8 juli 2011: ondanks de beloftes dat er vervolgstudies zouden komen kan ik weinig meer vinden dan een studie uit 2008. Ook hierbij merken de onderzoekers op dat Velcade - Bortezomib een (zeer) veelbelovend middel is voor behandelen van hersentumoren. Onderaan artikel abstract van meest rercente studie:

25 april 2006: Bron: University of California, San Francisco San Francisco Medical Center

Velcade - bortezomib (zie ook onder Kahler - Multiple Myeloma informatie, waarvoor Velcade een geregistreerd medicijn is) doodt hersentumorcellen - kwaadaardige gliomas - blijkt uit grote laboratoriumproeven. Hoewel het hier nog slechts gaat om laboratoriumstudies hebben deze wereldwijd veel aandacht gekregen omdat de resultaten ronduit spectaculair zijn te noemen en plaatsen ook wij twee artikelen hierover. Het blijkt namelijk dat wanneer Velcade - bortezomib wordt ingezet samen met Tamoxifen de hersentumorcellen niet overleven en worden aangezet tot apoptosis - zelfmoord. Inmiddels zijn verspreid over 55 ziekenhuizen wereldwijd eerste trials opgezet met patiënten waarbij alle andere behandelingen inmiddels zijn uitgewerkt. Een fase II studie met patiënten met recidieven van hersentumoren is vorig jaar al begonnen en volgens uitspraken van de onderzoekers in onderstaande artikelen bevestigen deze trials met patiënten de laboratoriumstudie resultaten. Hier twee artikelen over deze studie.

Study Affirms New Therapeutic Target for Malignant Gliomas
The proteasome inhibitor bortezomib (Velcade) kills malignant glioma cells and can enhance the ability of tamoxifen to do the same, NCI researchers reported last week at the American Association of Cancer Research (AACR) annual meeting in Washington, D.C. The findings, the researchers said, lend further support to the rationale behind a phase II clinical trial launched nearly 1 year ago that is testing bortezomib and tamoxifen in patients with recurrent, high-grade malignant gliomas.

There has been little progress in the treatment of gliomas, the most common type of brain cancer, over the past two decades; the median survival for those with the most aggressive and most common glioma, glioblastoma, is a little more than a year. Tamoxifen, a selective estrogen receptor modulator, or SERM, is primarily used to treat or prevent breast cancer in women at high risk for the disease. During the last 10 to 15 years, however, tamoxifen also has been a last option after standard treatments have failed in some glioma patients, said Dr. Howard Fine, of NCI's Center for Cancer Research, and has demonstrated a clinical benefit in some patients.

The current phase II trial, being conducted at the NIH Clinical Center, follows a series of studies conducted in Dr. Fine's lab over several years in which researchers have demonstrated the important role of the intracellular protein NF-κB in glioma cell survival, and that inhibition of NF-κB could enhance the glioma cell-killing activity of tamoxifen and at least one other investigational SERM.

Although tamoxifen induces breast cancer cell death by inhibiting the estrogen receptor, studies by Dr. Fine's lab and others have shown that it kills glioma cells even though those cells do not express the estrogen receptor.

In the study results presented at AACR, NF-κB was highly active in glioma cell lines but never in normal tissue, explained the study's leader, Dr. Ai-Min Hui. And gene-expression profiles on 203 glioma clinical samples revealed that other genes activated by NF-κB were upregulated, which was not the case in healthy samples.

Glioma cells appear intrinsically to always be on the verge of death, Dr. Fine added, and NF-κB seems to play an essential role in keeping them alive, acting like a full-time security system.
"The glioma tumor cells are not just turning NF-κB on in response to stress," he said. "They have this pathway overexpressed all of the time to be able to resist any stress, including chemotherapy or radiation therapy. It's probably one of the reasons gliomas are so resistant to treatment."
Dr. Fine's lab started testing bortezomib, which is approved for use in patients with multiple myeloma, because it's been shown to inhibit NF-κB. The proteasome is a large conglomeration of proteins, known as a complex, inside cells that is responsible for breaking down damaged or unneeded proteins. Bortezomib promotes cancer cell death by disrupting this essential regulatory process which, as a welcome side effect, disrupts NF-κB expression.

In this new study, Dr. Hui explained, they determined that bortezomib's ability to disrupt NF-κB is actually achieved by blocking the activity of another protein that regulates NF-κB's function, IκB-alpha.

Dr. Fine's lab also has found that bortezomib can enhance the cell-killing activity of radiation and chemotherapy.
In addition to the phase II trial at the NIH Clinical Center, the NCI-funded New Approaches to Brain Tumor Therapy Consortium is conducting a phase I/II trial testing bortezomib alone in patients with malignant gliomas for whom standard therapies have failed.

By Carmen Phillips

Cancerous vs. healthy cells: Researchers identify the road to success
Studies determine best route for targeted therapies
WASHINGTON, D.C. − Conventional cancer treatments are generally effective in wiping out tumor cells, but in the process they also may kill healthy cells. Researchers are focusing their efforts now on treatments that can target just the cancerous cells, without harming healthy tissue in their midst. These new types of drugs are known as targeted therapies, and physicians are studying their effectiveness and possible side effects in a variety of different types of cancer. Several targeted therapies are being studied alone and in combination to treat a variety of cancer types. In particular, cancerous brain tumors can be more difficult to treat than other cancers, and oncologists are developing therapies that target these cells to improve patients' survival. Researchers also are gaining a better understanding of the molecular differences between cancerous and healthy cells, improving current treatment and survival rates, according to studies presented today at the 97th Annual Meeting of the American Association for Cancer Research.

NF-kB as a Therapeutic Target in Malignant Gliomas: Abstract No. 1506

Researchers from the National Cancer Institute in Bethesda, Md., have found they may be able to successfully treat brain tumor cells with a new targeted therapy that inhibits the activity of a cell protein called nuclear factor-Kappa B (NF-kB).

The drug, called bortezomib or (Velcade®) – when used alone or in combination with other cancer treatments – represents a potential new way to treat malignant glioma, a particularly stubborn and aggressive brain tumor.

"Targeting the NF-kB pathway either alone or in combination with other chemotherapy agents, is an effective anti-glioma treatment," said Ai-Min Hui, M.D., Ph.D., research fellow at the NCI and the lead investigator of the study. In their study, the NCI researchers set out to determine the role of NF-kB in reversing the apoptotic (or programmed cell death) effect of selective estrogen receptor modulators (SERMs) in brain cancer, as well as potential therapies that can be used either alone or in combination to block the protein. High levels of NF-kB are activated and present in transplanted glioma cells and glioma tumor samples, but not in normal brain tissue cells.

SERMs have shown some value in inducing cell death in brain cancers by a previously unknown method. They are designed to deliver the benefits of estrogen without its negative side effects, although gliomas do not generally express the estrogen receptor. However, previous studies have shown that NF-kB protects glioma cells from breaking down, therefore reversing the effect of SERM therapies.

Researchers looked at 203 glioma samples and determined that NF-B was activated. They also noticed that the level of activation was related to the grade of the tumor, suggesting that NF-B is related to tumor progression. Treatment with bortezomib suppressed both unregulated and signal-oriented activation in NF-kB by inhibiting the breakdown of IkB-alpha. IkB-alpha is one of a series of inhibitory proteins that controls the activation of NF-kB, preventing it from binding to DNA in the nucleus. Bortezomib not only stops the degradation of IkB-alpha, it also suppresses the activation of NF-kB, thus stopping cell growth.

"By interfering with the function of IkB-alpha proteins, bortezomib was shown to induce glioma cell degradation and enhance anti-cancer effects of SERMs," said Ai-Min Hui, M.D., Ph.D., research fellow at the National Cancer Institute and lead investigator on this trial.

"New studies looking at the combined use of bortezomib and high-dose tamoxifen may provide a viable treatment option for patients with recurrent, high grade malignant gliomas," he said.

Malignant gliomas are one of the most common brain tumors, accounting for more than half of the 18,000 primary cancerous brain tumors diagnosed annually in the United States, and are the fourth most common cause of cancer death in patients aged 15 to 44.

Standard treatment for patients diagnosed with brain cancer is surgery followed by radiation, sometimes with added chemotherapy. However, current therapies are considered inadequate to fight this deadly disease and researchers have been trying to identify new targets and develop new agents with different mechanisms of action to help increase patients' survival.

Study results show that combining bortezomib with celecoxib or DMC very potently triggers the ER stress response and results in greatly increased glioblastoma cytotoxicity

Aggravated Endoplasmic Reticulum Stress as a Basis for Enhanced Glioblastoma Cell Killing by Bortezomib in Combination with Celecoxib or Its Non-Coxib Analogue, 2,5-Dimethyl-Celecoxib

  1. Adel Kardosh1, 
  2. Encouse B. Golden2, 
  3. Peter Pyrko1, 
  4. Jasim Uddin3,
  5. Florence M. Hofman2, 
  6. Thomas C. Chen4, 
  7. Stan G. Louie5, 
  8. Nicos A. Petasis3, and
  9. Axel H. Schönthal1

+Author Affiliations

  1. Departments of 1Molecular Microbiology and Immunology, 2Pathology, 3Chemistry, 4Neurosurgery, and 5Pharmacy, University of Southern California, Los Angeles, California
  1. Requests for reprints:
    Axel H. Schönthal, University of Southern California, 2011 Zonal Avenue, HMR-405, Los Angeles, CA 90089-9094. Phone: 323-442-1730; Fax: 323-442-1721; E-mail:schontha@usc.edu.

Abstract

The proteasome inhibitor bortezomib (Velcade) is known to trigger endoplasmic reticulum (ER) stress via the accumulation of obsolete and damaged proteins. The selective cyclooxygenase-2 (COX-2) inhibitor celecoxib (Celebrex) causes ER stress through a different mechanism (i.e., by causing leakage of calcium from the ER into the cytosol). Each of these two mechanisms has been implicated in the anticancer effects of the respective drug. We therefore investigated whether the combination of these two drugs would lead to further increased ER stress and would enhance their antitumor efficacy. With the use of human glioblastoma cell lines, we show that this is indeed the case. When combined, bortezomib and celecoxib triggered elevated expression of the ER stress markers GRP78/BiP and CHOP/GADD153, caused activation of c-Jun NH2-terminal kinase and ER stress-associated caspase-4, and greatly increased apoptotic cell death. Small interfering RNA–mediated knockdown of the protective ER chaperone GRP78/BiP further sensitized the tumor cells to killing by the drug combination. The contribution of celecoxib was independent of the inhibition of COX-2 because a non-coxib analogue of this drug, 2,5-dimethyl-celecoxib (DMC), faithfully and more potently mimicked these combination effects in vitro and in vivo. Taken together, our results show that combining bortezomib with celecoxib or DMC very potently triggers the ER stress response and results in greatly increased glioblastoma cytotoxicity. We propose that this novel drug combination should receive further evaluation as a potentially effective anticancer therapy. [Cancer Res 2008;68(3):843–51]


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