Precision highlights role of ChemoFx test, multi-gene predictors for breast cancer

[News]

In a new study in which Precision Therapeutics' Multi-Gene Predictors were independently validated by investigators at US Oncology and MD Anderson, Precision highlights the potential role of the ChemoFx® in vitro chemosensitivity test and multi-gene predictors in determining a patient's likelihood of response to multi-drug chemotherapy regimens in breast cancer.

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[gdpawel]

Precision Therapeutics Announced A New Tumor Profiling Product To Augment Utility Of ChemoFx And Further Personalize Cancer Treatment

Precision Therapeutics, Inc. announced that the launch of a new product line, BioSpeciFx, will help further the personalization of cancer treatments. BioSpeciFx is composed of carefully selected sets of well validated and clinically useful biomarker tests that identify critical molecular targets within a patient's cell. By using the information generated by BioSpeciFx in combination with Precision's sophisticated drug response marker ChemoFx, physicians may gain a more complete understanding of a patient's tumor.

When combined, both products offer a complementary sum of information which will enable physicians to look at both the relevant molecular targets as well as the synergistic activity of drug combinations on the entire cell. BioSpeciFx provides proteomic and genomic information, while ChemoFx takes into account all of the functional characteristics of a tumor including those not captured by biomarker testing, providing both sensitivity and resistance information.

"The Comprehensive Tumor Profile developed by Precision presents the most complete offering available to cancer patients today, because it integrates both genomic and proteomic information with the functional profiling of ChemoFx," says Sean McDonald, CEO of Precision Therapeutics. "We are very excited to provide physicians with a closer look at each patient's tumor as we continue to develop products aimed at personalizing treatments for cancer patients."

Source: Precision Therapeutics

Precision Therapeutics is using ChemoFx as a complement to BioSpeciFx. They run ChemoFx on a population of tumors (i.e. breast cancer). They identify the responsive, intermediately responsive, and non-responsive patients. Then they take the molecular markers and find out what these patients have in common with respect to 150 different genes. Then they work on eliminating the genes that are irrelevant.

What they get is a multi-gene predictor. It can't work without ChemoFx working. They claim their MGP for breast cancer is accurate 85% of the time according to MD Anderson and US Oncology. Each drug has it's own signature, but couldn't happen if ChemoFx wasn't accurate. ChemoFx is the backbone of MGP. The oncologist can pick and choose which markers he/she wants to see.

[Rich66]

But hey...
Isn't this using genomics in addition to in vitro sensitivity testing? Seems like it is an attempt to build upon in vitro chemosensitivity tests. Maybe an indirect acknowledgement of the fundamental value of sensitivity testing.

[gdpawel]

There have been attempts to develop molecular-based tests to examine a broader range of chemotherapeutic drugs. New technologies for measuring the expression (biological activity) of literally hundreds to thousands of genes as part of a single test. There are two main technologies involved: RT-PCR (reverse transcription polymerase chain reaction) and DNA microarray.

The main reason why the functional profile platform has not focused upon genomic analyses is that cancer is more complex than its gene signature.Contained within the genes of each human is the information to create every protein, every enzyme, every lipid, every carbohydrate and all the organs and systems dependent upon their function. What is not known is how all of those 25,000+ genes are regulated to produce the unique features that constitute us as human entities.

As one of the researchers in the functional profile platform describes it, from the moment of conception, when the male and female genetic materials are fused into what is known as a zygote, our informatics are established. What enables that single cell to become the multi-trillion-cell organism that we recognize as human is not the gene, but the gene regulation. The informatics are static — the regulation is highly fluid.

Simply exploring the information contained within the human cell provides you with a blueprint of what may be, but no clear evidence that the outline structure will ever come to be in all of its functional complexity. In this regard, genomic analyses cannot approximate the vagaries and manifold variations that define us as individuals.

To look at this a different way, we can describe genetic information as 'permissive', that is it tells you what you may or may not become. Functional information is 'predictive', it tells you exactly what you are. The functional profile platform has moved away from genomic analyses for the very reason that they provide only a veneer of information. The substance of cancer, its responsiveness to therapeutics and its ultimate cure, require a more definitive analysis. By studying human cellular behavior within the context of vascular, stromal and inflammatory elements, the functional profiling platform provides the closest approximation of human biology possible.

Human beings are demonstrably more than the sum of their genes. Cancer biology and the study of cancer therapy are many things, but simple is not one of them. Complex problems require solutions that incorporate all of their complexities, however uncomfortable this may be for genomic investigators.

Hence the headlong rush to develop tests to identify molecular predisposing mechansims 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.

Genetic profiles are able to help doctors determine which patients will probably develop cancer, and those who will most likely relapse. However, it cannot be suitable for specific treatments for "individual" patients. The NCI has concluded (J Natl Cancer Inst. March 16, 2010), it cannot determine treatment plans for patients. It cannot test sensitivity to any of the targeted therapies. It just tests for "theoretical" candidates for targeted therapy.

[Rich66]

we can describe genetic information as 'permissive', that is it tells you what you may or may not become. Functional information is 'predictive', it tells you exactly what you are.

Ok..might there be some value in knowing what the current sensitivity is while trying to discern what the cancer might be permitted to do? i.e. the road it's on now and what roads lie ahead??

[gdpawel]

The problem is in gene sequencing. Sequencing the genome of cancer cells is explicitly based upon the assumption that the pathways - network of genes - of tumor cells can be known in sufficient detail to control cancer. Each cancer cell can be different and the cancer cells that are present change and evolve with time. Cancer cells often have many mutations in many different pathways, so even if one route is shut down by targeted treatment, the cancer cell maly be able to use other routes.

In other words, cancer cells have "backup systems" that allow them to survive. The result is that the drug does not shrink the tumor as expected. The cancer state is typically characterized by a signaling process that is unregulated and in a continuous state of activation.

A challenge facing pharmacogenetics is the number and complexity of interactions a drug has with biological molecules in the body. Variations in many different molecules may influence how someone responds to a medicine. There is a great degree of variation in how people absorb drugs. Individuals have different levels of enzymes in the intestines and liver that breaks down drugs before they even have the chance to get into the bloodstream. Teasing out the genetic patterns associated with particular drug responses could involve some intricate and time-consuming scientific detective work.

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. Given the technical and conceptual advantages of the functional profiling platform, together with its performance and the modest efficacy of therapy prediction based on analysis of genome expression, there is reason for a renewal in there interest for optimized use of medical treatment of malignant disease.

The NCI has concluded, gene-guided chemotherapy (gene signatures) cannot determine treatment plans for patients. It cannot test sensitivity to any of the targeted therapies. It just tests for theoretical candidates for targeted therapy. And due to almost all patients being treated with combination chemotherapy, the molecular profiling methodology cannot even be calibrated without the use of cell-based functional profiling analysis. Cell-based functional profiling can actually integrate all the gene expresslion into one convenient test result.

[Jackie07]

One of the 'legendary' leaders in 'Ancient' China, the one who's said to have taught the Chinese people 'agriculture' (advancing from a hunter/gatherer society), used 'slaves' (enemy combatants captured in warfares) to test the effectiveness of hundreds of different types of herbs. [Legend has it that he had tasted 365 different kind of 'plants' himself and found 100 that were effective in treating different types of ailment. And he eventually died from eating a poisonous plant. But anthropologists believe it was a story about the transformation of the society after effective ways of making fire and building shelters were invented.]

Functional profiling sounds like a modern, more effective and humane way to test the effectivenss of availalbe chemo agents...

Another analogy might be that Multi-Gene Predictors is used as a main frame computer and Functional profiling is used like a personal, notebook computer...

I need to turn in ...

[gdpawel]

It's interesting that you brought up about the legendary leaders in China testing the effectiveness of herbs.

Ralph W. Moss' new book, "Customized Cancer Treatment" talks functional profile. He makes a very good case for drug sensitivity tests to see which drugs will work best. He does a tremendous job turning over every single stone why The Test (as he calls it in the book) has struggled to gain acceptance in the billion dollar cancer medicine industry, and putting together in one book all of the research I've ever read over the last decade about cell culture assays.

I was intrigued by Moss' association of cell culture assays and CAM in the final conclusions of the book. He feels that there are many treatments of natural origin that have been proposed as candidates for cancer therapy. Some of these may have great value. He reminds us that about one-quarter of all chemotherapeutic agents had a natural origin.

Moss feels that cell culture assays, when applied to CAM, would provide a similar service as it does to chemotherapy and could become the ultimate guide to choosing treatments that are likely to work and avoiding those that do not, at least in terms of causing programmed cell death (apoptosis).

He points out that at the present time, none of the American chemosensitivity laboratories "routinely" screens natural agents, although one of them has communicated to me that on occasion, they have screened such agents if the patient and physician explicitly requests it and provides a sample.

Moss feels that there is no reason that other labs could not and would not do this sort of CAM testing if the cell culture assays were made routine. Not all CAM treatments work by means of stimulating programmed cell death, but those that do could be discovered via the assay.

http://www.amazon.com/Customized-Can.../dp/1881025012

[gdpawel]

As Dr. Robert Nagourney, medical and laboratory director at Rational Therapeutics, and instructor of Pharmacology at the University of California, Irvine School of Medicine describes it, recent press coverage from the San Antonio Breast Cancer Symposium (SABCS) touched upon the development of multi-gene predictors for clinical response in breast cancer.

One report from that meeting described correlations between a laboratory assay model in use at the University of Pittsburgh and microarray analyses. However, the suggestion that this laboratory technique - described by its proponents as a chemosensitivity assay - could accurately identify gene profiles that would predict response seems at odds with the current literature.

Although the press coverage concluded that this technique showed “promising performance” it was largely exploratory and defined by the authors as a “validation study.”

What is interesting is that a team of highly reputable investigators from M.D. Anderson recently reported a very negative study using a similar approach of identifying target genes in cell lines and then correlating them with patient outcomes.

In the paper, published in the June 2010 issue of Breast Cancer Research and Treatment (Liedtke, C. et al. Breast Cancer Res Treat. 2010 Jun; 121(2):301-9) the authors reported “cell line derived predictors of response to four commonly used chemotherapy drugs did not predict response accurately in patients.”

Indeed, differential gene expression seemed only to correlate with paclitaxel. The authors found that false discovery rates were high for all other drugs tested. Thus, the report from the SABCS will need to be carefully examined to determine whether truly relevant clinically predictive information can be provided by this particular laboratory platform.

[Rich66]

differential gene expression seemed only to correlate with paclitaxel

In the grand tradition of glass half full/better than nothing, this might be helpful to those facing Taxol recommendation that don't have a tissue sample for functional profiling/chemosensitivity assay.

[gdpawel]

Precision Therapeutics is in no way abandoning ChemoFx, but looking at BioSpeciFx as a complement to the assay.

They run ChemoFx on a population of tumors, say in breast cancer. They identify the responsive, intermediately responsive, and nonresponsive patients. Then take the molecular markers and find out what these patients have in common with respect to 150 different genes.

Then they work on eliminating the genes that are irrelevant. What they get is a multi-gene predictor. It can't work without ChemoFx working. The BioSpeciFx for breast cancer is accurate 85% of the time according to MD Anderson and US Oncology. Each drug will have it's own signature, but it couldn't happen if ChemoFx wasn't accurate. ChemoFx is the backbone of BioSpeciFx.

The thing that is unique about BioSpeciFx, is that the oncologist can pick and choose which markers he wants to see. An ala carte selection if you will. According to Precision Therapeutics, Caris' Target Now does not do this. In fact, they are running 100-120 different markers, and charging for each one, with relatively no clinical relevancy to justify this.