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Cancerous vs. healthy cells: Researchers identify the road to success

10.04.2006


Studies determine best route for targeted therapies



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.

PTEN-Loss Mediated Herceptin (trastuzumab) Resistance and Targeting the PI3K Pathway as a Counteracting Strategy: Abstract No. IS-445

Researchers from The University of Texas M. D. Anderson Cancer Center, Houston, have identified why some women with Her-2 positive breast cancer, an aggressive form of the disease, do not respond to the drug trastuzumab (Herceptin®) or may actually develop a resistance to the treatment.

The investigators discovered that a combination of trastuzumab and a new kinase inhibitor, PI3K, may work together to increase these patients’ chances of survival.

Trastuzumab treats women with metastatic breast cancer whose tumors overproduce the ErbB2 gene. The overproduction of the ErbB2 gene, also called Her-2/neu, leads to aggressive breast cancer and poorer patient survival. ErbB2 is part of a family of genes called epidermal growth factor receptors (EGFR) that stimulate cell growth and division. Trastuzumab has shown outstanding efficacy for patients with high levels of the ErbB2 gene.

Approximately one-third of patients who possess the ErbB2 gene will respond to trastuzumab therapy, but the treatment is sometimes combined with other chemotherapy agents to make it more effective.

Still other patients develop resistance to the therapy over time.

In this study, researchers found that loss of PTEN can lead to resistance of trastuzumab. The PTEN gene (phosphatase and tensin homolog deleted on chromosome ten) acts as a tumor suppressor gene, helping to regulate the cycle of cell division by keeping cells from growing and dividing uncontrollably or too rapidly, and ultimately forming tumors. Normally, the PTEN enzyme acts as part of a chemical pathway that signals cells to stop dividing and causes cells to undergo apoptosis.

However, reduced levels of PTEN contribute to trastuzumab resistance, both in vivo (humans and mice) and in vitro (culture). Patients with PTEN-deficient breast cancer have poorer outcomes and response to trastuzumab therapy when compared to those with normal PTEN levels.

The researchers then examined the role played by phosphoinositide 3-kinase (PI3K) pathway inhibitors to reverse PTEN-reduction-mediated trastuzumab resistance. PI3K regulates several key signals that initiate cell processes frequently disrupted by carcinogenesis, a process by which normal cells are transformed into cancer cells.

Seven PI3K pathway inhibitors, either currently in use or under development in clinical trials, were examined. One inhibitor used in combination with trastuzumab successfully inhibited cell growth, and a second, when used with trastuzumab, sensitized the therapeutic effects of the drug. Researchers said the next step is to conduct a phase I/II study looking at these combinations in patients who did not respond to traztuzumab as a first-line therapy.

"PTEN seems to be a very sensitive and specific predictor to trastuzumab-based therapy and data suggest that activation of PTEN is a novel mechanism underlying the anti-tumor activity of trastuzumab.

Combination therapy may provide more effective therapeutic regimens, allowing more patients to benefit from trastuzumab," said Dihua Yu, M.D., Ph.D., professor in the department of surgical oncology and director of research in the Surgery Division, The University of Texas M. D. Anderson Cancer Center.

A Novel, Potent and Selective IGF-1R Small Molecule Inhibitor Blocks Activation of IGF-1R Signaling in Vitro and Inhibits IGF-1R Dependent Tumor Growth in Vivo: Abstract No. LB-281

Researchers from OSI

Pharmaceuticals have identified a new small molecule inhibitor that may stop the growth of colon cancer. In this study, investigators discovered and tested an IGF-1R inhibitor, referred to as Compound 1.*

Compound 1 was shown to hinder the signaling response of IGF-1R -- specifically blocking the activation of two downstream pathways, stopping tumor cell growth and survival. The study also showed that the colon cancer tumors respond to the drug because they produce and are dependent on the growth-promoting effects of IGF-II.

"We are very encouraged by the results seen in our pre-clinical IGF-1R inhibitor program. The most important finding of our study was that, when administered orally, our IGF-1R inhibitor prevented the growth of human colon cancer tumors in mice," said Jonathan A. Pachter, Ph.D., senior director of cancer biology, OSI Pharmaceuticals, Long Island, N.Y. Insulin-like growth factor 1 receptor (IGF-1R) is a cellular protein with a molecular structure similar to that of the receptor for insulin, a hormone that regulates the amount of glucose sugar in the blood. The IGF-1R has been shown to play roles in tumor cell growth and the inhibition of cell death. There are two circulating proteins (or ligands) that activate the IGF-1R (IGF-I and IGF-II). The excess production of IGF-II is thought to encourage tumor growth.

Certain tumors, including colorectal, non-small cell lung, ovarian and some cancers in children, drive their own growth and survival through the overproduction of IGF-II. This IGF-II activates the IGF-1R on the surface of cancer cells to stimulate tumor growth, making IGF-1R an important treatment target for many human cancers.

"This small molecule represents a potent and selective IGF-1R kinase inhibitor that could be effective in the treatment of IGF-II driven human cancers," said Dr. Pachter.

A variety of approaches to block IGF-1R signaling have been used to cause cell death in a broad range of cancers, both in cell cultures and live models. Through the use of structure-based design, OSI Pharmaceuticals has been able to identify small molecules that selectively block the ability of IGF-1R to increase cell growth.

Another major challenge in the development of IGF-1R inhibitors is to avoid blocking the closely related insulin receptor that regulates glucose levels in the blood. Results from the study showed that in addition to diminishing or halting tumor growth in human cancer cells transferred to live test animals, OSI’s IGF-1R inhibitor showed no substantial rise in blood sugar.

Warren Froelich | EurekAlert!
Further information:
http://www.aacr.org

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