Tuesday, October 7, 2008

Genentech Study Failure Highlights Pitfalls of Cancer Drug Combos

Traditional chemotherapy relies on multi-drug combinations, but combining Avastin and Tarceva to treat lung cancer was no better than using Tarceva alone, a Genentech study found.
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1 comment:

Greg Pawelski said...

The presence of molecular predisposing mechanisms does not guarantee that a targeted drug will be effective for an individual patient. Nor can they, for any patient or even large group of patients, discriminate the potential for clinical activity among different agents of the same class or even the susceptibility to targeted drug combinations.

The challenge is to identify which patients targeted treatment will be most effective. Tumors can become resistant to a targeted treatment, or the drug no longer works, even if it has previously been effective in shrinking a tumor. Drugs are combined to target the tumor more effectively. But most cancer doctors do not know how to detect drug synergy and drug antagonism through drug combinations.

What is needed is to measure the net effect of all processes within the cancer, acting with and against each other in real time, and test living cells actually exposed to drugs and drug combinations of interest. The key to understanding the genome is understanding how cells work. How is the cancer cell being killed regardless of the mechanism.

True synergy is rather uncommon in most adult solid tumors. Most drug combinations in diseases such as cancer are merely additive, where the whole equals the sum of its parts, and not synergistic.

In cases where drugs are only additive and not synergistic, nothing is learned by testing the drugs in combination over what is learned by testing them separately. So drugs in combination are only tested in cases where there is the realistic possiblity of seeing true synergy.

The best combinations are those in which there is true synergy and in which the toxicities of the drugs in the combination are non-overlapping, so that full doses of each drug may be given safely.

The theory behind combination chemotherapy is that you can’t give full doses of all drugs when you give them together. They have overlapping toxicity, which means you need to cut the doses when you give them together, so you get down to “homeopathic” dose levels.

Pharmaceutical companies have been attracted to studies looking at the maximum tolerated dose of any treatments. Cancer sufferers have been taking doses of expensive and potentially toxic treatments that are possibly well in excess of what they need.

Many of the highly expensive targeted cancer drugs may be just as effective and produce fewer side effects if taken over shorter periods and in lower doses. The search for minimum effective doses of treatments should be one of the key goals of cancer research.

Molecular testing methods detect the presence or absence of selected gene mutations which theoretically correlate with single agent drug activity (either Avastin or Sutent). Tests are performed using material from dead, fixed or frozen cancer cells, and are never exposed to anti-cancer agents.

Cell culture testing methods assess the net effect of all inter-cellular and intra-cellular processes occurring in real-time when cells are exposed to anti-cancer agents. Tests are performed using intact, living cancer cells plated in microclusters.

Cell culture methods allow for testing of different drugs within the same class and drug combinations to detect drug synergy and drug antagonism.

October 19, 2008 at 9:23 PM

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