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Targeted Cancer Therapy Improved: Chemosensitivity Analysis


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Targeted Cancer Therapy Improved with Ex-Vivo Chemosensitivity Analysis

Researchers at Rational Therapeutics and Todd Cancer Institute (Long Beach, Calif.) have reported clinical results obtained with a laboratory technique (Ex-Vivo Analysis of Programmed Cell Death - EVA-PCD) that accurately identifies patients who are candidates for targeted cancer therapy.

A team led by Robert Nagourney, M.D., laboratory director of Rational Therapeutics and medical director of the Todd Cancer Institute at Long Beach Memorial Medical Center, report that ex-vivo laboratory analysis accurately identified non-small cell lung cancer (NSCLC) patients likely to benefit from the EGFr inhibitor, Erlotinib (Tarceva). The team's findings are published in the official proceedings of the 43rd Annual Meeting of the American Society of Clinical Oncology (ASCO), held June 1-5 in Chicago.

"While targeted EGFr-TKI therapy has proven effective in treating advanced non-small cell lung cancer, response rates remain low in randomly selected patients," said Dr. Nagourney. "We have found that the EVA platform can help doctors select those patients most likely to benefit from the new generation of targeted anticancer therapies."

The researchers used ex-vivo analysis (EVA) to examine tissue from NSCLC patients as part of an IRB-approved assay-directed clinical trial. Patients found sensitive to the EGFr inhibitors received oral Erlotinib at 150mg/day as first line therapy. All of the patients selected responded to this oral therapy, with several achieving long-term remissions. This outcome demonstrates that patients whose cancer cells undergo programmed cell death in the laboratory due to EGFr inhibitor exposure are those who respond to targeted Erlotinib (Tarceva) therapy. The research team's findings are summarized in an abstract titled, "Clinical Responses to EGFr-TKI's Characterized by Drug-Induced Cell Death in Human NSCLC Primary Cultures" (ASCO Abstract # 07-AB-34058-ASCO).

Traditional anticancer drugs are toxic to both cancerous and normal cells. In contrast, targeted anticancer drugs target cancer cells with specific mutations. While such drugs hold promise, their use requires new methods to enable doctors to accurately and consistently identify patients whose particular type of cancer expresses the drug's specific target.

Dr. Nagourney explains, "Efforts to administer targeted therapies in randomly selected patients often result in low response rates at significant toxicity and cost. While researchers continue to develop molecular probes to select candidates, the ex-vivo platform used in this study serves as a functional profile capable of examining the nuances of cellular response to drugs. To exploit the full potential of targeted anticancer therapies, physicians will need laboratory tests that match patients to specific drugs. We believe the EVA PCD platform is such a test."

The Todd Cancer Institute at Long Beach Memorial Medical Center is the first cancer program in the nation to apply assay-directed therapy as the first-line treatment for advanced solid tumors. The Center is currently hosting clinical trials for cancers of the lung, colon, stomach, pancreas and prostate.

One of those has been Phase II assay-directed therapy in previously untreated, measurable, Stage IV NSCLC. Patients who had high activity for erlotinib in vitro and received first line single agent erlotinib had a 100% response rate.


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PET scans were not approved because they saved lives in a controlled clinical trial that compared the outcome of patients who received care with or without the benefit of a PET scan. They were approved because their performance characteristics (sensitivity/specificity) are reporducible, favorable and provide useful information to treating physicians.

Chemosensitivity analyses have performance characteristics that are reproducible, favorable and provide useful information to treating physicians. What's more, this information is a result of a clinical trial in which NSCLC patients underwent an assay as part of a Phase II assay-directed trial (IRB-approved). It so happens that these patients were found more sensitive to Tarceva than to other forms of chemotherapy, all of which were tested for the same $3,500 price.

If costs well in excess of $1,000 to do EGFR mutation and FISH for amplification. All of which tells you whether or not to give Tarceva (one drug). Chemosensitivity analyses more often find NSCLC patients sensitive to other compounds and combinations and can recommend these all from one assay. It costs a lot more to give a single cycle of chemotherapy than it does to test all of the possible options.

The evidence supporting a doctor's use of therapy may be far less solid than the evidence supporting chemosensitivity analysis. If a physician uses chemotherapy for NSCLC, does he/she give second-line chemotherapy to patients with good performance status who fail first-line therapy? If so, there is only one study to support it, Docetaxel. There is also one non-inferiority trial for Alimta. If the physician does anything other, he/she is not adhering to the evidence. I'm sure there are dozens of practices that fail to meet these lofty evidence standards.

As increasing numbers and types of anti-cancer drugs are developed, oncologists become increasingly likely to misuse them in their practice. There is seldom a "standard" therapy which has been proven to be superior to any other therapy. When all studies are compared by meta-analysis, there is no difference. What may work for one, may not work for another.

Cancer chemotherapy could save more lives if pre-testing were incorporated into clinical medicine. The respected cancer journals are publishing articles that identify safer and more effective treatment regimens, yet few community oncologists are incorporating these synergistic methods into their clinical practice. Cancer patients suffer through chemotherapy sessions that do not integrate all possibilities.

The current clinical applications of in vitro chemosensitivity testing is ever more important with the influx of new "targeted" therapies. Given the technical and conceptual advantages of "functional profiling" of cell culture assays together with their performance and the modest efficacy for therapy prediction on analysis of genome expression, there is reason for renewed interest in these assays for optimized use of medical treatment of malignant disease.

The chemotherapy regimen chosen by most community oncologists is based on the type of cancer being treated. However, there are factors other than the type of cancer that can be used to determine the ideal chemotherapy drugs that should be used to treat an individual patient.

It is highly desirable to know what drugs are effective against particular cancer cells before these toxic agents are systemically administered. Pre-testing on "fresh" specimens of cancer cells to determine the optimal combination of chemotherapy drugs could be highly beneficial.

http://weisenthalcancer.com/Patient%20P ... tients.htm

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  • 4 months later...

The "forest and trees" analogy can explained the fact that conventional chemo treatments try to kill "all" cancerous cells (along with non-cancerous cells). The whole forest of cells. The new "targeted" drugs go after a "pathway" within or on cancerous cells. Hence the "trees" instead of the "forest."

With "functional" cell-based assays, the "forest" is looked at and not the "trees." There are many pathways to altered cellular (forest) function (hence all the different "trees" which correlate in different situations). The "functional" profiling technique of cell-death assays, measures what happens at the end (the effects on the forest), rather than the status of the individual trees. Cancer is a complex disease and needs to be attacked on many fronts.

Cancer therapy needs to be thought of "outside the box" with "personalized" treatments for "individual" patients, and requires a combination of novel diagnostics and therapeutics. If "some" drugs are working for "some" people (not average populations), then obviously there are others out there who would also benefit. Who are those that would benefit? All the more reason to test the tumor first.

A cell culture assay with "functional" profiling, using a cell-death endpoint, can help see what treatments will not have the best opportunity of being successful (resistant) and identify drugs that have the best opportunity of being successful (sensitive). Cell "function" analysis doesn't claim to have a perfect model, but all retrospective studies have documented that killing cells in the test tube does correlate with dead cancer cells in the patient.

"Funtional" profiling measures the response of the tumor cells to drug exposure. Following this exposure, they measure both cell metabolism and cell morphology. The integrated effect of the drugs on the whole cell (forest), resulting in a cellular response to the drug, measuring the interaction of the entire genome. No matter which genes are being affected (trees), "functional" profiling is measuring them through the surrogate of measuring if the cell is alive or dead.

For example, the epidermal growth factor receptor (EGFR) is a protein on the surface of a cell. EGFR inhibiting drugs certainly do target specific genes, but even knowing what genes the drugs target doesn't tell you the whole story. Both Iressa and Tarceva target EGFR protein-tyrosine kinases. But all the EGFR mutation or amplificaton studies can tell us is whether or not the cells are potentially susceptible to this mechanism of attack.

It doesn't tell you if Iressa is better or worse than Tarceva or other drugs which may target this. There are differences. The drugs have to get inside the cells in order to target anything. So, in different tumors, either Iressa or Tarceva might get in better or worse than the other. And the drugs may also be inactivated at different rates, also contributing to sensitivity versus resistance.

In an example of this testing, researchers have tested how well a pancreatic cancer patient can be treated successfully with a combination of drugs commonly used to fight lung, pancreatic, breast and colorectal cancers. The pre-test can report prospectively to a physician specifically which chemotherapy agent would benefit a cancer patient. Drug sensitivity profiles differ significantly among cancer patients even when diagnosed with the same cancer. One-size-does-not-fit-all.

http://meeting.ascopubs.org/cgi/content ... uppl/17117

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