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 and Erbitux 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.

Exciting results have come from studies of multitargeted tyrosine kinase inhibitors, "small" molecules that act on multiple receptors in the cancerous cells, like Tyberb and Sutent. Targeted "small-molecule" therapies ruled at the recent annual ASCO meeting of oncologists. The trend is away from the monoclonals to the small molecules, a trend in which a new predictive test may be able to hasten.

The EGRFx (TM) assay is able to test molecularly-targeted anti-cancer drug therapies like Iressa, Tarceva, Tykerb, Sutent and possibly Nexavar, because of being small molecules. The EGFRx (TM) assay relies upon a technique known as Whole Cell Profiling, in which living tumor cells are removed from an individual cancer patient and exposed in the laboratory to the new drugs.

Basically, Whole Cell Profiling measures the response of the tumor cells to drug exposure. Following this exposure, it measures both cell metabolism and cell morphology. The effect of drugs on the whole cell, resulting in a cellular response to the drug, measures the interaction of the entire genome.

A variety of metabolic and apoptotic measurements are then used to determine if a specific drug was successful at killing the patient's cancer cells. The whole cell profiling method differs from other tests in that it assesses the activity of a drug upon combined effect of all cellular processes, using several metabolic (cell metabolism) and morphologic (structure) endpoints, at the cell "population" level (rather than at the "single cell" level).

Other tests, such as those which identify DNA or RNA sequences or expression of individual proteins often examine only one component of a much larger, interactive process. Whole Cell Profiling measures genes before and after drug exposure. Gene Expression Profiles measures the gene expression only in the "resting" state, prior to drug exposure.

FDA Approves Tykerb for Advanced Breast Cancer Patients

http://www.fda.gov/bbs/topics/NEWS/2007/NEW01586.html *** Edited 12/21/2007 6:00:01 PM UTC by gdpawel***

Tykerb (lapatinib) is one of the first oral agents with the potential to compete directly with the IV drugs which is both a high-volume and high-revenue part of office-based practices. Early use of Tykerb will likely be limited to patients whose breast cancer is refractory to Herceptin (trastuzumab). In the longer term, it could supplant or perhaps find a place in combination with Herceptin.

Of course, will patients be able to afford the cost of these drugs? Herceptin's wholesale price on an annualized basis is approximately $45,000 per year. Tarceva, $40,000 per year. Nexavar, $60,000 per year. Avastin, $47,000 per year. Will the price of Tykerb approximate these novel agents or exceed their costs? The problem is not unique to these drugs, but also to all of the new molecularly-targeted agents.

Lee Newcomer, former chief medical officer and currently an executive with United Health Group, stated at the 12th annual conference of the National Comprehensive Cancer Network, that "Avastin improves outcomes in about 20% of patients, but we have no idea which cancer patients will benefit from a course of treatment. Because Avastin is included with numerous drug cocktails, it costs $354,000 per year of life extended with Avastin because of today's 'cookie-cutter' approach to chemotherapy. You don't know in advance who is going to respond."

Everyone is scared to death (and rightly so) at what is going to happen to the healthcare economic system with the introduction of increasingly expensive new drugs that benefit only a small percentage of patients who receive them, hence the 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.

Profit is a powerful motivating force. Among medical benefit payors, the profit motive is entirely consistent with the goal of developing a molecular test, which is to identify efficacious therapies irrespective of drug mark-up rates.

The FDA finds themselves under increasing pressure to allow new drugs into the marketplace, while at the same time protecting the safety of potential recipients of those drugs and also the financial interests of those who will have to pay for them. The pressure is so great that companion molecular diagnostics approved often have been mostly or totally ineffective at identifying clinical responders (durable and otherwise) to the various therapies.

It should be in the FDA's interest in saving the healthcare system perhaps billions of dollars a year (and thereby the healthcare system itself) by ensuring that expensive treatments are used appropriately. It should serve their interest not only in discovering new cancer treatments, but also using currently-available cell culture technologies to improve the effectiveness of existing drugs and save lives today by administering the right drug to the right patient at the right time.

The methods of cancer medicine during the last thirty some years are coming to haunt the "one-size-fits-all" establishment. Technologies, developed over the last twenty years by private researchers, hold the key to solving some of the problems confronting a healthcare system that is seeking ways to best allocate available resources while accomplishing the critical task of matching individual patients with the treatments most likely to benefit them.

*** Edited 6/29/2007 7:22:42 AM UTC by gdpawel***

Although oral tyrosine kinase inhibitors, like Tykerb, offer patients a well-tolerated, conveniently administered alternative to intravenous (IV) therapy, Decisions Resources, one of the world's leading research and advisory firms for pharmaceutical and healthcare issues, found that oncologists are not yet ready to use Tykerb as a replacement for Herceptin. Ninety-one percent of surveyed oncologists stated that intravenous (IV) cancer therapies are more profitable than oral therapies. And fifty-eight percent of oncologists say they would favor IV Herceptin over oral Tykerb because administration of IV drugs remains an important source of income for their practices.Selling cancer chemotherapy with concessions creates conflicts of interest for oncologists

http://www.healthyskepticism.org/news/2007/Jun.php

A precursor to the modern Chemotherapy Concession going on in the United States had been forbidden in Germany since the 13th century, as a result of a very visionary German ruler, Frederick II of Hohenstaufen, Emperor of the Holy Roman Empire of the Germanic Nation, and his visionary law (Edict of Salerno) regarding the separation of the professions of Physician and Pharmacist.

His 1241 Edict of Salerno (sometimes called Constitution of Salerno) made the first legally fixed separation of the occupations of physician and apothecary. Physicians were forbidden to double as pharmacists and the prices of various medicinal remedies were fixed. This became a model for regulation of the practice of pharmacy throughout Europe.

Medical oncologists should be taken out of the retail pharmacy business and force them be doctors again. *** Edited 12/21/2007 6:00:46 PM UTC by gdpawel*** *** Edited 12/24/2007 5:29:17 AM UTC by gdpawel*** *** Edited 12/24/2007 5:30:33 AM UTC by gdpawel***

A recent company-sponsored study showed that Tykerb's blood levels increased by 167% when taken with a low-fat meal, compared with taking the drug on an empty stomach, and by 325% after a high-fat meal.

In a recent editorial in the Journal of Clinical Oncology, researchers ruffled some industry feathers by arguing that taking Tykerb with food (THE LABEL SAYS NOT TO) might allow patients to take lower doses, leading to a potential cost savings of 60% off the drug's $2,900-a-month price tag.

Savings could be about 80% if Tykerb were taken with grapefruit juice, since the drug interacts with an enzyme in the gut (CYP3A4) that breaks down drugs before they enter the bloodstream. People with lots of CYP3A5 may have less medicine enter their bloodstream than people who don't have so much.

Grapefruit juice has a compound that temporarily gets rid of CYP3A4, which allows more of a drug to enter the bloodstream. For people who take statins with grapefruit juice, the drug can build up to unhealthy levels in the body.

Some researchers feel that the grapefruit effect could ultimately allow patients to take lower doses of drugs like Tykerb. With oral oncology therapies being very expensive, this may lower the costs by as much as 50% saving hundreds of millions of dollars.