1. Predictive Tests for Targeted Drugs

Several new "targeted" drugs (like Tarceva and Iressa) have been introduced during the last few years. Most of them have been developed for use in solid tumors but some have also emerged for hematological maligancies. These new "targeted" drugs mostly need to be combined with active chemotherapy to provide any benefit and the need for predictive tests for individualized therapy selection has increased.

Unfortunately, the introduction of these new drugs has not been accompanied by specific predictive tests allowing for a rational and economical use of the drugs. Given the technical and conceptual advantages of Cell Culture Drug Resistance Tests (CCDRTs) together with their performance and the modest efficacy of therapy prediction based on analysis of genome expression as published so far, there is reason for a renewal in the interest for CCDRTs for optimized use of medical treatment of malignant disease.

There was a recent study using an angiogenesis assay, describing correlations between cell culture assay results (cell death in response to Iressa exposure) and survival of 31 patients with non-small cell lung cancer who had received extensive prior chemotherapy. These correlations were based on the actual assay results which had been reported, in real time, prospectively to the doctors who had ordered the assay laboratory tests. There were striking correlations between test results and patient survival, not just response (L.Weisenthal Abstract 06-AB-33175-ASCO).

By inhibiting anti-apoptosis with Iressa (or even Tarceva), the cells undergo apoptosis and die. And it is detected at the whole cell level in the cell culture assays and reported out -- prospectively -- that this correlates strikingly with patient survival. Not only is it a very important predictive test, but it is a unique tool for identifying newer, better drugs, testing drug combinations, and serving as a "gold standard" to develop new DNA, RNA, and protein-based tests of drug activity.

Over the past few years, gene expression profiling has been suggested as the best or only way of determining ex vivo drug sensitivity. However, the cliinical application of these DNA content assays have been shown to correlate only with response and not survival. And due to almost all patients being treated with combination chemotherapy, this methodology cannot even be calibrated without the use of CCDRT. CCDRTs can actually integrate all the gene expression into one convenient test result.

In obtaining information from gene mutations (DNA content assays) and/or gene expression (RNA content) it must be realized that DNA structure is only important insofar as it predicts for RNA content, which is only important insofar as it predicts for protein content, which is only important insofar as it predicts for protein function, which is important only insofar as it predicts for cell response, which is only important insofar as it predicts for tumor response and function. In other words, it correlates only with response and not survival, in entirely retrospective (not prospective) studies.

What are the data supporting the use of testing DNA, RNA and Protein expression? Two retrospective studies from two Harvard-affiliated hospitals, showing response, but not survival advantages, with a grand total of twenty six correlations. And a subsequent study, presented in the July 14, 2005 issue of the New England Journal of Medicine from another laboratory that did not show correlations between gene mutations and patient survival (Volume 353:133-144 Number 2).

Source: Human Tumor Assay Journal

Posted at 7:59PM on Jun 2nd 2006 by Gregory D. Pawelski

2. Adapt treatment to the patient

Laboratory screening of samples from a patient's tumor can help select the appropriate treatment to administer, avoiding ineffective drugs and sparing patients the side effects normally associated with these agents.

Under this approach, scientists study how an individual's cancerous cells respond to several drugs. Doctors have learned that even when the disease is the same type, different patients' tumors respond differently to chemotherapeutic drugs.

More and more physicians and patients are turning to individualized therapies to treat cancers. Without individualized testing, it's difficult to determine which drugs are best for patients who don't respond to standard therapies.

Assay-directed chemotherapy is an individualized approach to killing cancer. A method used to determine what precise medications would kill the particular cancer.

Doctors have assumed that stopping cell division would stop cancer, because most cancer cells divide and grow rapidly. But the approach didn't always kill the malignant cells. Cancer isn't a case of cells growing out of control, but of cells refusing to die on schedule.

Assay testing can provide predictive information to help physicians choose between chemotherapy drugs, eliminate potentially ineffective drugs from treatment regimens and assist in the formulation of an optimal therapy choice for each patient.

This can spare the patient from unnecessary toxicity associated with ineffective treatment and offers a better chance of tumor response resulting in progression-free survival.

Preponderance of currently-available evidence argues persuasively in favor of the use of the assays.

Posted at 1:59AM on Jul 25th 2006 by Gregory D. Pawelski

3. July, 2006 has brought lots of good news about various drugs that are being looked at. I have BAC (Bronchoalveolar carcinoma), mucinous variety, and because there is more than one kind of lung cancer I prefer hearing more info (SCLC, NSCLC, BAC, mucinous, non-mucinous etc.) as the treatment does vary. I am on Avastin, Capecitabine, and celebrex.
A search of the internet using the terms - thymidine phosphylase expression - along with the name of a cancer (pancreatic or whatever) finds various sites that say things like "Expression of thymidine phosphorylase (TP) is associated with a poor prognosis in patients with ductal adenocarcinoma of the pancreas".

Then we find the following: "Thymidine phosphorylase is the enzyme that metabolizes 5’-deoxy-5-fluorouridine, an intermediate metabolite of capecitabine, to the active drug 5-fluorouracil". (This happens inside the cancer cell). Gastric cancers often express thymidine phosphylase and even though capcitabines relationship to thymidine phosphylase has been known about since 1998 the FDA just got around to approving it's use for Gastric cancer in July of 2006. Although it is not a panacea, some people's cancer responds dramatically to it's use just as some cancers respond well to other drugs. I suppose it depends on how much TP is expressed.

The point is that TP is a biomarker which indicates the use of certain drugs. Various cancers have various biomarkers and I am hoping that in the very near future the people doing biopsies will start looking for the biomarkers of whatever kind of cancer they diagnose. People with pancreatic, gastric and non small cell lung cancer should have their biopsy tissue examined for TP expression. The amount of TP expressed in my (BAC variety) non small cell lung cancer can vary pretty wildly, but there is always some as versus none in small cell lung cancer which seems to have it's own bio markers which could be used to help indicate which drugs to use. Regardless I like the "drug cocktail" approach because it has proven to work well for HIV patients, speaking of which Kaposi sarcoma also expresses TP quite strongly in some cases which would indicate to me at least the use of capcitabine. Another search finds that hand-foot syndrome is a result of the interaction of thymidine phosporylase and capecitabine. Although vitamin B6 suppresses hand- foot syndrome, one might want to skip the B6 to see how bad the hand-foot gets, keeping in mind that hand-foot has four grades and the last two can be debilitating so one might not want to skip the B6.

Posted at 12:54AM on Jul 27th 2006 by Rodney Eveland