Why Herceptin and not Tykerb?

[gdpawel]

Hutchibk. Cells are the most basic structure of the body. Cells make up tissues, and tissues make up organs, such as the lungs or liver. Each cell is surrounded by a membrane, a thin layer that separates the outside of the cell from the inside.

For a cell to perform necessary functions for the body and respond to its surroundings, it needs to communicate with other cells in the body. Communication occurs through chemical messages in a process called signal transduction. The purpose of these signals is to tell the cell what to do, such as when to grow, divide into two new cells, and die.

Targeted cancer therapies use drugs that block the growth and spread of cancer by interfering with specific molecules involved in carcinogenesis (the process by which normal cells become cancer cells) and tumor growth. By focusing on molecular and cellular changes that are specific to cancer, targeted cancer therapies may be more effective than current treatments and less harmful to normal cells.

However, the monoclonal antibodies like Herceptin are "large" molecules. These very large molecules don't have a convenient way of getting access to the large majority of cells. Plus, there is multicellular resistance, the drugs affecting only the cells on the outside may not kill these cells if they are in contact with cells on the inside, which are protected from the drug. The cells may pass small molecules back and forth (in the same way that neighbors can share food).

Exciting results have come from studies of multitargeted tyrosine kinase inhibitors, "small" molecules that act on multiple receptors in the cancerous cells, like Tykerb. The trend has away from the monoclonals to the small molecules, a trend in which new predictive tests may be able to hasten.

Some years ago, GSK had supplied some private cell-based assay labs with small molecule Tykerb so they can work out an assay for it before its impending FDA approval. A variety of metabolic and morphologic measurements were used to determine if it was successful at killing a patient's cancer cells.

Functional profiling can discriminate between the activity of different targeted drugs and identify situations in which it is advantageous to combine the targeted drugs with other types of cancer drugs. It measures over 100,000 genes before and after drug exposure. Gene expression profiles measures the gene expression only in the resting state, prior to drug exposure.

Researchers had put enormous efforts into genetic profiling as a way of predicting patient response to targeted therapies. However, no gene-based test as been described that can discriminate differing levels of anti-tumor activity occurring among different targeted therapy drugs. Nor can an available gene-based test identify situations in which it is advantageous to combine a targeted drug with other types of cancer drugs. Functional profiling tests have demonstrated this critical ability.

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.