functional profiling used to determine treatment

marie77

Functional Profiling is when your Medical Oncologist sends a live biopsy of your Cancer Cells to a pathologist and he treats these cells which are placed on a dish ( in vitro ) directly with diferent chemotherapy and targeted drugs and combinations of chemotherapy and targeted drugs to see which ones are most effective at killing the cancer cells.

The standard of treatment now at most hospitals is to give chemotherapy and targeted drugs to all patients who have the same pathalogy results,  its a one size fits all, yet we know BC is heterogenous and that each BC patients cancer cells are diferent and will therefore respond diferently to diferent drugs

The Functional Profiling advocates claim patients using their system attain better clinical responses. They also claim Avastin has been  shown to work in a small percentage of patients using this system so its worth doing just to test for that.

The cost of Functional Profiling is reasonable and could possibly save insurance companies money in the long run.

Also Functional Profiling seems similar to tests used in preclinical trials which do in vitro tests to determine if a drug is shown effective enough to go on to human phase 1 trials.

Does anyone know if Functional Profiling works and if so why it isn t the standard of care?               Is it possible to combine Functional Profiling with biomarkers

http://www.translational-medicine.com/content/9/1/94

gpawelski

Marie

You have been doing some serious cancer research.

Functional Profiling is when your Medical Oncologist sends a "fresh" live biopsy or tumor specimen to a Laboratory Oncologist. Sending it off to the Pathologist is to establish what is called a "cell-line." Cell-lines have always played an important role in drug screening and drug development, the problem is that cell-lines do not predict for disease or patient-specific drug effects. You can kill breast cancer cell-lines with a given drug, it doesn't tell you anything about how the drug will work in real world, clinical breast cancer (real-world conditions). But you can still learn certain things about general drug biology through the study of cell-lines.

http://cancerfocus.org/forum/showthread.php?t=3702

The Laboratory Oncologist receives an ice cold tumor or biopsy, straight from the patient (just as good as an ice cold kidney, straight from a patient). They isolate 3D (three-dimensional) cell clusters, straight from the tumor, exactly as they were in the patient, add the drugs (conventional and/or targeted) shortly after the tumor is re-warmed to body temperature, and then measured whether the drugs kill the tumor, in comparison with extensive databases of tumors with similar characteristics (apples to apples comparisons).

Gene tests attempt to figure out the "recipe" for your cancer. If it turns out that you have a certain mutation, statistically you may be more likely to respond to a particular treatment. But that is only based on statistics - what worked for other people with a similar cancer recipe.

A functional profile assay uses a freshly biopsied piece of your tumor and throws all the various anticancer drug agents at it to see which ones actually cause the most cancer cells to commit suicide (cell death or apoptosis). The drugs are ranked on their actual effectiveness. The most active is the drug you want to go with. It is a "real time" analysis of how your cancer cells are most likely to respond. No statistics and no guessing. Nothing is "grown" in the petri dish.

You do have to undergo a tissue biopsy in order to have a big enough sample to be tested. The reason this is important is that cancer cells don't grow in a vacuum. How they live or die has a lot to do with the chemistry and other biological functions that go on in your own body, so the cancer cells must be kept in a cluster and tested alive as if they were still inside you. You would have to arrange the biopsy through your oncologist or other doctor. The sample would then be sent to the lab for testing. It usually takes a week to get the results.

A functional profiling assay helps you and your doctor determine which anticancer drugs will most likely work best for you as an individual. The reason so many people suffer from chemotherapy is that treatment usually follows a "standard protocol" and many patients have to try 2 or 3 kinds before one works, making them sicker in the process.

The Translational Medicine url address you have supplied is published results of the first head-to-head clinical trial comparing gene expression patterns with functional profiling. Functional profiling was found to be substantially more accurate.

http://cancerfocus.org/forum/showthread.php?t=3490

Laboratory Oncologists are working with the GOG people to establish America's first head to head randomized clinical trial of Physician's Choice vs Molecular Profiling vs Functional Profiling.

http://cancerfocus.org/forum/showthread.php?t=3614

In regards to a biomarker for Avastin or any other anti-angiogenesis compound to better help choose which patients would be most likely to respond, thereby avoiding the need to treat everyone to gain a benefit in a few.

http://cancerfocus.org/forum/showthread.php?t=3566

In regards to a new generation of clinical trials that could help determine if a drug is shown effective enough for a patient to go on to human Phase I trials.

http://cancerfocus.org/forum/showthread.php?t=369

And one of your most important questions, why it isn't the standard of care.

http://cancerfocus.org/forum/showthread.php?t=3442

Greg

marie77

Thanks for the info

I was told they cannot test for Herceptin or Pertuzamab because these are

large monoclonal antibodies, to large to penetrate the 3 D structured cell clusters,

but they can test with Afinitor, Avastin and most of the other BC drugs

Does this seen right.

Do you think TDM1 will be to large to test.

Also if functional profiling can determine which of the small per centage of B C patients will respond to  Avastin , then why doesn t Roche pay to have a clinical trial performed using this test .

If this was successful the FDA could approve Avastin for those B C patients that were shown postive on a functional profiling test. This would be their new Biomarker.

Also functional profiling indicates some times off Label drugs are effective.This is another reason why you would think  Pharmaceutical companies would want to sponsor clinical trials using functional profiling

I don t understand why they are delaying a clinical trial to establish the effectiveness and accuracy of Functional Profiling, especially since theres quite a few highly acclaimed Medical Oncologists using it

cp418

I suspect it has to do with how much they would profit from the results.  My guess it would cost $$$$$ to run the clinical trials to identify a small population of patients who would benefit.  Also off label drugs are not a priority to these companies IMO.  Doctors and patients have to push for these better medical advances.

gpawelski

CP

Profit from the test has something to do with it. The drug discovery model over the last number of years has been limited to one gene/protein, one target, one drug. This area was ripe for proprietary tests, invented alongside the drug and owned by the drug developer and/or a partner in the diagnostics field.

This business opportunity evolved as more drugs were approved with companion diagnostics. 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.

With gene testing all the rage, the two biggest makers of DNA sequencing equipment are trying to snap up smaller players in an attempt to stake out a market expected to reach $8 billion by 2014 and $25 billion within a decade. Roche wants part of that market!

Marie

No! That does not seem right! I don't know who tried to tell you functional profiling cannot test for Herceptin (trastuzumab) or Perjeta (pertuzumab).

By examining drug-induced cell death events in native-state 3D (three dimensional) microclusters, the functional profiling platform has the unique capacity to capture stromal, cytokines (chemokines), macrophages, lymphocytes, vascular and inflammatory cell interactions with tumor cells, known to be crucial for clinical response prediction.

The microclusters recapitulate the human tumor environment, while the "3D" advancement recreates the extracellular matrix. The platform studies cancer response to drugs within this microenvironment, enabling it to provide clinically relevant predictions. It is this capacity to study human tumor microenvironments that distinguishes it from other platforms in the field.

Functional profiling analyses measure biological signals rather than DNA indicators, which provides clinically validated information and plays an important role in cancer drug selection, but this has nothing to do with regard to measuring large molecules or small molecules. It can measure both, providing the drug give strong cell-death signals.

Yes. T-DM1 is a large molecule drug and does not cross the blood-brain barrier (BBB). I've read on the BC boards suggesting give patients some straight Herceptin, which some thought would cross the BBB and give a certain amount of protection. However, the only way for that to happen is a patient may have to be subjected to an "intrathecal" injection of T-DM1. Herceptin does not cross the BBB because it is a large molecule drug. T-DM1 can be tested, if and when made available.

http://cancerfocus.org/forum/showthread.php?t=3768

I also remember some BC board members trying to say that the functional profiling platform could not test the PARP inhibitors. The PARP inhibitors are not new to the functional profiling technique. These Laboratory Oncologists have been interested in them since 1988. PARP inhibitors are easily studied and provide interesting signals in the tissues studied. They have seen activity in BRCA+ patients and some triple negative breast cancers. And they also identified synergy with other classes of drugs. The compounds continue to be actively studied in the cell-based functional profiling platform.

http://cancerfocus.org/forum/showthread.php?t=3383

With regard to Afinitor (everolimus) and Torisel (temsirolimus), both rapamycin derivatives that target mTOR. Unlike drugs that target a specific tyrosine kinase, mTOR is a complex and multifaceted target. According to Laboratory Oncologists, they have found that there are actually two separate forms of mTOR: TORC1 and TORC2, and they sit at a critical point in cellular determination. Stimulated by the insulin growth pathway, cells must decide whether they will grow in size or divide. The mTOR proteins participate in this process by regulating protein synthesis and glucose uptake among other functions. In turn, the mTOR pathway is regulated by numerous other factors like AMP kinase and AKT. The current crop of mTOR inhibitors all target TORC1.

New classes of compounds are being developed that inhibit both TORC1 and TORC2. More interesting are the compounds that influence upstream signaling, including phosphoinositol kinase (PI3K) and AKT. What they are coming to learn, however, is that these are not targets but collections of targets. Indeed, the PI3K inhibitors themselves have influence on one, two or all of the distinct classes of phosphoinositol kinases.

Most of the studies to date have used compounds that affect all the classes equally (pan-inhibitors). Pharmaceutical companies are now developing highly selective inhibitors of this fundamental pathway. In addition, duel inhibitors that target both PI3K and mTOR are in clinical trials. What they are coming to realize is the complexity of these pathways. And can be very much studied in the functional profiling platform.

The AngioRx Assay is a functional profiling biomarker for Avastin or any other anti-angiogenesis compounds to better help choose which patients would be most likely to respond to them. One of the biggest challenges with VEGF (vascular endothelial growth factor) therapy has been the lack of a predictive biomarker. Well, here it is! (Biomarker for Avastin - above).

Pharmaceutical companies sponsoring clinical trials using the functional profiling platform? LOL! They do not want to be sponsoring clinical trials if their competitors drugs may turn up showing to be more beneficial. They want what I describe above about "companion diagnostics" (one gene/protein, one target, one drug).

One of the major reasons why the clinical trial establishment (a.k.a. ASCO above) is the direct competition with clinical trials. If the functional profiling platform would be proven effective, why have clinical trials. Think about it!

Laboratory Oncologists have been working on a (battle-of-the-bands) three-armed clinical trial: Physician's Choice vs Molecular Profiling vs Functional Profiling. Perhaps cancer patient advocate can help speed up this process with some advocacy action? I've been plugging this idea with the powers-that-be for a decade now. I can use some help!

http://cancerfocus.org/forum/showthread.php?t=3614

Greg

marie77

This is an Oct, 2012 clinical trial done on Lung Cancer which showed Function Profiling more then doubled response rates and almost doubled overall survival , which I believe is in line with other studies.

Also, Drs that use Functional Profiling believe having access to phase 1 and 2 drugs for functional profiling tests,as well as doing new biopsies after each recurrence would increase these positive results much more.

http://www.news-medical.net/news/20121008/Functional-profiling-using-EVAPCD-doubles-response-rate-and-improves-survival-in-NSCLC-patients.aspx

marie77

Hi Greg

Could you tell me please if the 60 cell lines used by the NCI in this trial are similar to the cell clusters used in Functional Profiling tests and as accurate

http://medicalxpress.com/news/2012-11-scientists-combinations-cancer-drugs-effective.html

Also I heard that many recent trials have been discredited because researchers

used the wrong cell lines eg breast cancer researchers were mistakenly

sent melanoma cell lines, are you familiar with this mix up, and how it can

happen

gpawelski

Marie

Short answer to your question is no and no.

Many more than 60 cell-lines are probably needed to create accurate in-vitro models of drug response. But even 500-1000 cell-lines will not create accurate in-vitro models of drug response. Traditionally, in-vitro (in lab) cell-lines are studied in two dimensional (2D) monolayers, which has inherent limitations in applicability to real life three dimensional (3D) in-vivo (in body) states (which functional cytometric profiling does). 

Established cell-line is not reflective of the behavior of "fresh" live tumor cells in primary culture in the lab, much less in the patient. You get different results when you test passaged cell-lines compared to primary, fresh tumors. You can't use cell-blocks at a later date. Researchers have pointed to the limitations of 2D cell-line study and chemotherapy to more correctly reflect the human body.

When cells are pre-cultured in monolayers, the assay endpoint is detachment of cells from the surface of the culture plates, which corrlates with with loss of viability. However, when monolayer assays are testing a subcultured cell population, studies by the NCI Navy medical oncology branch did not find that monolayer assays performed on pre-cultured, pre-amplified tumor cells clearly gave clinically relevant results.

Studies by Teicher and Kerbel in mouse tumors showed that in vitro drug activity correlated with in vivo drug activity when tumors were tested in vitro as three dimensional clusters, but not when they were tested in two dimensional monolayers.

Cancer is already in 3D conformation. Fresh "live" cancer cells need to be profiled in 3D conformation. Due to their enormous potential, 3D tumor cultures are currently being exploited by many branches of biomedical science with therapeutically orientated studies becoming the major focus of research. Recent advances in 3D culture and tissue engineering techniques have enabled the development of more complex heterologous 3D tumor models.

What I read about contaminated cell-lines was a cancer researcher's reporting to a journal about studying the wrong cell-lines. I understand this reporting entered a largely secret fellowship of scientists whose work had been undermined by the contamination and misidentification of cancer cell-lines used in research labs around the world.

It was a problem hiding in plain sight. I understand that warnings to properly test cancer cell-lines have sounded since the 1960s, a decade after scientists started making human cancer cell-lines. Now I can understand why (when I found out years ago) established cell-lines have been a huge disappointment over the decades. Thanks in connecting the dots for me!

Greg