Avastin (bevacizumab)-induced tumor calcifications can be elicited in glioblastoma

[Rich66]

Cytotoxic anticancer drugs (topotecan, vinorelbine, melphalan, doxorubicin, cisplatin) antagonize the ability of Avastin to kill endothelial cells through this specific cell death mechanism. The standard, traditional cytotoxic drugs all inhibited Avastin, but the new, "targeted" drugs either don't inhibit it or actually enhance it (e.g. lapatinib, erlotinib).

Clinical trials have shown that the combination of chemotherapy with Avastin generally works better than either alone (that is, in situations where Avastin works at all). But this is because Avastin has a very long half life (weeks) and it has the opportunity to work at times when the drug levels of the standard anticancer drugs go down to undetectable levels (where they won't antagonize the ability of low VEGF to cause death of the tumor endothelial cells).

Potentially HUGE ramifications here. Essentially..the traditional maximum tolerated dose approach of most standard chemos schedules may be undoing Avastin. Roche should be all over this like roaches on..just pick something.
But it does seem to me the metronomic combination of daily Cytoxan with Avastin has not proved to be a winner.

The cellular calcium overdose issue is intriguing since I believe Tamoxifen has that as part of its numerous mechanisms. I bet very few have paired Avastin with Tamoxifen or other hormonals. Tamoxifen crosses the blood brain barrier too.

[gdpawel]

Dr. Robert Nagourney blogged some interesting insight into this. 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 VGEF inhibition a driver of response or an epiphenomenon? What about the fibroblast matrix, lymphatic vessels, infiltrating monocytes, T-cells, B-cells and neutrophils?

[url]http://robertanagourney.wordpress.com/2012/06/08/tumor-ecology-not-tumor-biology/

In pharmacology, the term agonist-antagonist is used to refer to a drug which exhibits some properties of an agonist (a substance that fully activates the neuronal receptor that it attaches to) and some properties of an antagonist (a substance that attaches to a receptor but does not activate it or if it displaces an agonist at that receptor it seemingly deactivates it thereby reversing the effect of the agonist).

In cell-based functional profiling assays, conducted on human tumor samples utilizing native microspheroids (fresh, live cells, not cell lines) replete with vascular, stromal and inflammatory cells to analyze cellular responses in the context of the tumor microenvironment, this snapshot of cellular response recapitulates patient response to cytotoxic compounds, signal transduction inhibitors, and growth factor agonists/antagonists in real time.

Tamoxifen acts as an antagonist in breast and conversely an agonist in uterus. Agonist (potentiating) effects at high doses. Sometimes agents can "chemosensitize" tumor cells. To alter susceptibility of a targeted cell or organism having become ineffective, becomes effective again. There is a chemosensitizing effect of tamoxifen.

The Tamoxifen administration is in combination with cytotoxic drugs. High-dose tamoxifen has been turning up with very nice responses in cell culture assays. It turns up synergistic (cooperative) in brain tumors, lung cancers, ovarian cancers and the like.

High-dose tamoxifen significantly inhibits the P-glycoprotein (gatekeeper in the blood-brain barrier) multidrug resistant membrane pump, as well as inhibiting protein kinase C (preventing the increase in vascular resistance).

So in this case, tamoxifen acts as an agonist (makes the chemotherapy more potent) in ovarian cancer. It can "chemosensitize" tumor cells. In other words, tamoxifen can help chemotherapy be more effective, by being a resistance modifying drug.

Although a cytostatic agent like Tamoxifen does not induced programmed cell death (apoptosis) and the functional profiling platform usually does not give strong cell-death signals for Tamoxifen exposure in most tumors, high-dose Tamoxifen can be a potentiator (make more potent) for a cytotoxic drug and also act as an anti-angiogenic effect (limiting formation of new blood vessels).

The P-glycoprotein is not measured, per se. What is measured is a drug alone, a drug with high dose tamoxifen, and high dose tamoxifen alone. Sometimes a drug alone doesn't work and high dose tamoxifen alone doesn't work, but a drug PLUS high dose tamoxifen works brilliantly. This can be tested in any of the cell death endpoints: DISC, MTT, ATP, resazurin, or potentially others.

[gdpawel]

A new population-based study has found that patients with glioblastoma who died in 2010, after the Food and Drug Administration (FDA) approval of bevacizumab, had lived significantly longer than patients who died of the disease in 2008, prior to the conditional approval of the drug for the treatment of the deadly brain cancer. Bevacizumab is used to treat patients with certain cancers whose cancer has spread. The study appears in the journal Cancer.

"There has been a great deal of debate about the effectiveness of bevacizumab in treating patients with glioblastoma," says lead author Derek Johnson, M.D., a neuro-oncologist at Mayo Clinic Cancer Center. "Our study found that, at the population level, treatment strategies involving bevacizumab prolonged survival in patients with progressive glioblastoma."

Researchers analyzed data on 5,607 adult patients from the National Cancer Institute (NCI) Surveillance, Epidemiology and End Results (SEER) database before and after the conditional approval of bevacizumab for the treatment of glioblastoma in 2009. The SEER database covers 18 geographic areas of the U.S., which collectively represent 28 percent of the U.S. population.

Researchers studied survival in 1,715 patients with glioblastoma who died in 2006, 1,924 who died in 2008 and 1,968 who died in 2010. "The difference in survival between 2008 and 2010 was highly significant and likely unrelated to any advancements in supportive care," Dr. Johnson says. "This study provides the strongest evidence to date that bevacizumab therapy improves survival in patients with glioblastoma."

Glioblastoma, is an aggressive cancer in which tumors grow rapidly and spread rapidly to new sites. It is the most common malignant brain tumor in adults and accounts for about 22 percent of all brain cancers. About 3,000 people develop a glioblastoma each year in the U.S.

References:

Glioblastoma survival in the United States improved after Food and Drug Administration approval of bevacizumab: A population-based analysis

http://onlinelibrary.wiley.com/doi/1...28259/abstract

Co-authors include Heather Leeper, M.D., and Joon Uhm, M.D. both of Mayo Clinic. Article first published online: 18 JUL 2013; DOI: 10.1002/cncr.28259

Citation: Mayo Clinic. "Glioblastoma survival improved following FDA approval of bevacizumab." Medical News Today. MediLexicon, Intl., 21 Aug. 2013.

[gdpawel]

Advanced imaging techniques may be able to distinguish which patients' tumors will respond to treatment with anti-angiogenic drugs and which will not. In patients newly diagnosed with the dangerous brain tumor glioblastoma, Massachusetts General Hospital (MGH) researchers report, those for whom treatment with the anti-angiogenic drug cediranib rapidly 'normalized' abnormal blood vessels around their tumors and increased blood flow within tumors survived significantly longer than did patients in whom cediranib did not increase blood flow. The report appears in PNAS Early Edition.

"Two recent phase III trials of another anti-angiogenic drug, bevacizumab, showed no improvement in overall survival for glioblastoma patients, but our study suggests that only a subset of such patients will really benefit from these drugs," explains Tracy Batchelor, MD, director of the Pappas Center for Neuro-Oncology at the MGH Cancer Center and co-lead and corresponding author of the current study. "Our results also verify that normalization of tumor vasculature appears to be the way that anti-angiogenic drugs enhance the activity of chemotherapy and radiation treatment."

Anti-angiogenic drugs, which block the action of factors that stimulate the growth of blood vessels, were first introduced for cancer treatment under the theory that they would act by 'starving' tumors of their blood supply. Since that time, however, new evidence has suggested that the drugs' benefits come through their ability to 'normalize' the abnormal, leaky vessels that usually surround and penetrate tumors, improving delivery of both chemotherapy drugs and the oxygen that is required for effective radiation therapy. This hypothesis was first proposed and has subsequently been developed by Rakesh Jain, PhD, senior author of the current study and director of the Steele Laboratory for Tumor Biology in the MGH Department of Radiation Oncology.

A 2007 clinical study led by Batchelor found evidence suggesting that cediranib, which has not yet received FDA approval, could temporarily normalize tumor vasculature in recurrent glioblastoma, but it was not clear what role normalization might have in patients' survival. In the past few years, several research teams with leadership from Batchelor, Jain and other co-authors of the current paper reported evidence that cediranib alone improved blood perfusion within recurrent glioblastoma tumors in a subset of patients and improved their survival. A Nature Medicine study published earlier this year used a technique called vessel architectural imaging (VAI), developed at the Martinos Center for Biomedical Imaging at MGH, to reveal that cediranib on its own improved the delivery of oxygen within tumors of some patients with recurrent glioblastoma.

Patients in the current study were participants in a clinical trial of cediranib plus radiation and chemotherapy for postsurgical treatment of newly diagnosed glioblastoma. Among participants in that trial, 40 also had advanced brain imaging with VAI and other MR imaging techniques. While all but one of the participants in the overall trial showed some evidence of vascular normalization and reduced edema - tissue swelling that can be dangerous within the brain - of the 40 who had imaging studies, only 20 were found to have persistent improvement in vessel perfusion. VAI also revealed improved oxygen delivery only in the patients with improved perfusion. Those patients ended up surviving about 9 months longer - 26 months, compared with 17 months - than did those whose perfusion levels remained stable or worsened. A comparison group of glioblastoma patients treated with radiation and chemotherapy only survived an average of 14 months.

"It's quite likely that the results we've found with cediranib will apply to other anti-angiogenics," Batchelor says. "In fact a presentation at a recent meeting showed that patients with improved perfusion from bevacizumab were also the ones in that study who lived longer. More research is needed, but these findings suggest that MR imaging techniques should play an essential role in future studies of anti-angiogenic drugs in glioblastoma and possibly other types of solid tumors. We've received National Cancer Institute funding to study this approach with bevacizumab treatment, and we will also be investigating tumor delivery of chemotherapy and oxygen status using combined MR/PET techniques at the Martinos Center's MR/PET facility."

Jain adds, "We originally introduced the normalization hypothesis for anti-angiogenic treatment in 2001, but it's taken more than a decade to confirm that vascular normalization actually increases tumor perfusion and that increased perfusion, rather than tumor starvation, is what improves survival. This study provides compelling evidence that normalization-induced increased vessel perfusion is the mechanism of benefit in glioblastoma patients." Jain is the Cook Professor of Radiation Oncology (Tumor Biology), and Batchelor is the Armenise-Harvard Professor of Neurology at Harvard Medical School.

References: Co-lead authors of the PNAS Early Edition report are Elizabeth Gerstner, MD, MGH Neurology; Kyrre Emblem, PhD, Martinos Center; and Dan Duda, PhD, DMD, Steele Laboratory. Additional co-authors include Jay Loeffler, MD, MGH Radiation Oncology; Bruce Rosen, MD, PhD, Martinos Center; Gregory Sorensen, MD, formerly of the Martinos Center and now with Siemens Healthcare; Patrick Wen, MD, Dana-Farber Cancer Institute, and Percy Ivy, MD, National Cancer Institute. Support for the study includes National Institutes of Health grants R01CA129371, K24CA125440A, P01CA080124 and R01CA163815, and a grant from the National Foundation for Cancer Research.

Citation: Hospital, Massachusetts General. "Predicting tumor response to anti-angiogenic drugs." Medical News Today. MediLexicon, Intl., 6 Nov. 2013.

[gdpawel]

MCED explains why glioblastoma (the most common primary brain tumor) patients who have favorable responses to bevacizumab (Avastin) develop early calcifications in the tumor bed while glioblastoma patients with poor responses to bevacizumab do not develop calcifications.”

http://www.vasocell.com/MCED_Home.html

MCED Discovery

http://www.vasocell.com/MCED_Discovery.html