[gdpawel]

I’ve been researching cell function analysis for the last 12 years, and even during that period, I’ve come across the resistance mechanism from the so-called trialist system, time and time again. I’ve researched the history of this apprehension; one example coming from NCI’s feeble attempt to study assay-directed therapy of lung cancer some years ago.

The study was a failure because it was done with established permanent cell-lines (instead of fresh cells), which have been conclusively proven to have no predictive value at all with respect to the clinical activity spectrum. The result was a dismal 11% response.

The NCI used “cell-lines” because the major expertise of the investigators who carried out any study was in the creation of cancer cell-lines, and they wanted to see if they could perform assays on these cell lines to use in patient therapy. The results showed they were able to test successfully only 22% of specimens received, including only 7% of primary lesions.

This contrasts with a 75% overall success rate reported by earlier investigators who used the same assay system in “fresh” tumor and a routinely obtained >95% success rate using improved (cell death) methods available today.

The NCI spent $15 million on a single-cell suspension “fresh” tumor assay with cell proliferation (cell growth) rather than cell death as an endpoint. When that didn’t work, they folded their hand and specifically discouraged future applications of cell culture testing in their grant and contract guidelines, dating from the late 1980′s.

They never supported any drug development work based on primary cultures of three-dimensional (3D) cell clusters with cell death endpoints, which very nicely recapitulate known disease specific activity endpoints.

Then later, there were sophisticated programs to discover gene expression microarrays which predict for responsiveness to drug therapy. The NCI had a huge lab working on microarrays to look for patterns of mRNA and protein expression which are predictive of chemotherapy response. They spent 2 years trying to find patterns which correlated using the NCI’s various established ovarian “cell-lines.”

They thought they had something, but when they started to apply them to “fresh” tumor specimens, none of the results in the “cell-lines” was applicable to the “fresh” tumors. Everything they worked out in the “cell-lines” was not worth anything and they had to start over from square one.

However, the limitations and non-applicability of the NCI efforts, failed to realize that the way to identify informative gene expression patterns is to have a “gold standard” and the (cell-death) cell culture assays are by far the most powerful, efficient, useful “gold standard” to have, adding the potential value of the assays to individualize cancer therapy.

It was routine for the NCI to append statements to grant and contract initiative announcements that applications relating to cell culture assays were strongly discouraged. Dr. Daniel Von Hoff (after his failed attempt at old technology cell-proliferation assays) published a paper around 1990 in which he stated that clinical trials of cell culture assays would never be supported. And the cooperative groups have utterly refused to do the studies. Why should they? Five times as much work for much less (financial) reward.

There was an enormous amount of published, peer-reviewed research documenting the “accuracy” of cell culture assays. Scores of studies in thousands of patients. Based on both response and survival, but all of it excluded from the ASCO and insurance industry reviews. And it’s the only evidence existing to validate any other medical test used as an aid in drug selection.

Disallow the introduction of published, peer-reviewed evidence documenting accuracy. While allowing the introduction of hearsay, unstated, undocumented, undescribed, unpublished, unpeer-reviewed non-evidence.

And the fact that “proving” efficacy in one situation would do nothing to prove efficacy in any other situation. This is why the FDA demands clinical trials data showing efficacy for each and every indication relating to drugs.

Let’s say a plan assay-directed clinical trial in relapsed NSCLC proves efficacy. All we prove is that it improves things for one small indication. Relapsed NSCLC, not ovarian cancer. And it gets worse. The year after the close of the study, two new drugs become available and the assay-directed clinical study only proves efficacy with the old drugs. It doesn’t prove efficacy involving the new and improved drugs. A constantly moving target.

So then you say, just go out and get a grant to do another one. Sounds like the Twilight Zone! If NCI can’t do it (a.k.a. Von Hoff), nobody can. And you wonder why some NCI hospital is not doing chemosensitivity tests? Thank goodness for private researchers.

BTW. In the first head-to-head clinical trial comparing gene expression patterns (molecular gene testing) with personalized cancer cytometric testing (also known as functional profiling or chemosensitivity testing), and personalized cancer cytometrics was found to be substantially more accurate (Arienti et al, Journal of Translational Medicine 2011, 9:94).

What the investigators did was to examine the “Target Now” types of targets and compare clinical responses against the results with functional analyses, establishing that when one measures the biology of the disease it provides as more robust prediction of response. The “driver” term is less operative as these genes are not causative of the disease but causative of drug resistance.