Predicting Individuals' Responses To Chemo

There is a headlong rush to develop tests to identify molecular predisposing mechanisms, whose presence still does not guarantee that a 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.

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 with existing ones to target the tumor more effectively. Most cancers cannot be effectively treated with targeted drugs alone.

Paraffin embedded, fixed, minced, or frozen tissue can change over time. One gets more accurate information when using intact RNA isolated from "fresh" living tissue than from using degraded RNA, which is present in paraffin-fixed tissue.

Established cell line is not reflective of the behavior of fresh tumor cells in primary culture in the lab, much less in the patient. You get different results when you test passaged cells compared to primary, fresh tumors. Molecular testing methods detect the presence or absence of selected gene mutations which theoretically correlate with single agent drug activity. Cells are never exposed to anti-cancer agents.

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 cell being killed regardless of the mechanism?

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 3D microclusters. It allows for testing of different drugs within the same class and drug combinations to detect drug synergy and drug antagonism.

The core understanding is the cell, composed of hundreds of complex molecules that regulate the pathways necessary for vital cellular functions. If a targeted drug could perturb any of these pathways, it is important to examine the effects of drug combinations within the context of the cell.

Both genomics and proteomics can identify potential therapeutic targets, but these targets require the determination of cellular endpoints. You still need to measure the net effect of all processes, not just the individual molecular targets.

Literature Citation:

Eur J Clin Invest, Volume 37(suppl. 1):60, April 2007

BMJ 2007;334(suppl 1):s18 (6 January), doi:10.1136/bmj.39034.719942.94