogenesis is the formation of new blood vessels. Many tumors build new blood vessels to help them grow and spread. Angiogenesis inhibitors prevent new blood vessel formation.

Tumor growth is dependent on angiogenesis. Angiogenesis is essential for the growth and metastasis (spread) of cancer. A growing tumor requires nutrients and oxygen (angiogenesis), which helps it grow, invade nearby tissue, and metastasize. To reach these nutrients, the tumor builds new blood vessels. In fact, growing tumors can become inactive if they can't find a new supply of nutrients.

Angiogenesis is dependent on VEGF (Vascular Endothelial Growth Factor), a chemical signal produced by cells that stimulates the growth of new blood vessels. Avastin is known to be driven by the VEGF pathway. Avastin directly binds to VEGF to directly inhibit angiogenesis.

In cell function analysis, within 24 hours of VEGF inhibition, endothelial cells have been shown to shrivel, retract, fragment and die by apoptosis. Tumors which secrete relatively low levels of VEGF might be more susceptible to an agent like Avastin which works by blocking VEGF (Avastin "sensitive" tumors). It potently inhibits the formation of new blood vessels.

However, there are additional functions of VEGF signaling (cell survival signaling). Clinical work suggests that there could be several possible mechanisms for Avastin, including potentially decreasing the oncotic pressure within the center of a necrotic tumor, which can limit the ability of the drug it is given with to be delivered into the tumor.

The mechanism of action may more reflect the vascular permeability factor effects and less the anti-angiogenesis effects. There can be several possible mechanisms for Avastin.

Some scientists are not sure whether Avastin or any other anti-angiogenic agents are working primarily by pruning new blood vessels, increasing the delivery of another anti-cancer therapy, or potentially another mechanism.

According to cell function analysis, by clinical oncologists involved with cell culture testing, Avastin as a single agent is relatively ineffective in virtually all tumor types other than Renal cancer. Beyond that, it appears to better deliver the effects of other classes of durgs.

Avastin facilitates vascular access of cytotoxics to tumors. It will take combination antivascular therapy to make a big difference, but this is definitely coming and it's the most promising thing on the near term therapeutic horizon.

Dr. Rakesh Jain presented his observations at an AACR Special Symposium, on tumor vascularity and its implications for therapy, describing the dynamics of blood flow through the network of disorganized tumor blood vessels. He showed that anti-anngiogenic factors "pruned" the blood supply and returned normal flow. But Avastin, by itself had a miniscule response rate. In the absence of chemotherapy, it was single digits.

Jain developed a novel tissue "window" method that enabled him to explore the temporal sequence of cellular response to VEGF therapy. He found that it all wasn't as simple or tidy as it had seemed. The short-term control of vasculature was followed by revascularization. Cells deprived of oxygen and nutrients developed into more stem cell-lie phenotypes. Therapies based on an incomplete understanding of angiogenesis might be adding to the problem.

At a subsequent AACR presentation by Napoleon Ferrara, PhD, Dr. Ferrara, who developed Avastin, reminded his audience that VEGF was originally known as VPF (vascular permeability factor). Perhaps this aspect of the VEGF effects were responsible for its minimal single agent activity, yet profound combinatorial effect.

Cancer is not a cell, but a system. Tumor cells are but a small portion of the process. Carcinogenesis may represent a response to cellular stress, some of which medical oncologists may inflict. The indiscriminate use of cytotoxic agents and antivascular drugs may be more harmful than helpful to patients.

What is the appropriate dose of Avastin? How should it be given? In what sequence with radiation or chemotherapy? With what drugs or targeted agents? Are low doses better than high doses? Is the effect of VEGF inhibition a driver of response or an epiphenomenon? What about the fibroblast matrix, lymphatic vessels, infiltrating monocytes, T-cells, B-cells and neutrophils? Dr. Jain outlined the complexities of the human tumor microenvironment.

Lecture on issues related to cell culture testing

A 33 minute lecture on functional profiling of human cancer, using cell culture drug resistance testing on fresh human tumor specimens obtained by surgical biopsy. This lecture was given at Charite University Medical Center in Berlin, Germany on March 19, 2009 by Larry Weisenthal, M.D., PhD. The audience consisted primarily of oncologists and surgeons working in the field of gynecologic oncology. Thanks to Dr. Frank Kischkel, TherapySelect GmbH & Co. KG, Heidelberg, Germany [url]http://vimeo.com/7577309
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Last edited by gdpawel : 03-01-2013 at 02:14 AM. Reason: additional info
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