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CSHL scientists identify new drug target against virulent type of breast cancer
By Dross at 2008-08-25 21:12
CSHL scientists identify new drug target against virulent type of breast cancer
The enzyme target, Brk, is shown to be an accelerator of HER2-positive tumors

Tumor cells in a particular subset of breast cancer patients churn out too much of a protein called ErbB2 -- also often called HER2 -- which drives the cells to proliferate unchecked. Patients unlucky enough to be in this group -- about one in four -- have poorer prognoses and clinical outcomes than those who don't.

The drugs Herceptin and Lapatinib, prescribed in combination with other chemotherapeutic agents, have improved this picture significantly, but leave plenty of room for improvement: they suppress ErbB2 but are effective against less than half of ErbB2-producing tumors. Moreover, patients with tumors that do respond usually develop resistance to these drugs.

A team of scientists at Cold Spring Harbor Laboratory has just published research identifying an enzyme called Brk that may serve as a target for future drugs developed to fight ErbB2-positive tumors. Brk, they report, helps these tumors become virulent and is also implicated in the process through which the tumors develop drug resistance.

The search for co-conspirators

"The limited success of existing therapy suggested to us that factors besides ErbB2, or proteins that collude with ErbB2, might nullify the effects of Herceptin and Lapatinib," explained CSHL Professor Senthil Muthuswamy, Ph.D., leader of the research team and corresponding author of the paper, published online August 21 ahead of print in Proceedings of the National Academy of Sciences.

In the hunt for ErbB2's co-conspirators, Dr. Muthuswamy's team focused on Brk, which they knew to be over-produced in many other types of cancer, including two-thirds of all breast cancers. A detailed analysis of changes that occurred in the genomes of a sample of breast cancer patients helped the group confirm that the expression of ErbB2 and Brk was directly linked.

By forcing the production of both ErbB2 and Brk within the same cell, they determined how Brk enhances ErbB2 activity and fortifies tumor cells against ErbB2-targeting drugs. "Our results might explain why the strategy of using ErbB2 inhibitors alone to treat breast cancers has fallen short," noted Dr. Muthuswamy. "These findings may also suggest a way to treat patients with advanced ErbB2-positive tumors and those who've developed resistance to ErbB2 inhibitors – an idea that we're eager to test."

ErbB2 and Brk go hand-in-hand

ErbB2 is a member of a family of enzymes called receptor tyrosine kinases -- cell-surface molecules that goad cells into proliferating when they sense growth cues in the environs of cells that express them. It turns out that the over-production of ErbB2 in breast cancers is due to a gene mutation that results in the accumulation of multiple copies of the erbB2 gene.

Other genes that undergo such "amplification" due the duplication of DNA segments include brk, which is the gene that instructs cells to manufacture the enzyme Brk. This enzyme is absent in healthy cells but is found at high levels in a majority of breast cancers. As some of these cancers also over-express ErbB2, the CSHL team wondered whether the offending genes, erbB2 and brk, are mutated in tandem, or "co-amplified." This idea in turn raised the possibility that the proteins encoded by these genes are also co-activated and feed into the same proliferation-promoting pathway.

The team checked breast cancer tissue from more than two hundred patients for variations in the number of copies of both genes and found that they were both amplified abnormally in a significant number of these samples. Re-analyzing the samples for the expression levels of both genes revealed that "co-amplified" genes were also "co-overexpressed" -- they were the source of abnormally high levels of their corresponding proteins.

Brk acts as an accelerator of proliferation

Further experiments by Muthuswamy's team revealed that although Brk does not induce cancerous proliferation on its own, it enhances the proliferation of cells that also express ErbB2 by speeding up their entry into the cell cycle. Proliferation in cancer is the result of the cell cycle gone out of control -- beyond limits that healthy cells impose on their own multiplication.

Dr. Muthuswamy likened the cooperation between the Brk and ErbB2 proteins to that between factors that propel a car. "If ErbB2 is the accelerator that makes the car move, Brk helps shift the gear to gain more speed," he explained.

How Brk is implicated in drug resistance

Aside from hurrying along tumor progression, Brk was also found to diminish the effectiveness of ErbB2-inhibiting drugs on tumor growth. This finding reinforces the need for combination therapies. "We might need to hit ErbB2-expressing cancers with drugs against both ErbB2 and Brk," said Muthuswamy.

Brk-inhibitors might also be useful on their own. The CSHL scientists speculate that these drugs might fight tumors that never react to or become resistant to ErbB2-inhibitors.

Targeting Brk is also a safe strategy, according to the scientists, because "Brk does not promote the proliferation of normal cells, and its expression in normal tissues is restricted to non-proliferating cells." Inhibiting this protein might thus "produce fewer unwanted side effectsterm than (targeting) other cancer-promoting proteins" which may be present in larger numbers.

The scientists have also thought up other ways of putting their discovery of the role of Brk in cancer progression to good use. "We also think that Brk would be an ideal clinical marker than could be used to provide both a diagnosis and prognosis for breast cancer," said Dr. Muthuswamy.



1 comment | 2711 reads

by gdpawel on Mon, 2008-08-25 23:34
Targeted drugs are based on a variety of biological mechanisms (pathways) that essentially stop cancer from spreading. They interfere with specific molecules (receptors and enzymes inside and outside a cancer cell) involved in carcinogenesis (the process by which normal cells become cancer cells) and tumor growth.

The most common targets on the outside of a cancer cell are receptors, which are proteins that help relay chemical messages. Many targets on the inside of a cell are enzymes, which are proteins that help speed up chemical reactions in the body.

By focusing on these molecular and cellular changes, targeted cancer drugs go after the "target" in these cells, rather than just all cells. In other words, they focus on molecular and cellular changes that are specific to cancer.

Because many cancer cells use similar pathways, the same drug could be used to treat one person's breast cancer and another person's lung cancer, as long as each tumor contained similar targets. This is why many of these treatments are being used in a variety of cancer types.

Although targeted therapy is appealing, it is more complex than meets the eye. Cancer cells often have many mutations in many different pathways, so even if one route is shut down by a targeted treatment, the cancer cell may be able to use other routes.

In other words, cancer cells have "backup systems" that allow them to survive. The result is that the drug does not shrink the tumor as expected. One approach to this problem is to target multiple pathways in a cancer cell.

There has been a continuous parade of new targeted small and large molecule therapies that will continue to be introduced into the market virtually blind. Most of them have been developed for use in solid tumors but some have also emerged for hematological malignancies. These targeted drugs mostly need to be combined with active chemotherapy to provide any benefit and the need for predictive tests for individualized therapy selection has increased.

Multi-targeted drugs can be well-predicted by measuring the effect of the drugs on the "function" (is the cell being killed regardless of the mechansim) of live cells, as opposed to a "target" (does the cell express a particular target the the drug is supposed to be attacking).

While a "target" assay tells you whether or not to give "one" drug, a "functional" assay can find other compounds and combinations and can recommend them from the one assay.

Functional profiling can discriminate between the activity of different “targeted” drugs and identify situations in which it is advantageous to combine the “targeted” drugs with other types of cancer drugs. Because these new “smart” drugs will work for “some” but not “all” cancer patients who receive them, functional profiling can accurately identify patients who would benefit from treatment with molecularly-targeted anti-cancer therapies.

The study of cell function analysis tells us that even when the disease is the same type, different patients' tumor respond differently to the same agents. A large molecule targeted drug may be more beneficial to some patients than a small molecule targeted drug (sometimes not).

Whatever the percentage of patients benefit from these drugs, the point is, targeted drugs are not for everybody. Pre-tests can help identify the individual cancer patient the drug works extremely well for, or it can tell that the drug is resistant. It is important to "personalize" cancer treatment, and this can be accomplished by testing the tumor first.

The ordinary trial system will not suffice if we are to encourage new drugs for restricted numbers of patients. More and more physicians and patients are turning to individualized therapies to treat cancers. Without individualized testing the efficacy of these drugs, it's difficult to determine which drugs are best for patients who don't respond to standard therapies.

Literature Citation:
Eur J Clin Invest 37 (suppl. 1):60, 2007
J Intern Med 2008; 264: 275-287

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