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Gene Known as KRAS

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http://blogs.wsj.com/health/2008/05/30/ ... lenews_wsj

Excerpt from commentary:

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New Bullseye for Cancer Treatment: A Gene Called KRAS

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Among the 5,000 studies being discussed by 30,000 oncologists at this weekend’s meeting of American Society of Clinical Oncology, listen for the buzz over a single gene.

It’s called KRAS, and a growing body of evidence suggests that cancers with the standard form of this gene respond better to an important class of cancer drugs than tumors with a common mutation of the gene. The class of cancer drugs, known as EGFR inhibitors, includes Imclone’s Erbitux and Amgen’s Vectibix, as well as several experimental drugs.

Data from one of the most eagerly awaited studies of the weekend will show how colorectal cancer patients with the KRAS mutation respond to Erbitux, compared to those whose cancer has the standard form of the gene. While those data haven’t been published yet, data from plenty of other KRAS studies on this weekend’s agenda were posted online a few weeks ago — including this one, which suggested Erbitux works better in patients who had the normal form of the gene.

Indeed, searching the ASCO abstracts for KRAS turns up nearly 300 results. (You can sort through them yourself here.

While studies of KRAS are continuing, the industry is already betting that the connection will hold up. In a recent phone interview, Pfizer’s Charles Baum, in oncology R&D, told the Health Blog that the company is testing an experimental drug that blocks EGFR (as well as a few other receptors) in patients who have the standard form of the gene.

And as Dow Jones Newswires notes, drug makers including AstraZeneca are also rummaging through the drawers looking for molecules that may work in patients who do have the KRAS mutation — and who may need alternatives to EGFR inhibitors.

Update: Just today, European regulators recommended that Erbitux be approved as first-line therapy for advanced colorectal cancer — but only in patients who have the standard form of the KRAS gene (sometimes referred to as “wild type”). Here’s the announcement from Merck KGaA, which markets Erbitux in Europe.

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(WSJ, Wall Street Journal, Health, Posted by Jacob Goldstein, May 39, 2008)


The information contained in these articles may or may not be in agreement with my own opinions. They are not posted as medical advice of any kind.

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For decades, scientists have been trying to get around the drug resistance that is characteristic of all cancers. Some say, not a single drug or combination of drugs has succeeded.

The assumption behind all the efforts has been the gene mutation theory of cancer. Mutated genes somehow either cause cancer directly or inactivate genes thought to guard against cancer, the so-called oncogenes and tumor suppressor genes. However, there is no functional proof that the gene mutation theory is correct.

The gene mutation theory of cancer hasn’t yet produced the types of breakthroughs we all want. Everyone in cancer research seems to have centered their attention on gene being the culprit. It would be expected that after more than a century of pursuing this one angle, and the numerous links that have been made, this should have lead to more progress than is presently observed.

Sequencing the genome of cancer cells is explicitly based upon the assumption that the pathways of tumor cells can be known in sufficient detail to control cancer, an assumption that some scientists believe to be false. The assumption that the pathways of tumor cells can be known in a patient with metastatic cancer is logically inconsistent with the reality of tumor cell evolution.

The problem is that a patient with metastatic cancer can have billions of unknown cancer cells disseminated throughout the body at unknown locations. Each cancer cell can be different. And the cancer cells that are present change and evolve with time.

There is another effort in research called the chromosomal theory of cancer. Even if cancers are from the same tissue, and are generated with the same carcinogen, they are never the same. There is always a cytogenetic and a biochemical individuality in every cancer.


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In some cancer cells, Epidermal Growth Factor Receptor (EGFR) triggers uncontrolled cell division (enzyme inhibitor). There are targeted drugs that inhibit EGFR. There are rare patients that respond very well.

However, cancer cells evolve resistance to some of these targeted drugs by multiple mechanisms related to genetic alterations both within the EGFR gene and at other sites.

For example, over-activity of the insulin growth factor signaling pathway can confer resistance (mutations involving the oncogene k-Ras are also associated with resistance).

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.

Targeted therapies are typically not very effective when used singularly or even in combination with conventional chemotherapies. The targets of many of these drugs are so narrow that cancer cells are likely to eventually find ways to bypass them.

Physicians may have to combine several targeted treatments to try an achieve cures or durable responses for more complicated tumors like those that occur in the breast, colon and lung.

These targeted therapies produce limited results because they can help a relatively small subgroup of cancer patients, and tests to pinpoint those patients are needed (and you should know by now where I come from on the matter of pre-tests). With targeted therapy, the trick is figuring out which patients will respond.

We have targeted agents that will do some good, and the challenge is to figure out which patients to give them to. There are targeted assays to match targeted cancer therapies to those cancer patients (EGFRx™ Anti-Tyrosine Kinase Profile).

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Thanks again, Greg. My interest in the above-referenced IFG-R is because it showed such high results for squamous cell. I realize that it (like all the rest of the chemo and targeted therapies) has a short "shelf life" but then so do I, and at this point (given that my tumor and nodes are steadily growing), so long as my quality of life isn't affected, I've no problem with short term solutions (sure beats the alternative :D).


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