Targeted drug combos could outsmart cancer

[gdpawel]

By Julie Steenhuysen

CHICAGO (Reuters) - Cancer cells often have a way of outsmarting new targeted drug therapies, but U.S. researchers said on Thursday a combination of targeted drugs could shut down a tumor's backup plan, resulting in much more effective treatments.

A number of these so-called targeted cancer drugs -- such as Roche's Tarceva and Novartis' Gleevec -- work by blocking the activity of various protein switches that tell the cell to grow. They are known as receptor tyrosine kinases or RTKs.

"They essentially allow the cell to communicate with the external world to sense growth factors that could maintain the survival of a cancer cell," said Dr. Ronald DePinho of the Dana-Farber Cancer Institute and Harvard Medical School, whose study appears in the journal Science.

These protein switches are on the surface of all cells, and they go haywire in a number of cancers.

Drugs that target a single switch have transformed the treatment of some patients with certain cancers -- for instance, Gleevec and chronic myelogenous leukemia.

But they only work in a small percentage of people. And certain tumors, including the aggressive brain cancer glioblastoma multiforme, respond poorly to such drugs.

DePinho and colleagues now believe they know why. His team studied 20 different batches of glioblastoma cells in the lab and found that many growth switches were flipped on at once.

In 19 of the 20 cell lines, three or more were switched on. They tested tumor samples from newly diagnosed cancer patients and got a similar result.

"We found there was a multitude of activated receptor tyrosine kinases," DePinho said in a telephone interview. "When you would extinguish one with a specific targeted agent, the other ones would simply step in."

'BROADLY APPLICABLE'

When they tried Gleevec, known generically as imatinib, it had little effect on the cells. But when they combined it with two other drugs -- Tarceva, known generically as erlotinib, and Pfizer's SU-11274 -- the growth signal was shut down and the cancer cells died.

"It's a very important observation scientifically and it has immediate clinical implications," DePinho said. "This is broadly applicable. This paradigm is true for virtually all solid tumors that we've looked at."

He and colleagues hope to start testing combinations of these targeted therapies in patients.

A person's tumors would be profiled first to determine which signals are active, and then doctors would pick a drug combination that would work best.

DePinho said it would take some time to get these therapies to cancer patients because the drugs used in combination might turn out to be toxic.

He agreed that a cocktail of targeted drugs would be costly. Tarceva -- approved to treat lung and pancreatic cancer -- costs around $3,000 for a 30-day supply.

But he said one of the reasons for the drugs' current high cost is the high failure rate of drug development.

"If we can use science ... to design better clinical trials, the costs will be a lot less," DePinho said.

http://www.upmccancercenters.com/new...?article=12573

[gdpawel]

This is a perfect example that it would be more advantageous to sort out what's the best "profile" in terms of which patients benefit from this drug or that drug. Can they be combined? What's the proper way to work with all the new drugs? If a drug works extremely well for a certain percentage of cancer patients, identify which ones and "personalize" their treatment. If one drug or another is working for some patients then obviously there are others who would also benefit. But, what's good for the group (population studies) may not be good for the individual.

Patients would certainly have a better chance of success had their cancer been chemo-sensitive rather than chemo-resistant, where it is more apparent that chemotherapy improves the survival of patients, and where identifying the most effective chemotherapy would be more likely to improve survival above that achieved with "best guess" empiric chemotherapy through clinical trials.

Gene expression means, is RNA being made from the gene. So gene expression assays can be either probing for the specific RNA messengers (messenger RNA) or it can mean looking for the proteins themselves. Like testing cancer for the presence of receptors and over-expression of growth factor receptors. However, most drugs cannot be looked at in this way and tests that are now in use have limited predictive accuracy.

It may be very important to zero in on different genes and proteins. However, when actually taking the "targeted" drugs, do the drugs even enter the cancer cell? Once entered, does it immediately get metabolized or pumped out, or does it accumulate? In other words, will it work for every patient?

All the validations of this gene or that protein provides us with a variety of sophisticated techniques to provide new insights into the tumorigenic process, but if the "targeted" drug either won't "get in" in the first place or if it gets pumped out/extruded or if it gets immediately metabolized inside the cell, it just isn't going to work.

To overcome the problems of heterogeneity in cancer and prevent rapid cellular adaptation, oncologists are able to tailor chemotherapy in individual patients. This can be done by testing "live" tumor cells to see if they are susceptible to particular drugs, before giving them to the patient. DNA microarray work will prove to be highly complementary to the parellel breakthrough efforts in targeted therapy through cell function analysis.

Dr. Ronald DePinho, director of the Center for Applied Cancer Science at the Dana-Farber Cancer Institute and lead researcher of this study, argues for quick movement to clinical trials "that combine three or more such targeted drugs for such cancers to shut down all the malfunctioning growth switches."

Dr. Len Lichtenfeld, deputy chief medical officer for the American Cancer Society, in a response about the Cancer Genome Project, said "We're going to be able to take a cancer specimen, analyze it, and follow those genetic changes that influence particular pathways, then we'll use one, two, three of more "targeted" therapies, perhaps simultaneously, and be able to completely interrupt the flow of the cancer process."

Dr. Arny Glazier, cancer researcher in his book, "Cure: Scientific, Social and Organizational Requirements for the Specific Cure of Cancer," the consistent and specific cure or control of cancer will require multiple drugs administered in combination targeted to abnormal patterns of normal cellular machinery that effect or reflect malignant behavior. It means finding the patterns of malignant cells and develop a set of five to ten drugs in order to cure or control cancer.

I agree! Upgrading clinical therapy by using drug sensitivity assays measuring "cell death" of three dimensional microclusters of "live" fresh tumor cell, can improve the situation by allowing more drugs to be considered. The more drug types there are in the selective arsenal, the more likely the system is to prove beneficial.

As we enter the era of "personalized" medicine, it is time to take a fresh look at how we evaluate new medicines and treatments for cancer. More emphasis should be put on matching treatment to the patient, through the use of individualized pre-testing.

EGFRx™ Targeted Therapy Profile

http://weisenthalcancer.com/Patient%...RXPatients.htm

[Joy]

Thank you so much for posting that!