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Small quick trials may help shape the development of new drugs.
New clinical-trial results offer not just a modicum of hope for some future cancer patients, but also encouragement for those looking at more efficient techniques for developing new drugs.
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Posted by Oliver Morton on June 04, 2007
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But what happens if the compound does not hit the intended target in patients? Will anybody ever look if it still has a therapeutic effect or will these phase 0 trials be the end of the story? Are there not targeted drugs which show activity on cancer cells which have lost the target? Has the obsession with targeting single cellular molecules not already resulted in too much tunnel vision in drug discovery? Is a cancer not really a family of diseases with complex causes? Is a tumour not a heterogenous mass of cells competing with each other for growth and survival of the fittest. Who really believes that linear thinking and a reductionist approach will lead to a solution of the cancer problem?
Posted by: Burkhard Haefner | June 5, 2007 03:03 PM
Re: Burkhard Haefner
That's just silly. You think we should test potentially dangerous drugs in patients even though we know it doesn't hit the intended target - because there might be a beneficial off-target effect? Why even bother developing drugs then? Just pull every chemical we have of the shelf and administer it to the poor people. It worked for Paul Ehrlich. Of course he only had around a thousand compounds at his disposal and he had a very good animal model of the infectious disease he was working on. But still.
Cancer is a bunch of horrible diseases and like you point out, even in a single tumor there can be great heterogeneity. Genetic instability is in the definition of cancer. Therefore many attempts to kill these cells without killing the patients are unsuccessful (19 in 20 cancer drugs that make it to clinical trials fail).
To develop drugs with fewer side-effects though we have to choose a single molecule to target - even if it's only our best guess that it will have a therapeutic effect.
Personally I think there's a great risk associated with phase 0 trials. You have to be very confident that you don't get any false negatives from your chosen bio-marker.
PS. Survival of the fittest is at best redundant. Evolutionary fitness is a function of survival and other factors. Low survival => low fitness, not the other way around. A more reasonable bon mot would be: Reproduction of the luckiest and best reproducer. It sounds redundant too but it describes evolution much better.
Posted by: Morten Groftehauge | June 5, 2007 07:42 PM
Silly??? Phase 0 is not about toxicity!!! It is about hitting the intended target (pharmacodynamic marker!!!). Why even bother developing so-called targeted drugs is the right question to ask when all they do is to prolong misery for a couple of month (median survival increase without improved quality of life). To give you one example, Tarceva increases median survival of pancreatic cancer patients by two weeks according to a talk by a clinical researcher from Norvatis, I attended. No wonder healthcare systems are increasingly reluctant to pay for such drugs. Look what NICE had to say about Erbitux! You are suffering from the 'targeted therapy mindset', methinks. Give me some examples where targeted therapy has made a major difference in cancer treatment. Gleevec is treting a premalignant condition. When blast crisis sets in, that is it! Velcade has pleiotropic effects due to the protein it targets being involved in the breakdown of many proteins. Moreover, many drugs that do work well do so only because of their "off-target effects". Take an old drug like aspirin! There are new relevant targets found every other year: Cox, IKK, proteasome.
Posted by: Burkhard Haefner | June 6, 2007 12:06 PM
So far, target-oriented drug discovery has been tantamount to aiming chemically at a single molecular entity38. Overall, the outcome of this widely hailed approach has been disappointing.
Jürgen Drews in his essay 'Case histories, magic bullets and the state of drug discovery' in Nature Reviews Drug Discovery August 2006.
Need I say more???
Posted by: Burkhard Haefner | June 6, 2007 12:37 PM
Just one more thing!
In anti-cancer drug
discovery, we are not
so much concerned with
toxicity but with efficacy.
That is where we fall
short of expectations.
Ask Lance Armstrong how
he felt when he was given
platinum drugs. My prediction
is that had targted therapy
been available for him, he
would indeed have suffered
less but he would probably
be long dead.
Posted by: Burkhard Haefner | June 6, 2007 01:24 PM
I think missing potential targets due to tunnel vision will be close to a non-issue. Remember that these are Phase 0 Human trials. These compounds (hopefully) will have been extensively tested previously in animal models, where the biomarkers to be used will have been seen to be positive, and to correlate with efficacy and putative mode of action. So a negative biomarker means that the drug isn't working in humans the way it was in the animal model. We therefore now have no evidence that it will be effective in humans.
This is vastly different than the situation of missing a potential lead in an in vitro assay, where a compound may be active against a target disease, but is not active against the particular enzyme/receptor you're panning against. In the latter you miss a compound because you are looking for the wrong mode of action, but in the former you've extensively characterized your compound and determined the actual mode of action, but you now find out that your assays and model systems are irrelevant to humans.
Phase 0 trials serve to catch, at a very early stage, those cases where our animal models don't accurately recapitulate the actual human disease state.
Posted by: RM | June 7, 2007 12:11 AM
The disease is Interstitial Cystitis (I.C.) of the bladder. The bladder is inflamed and pain worsens when urine fills it. Women are disproportionately afflicted with I.C. Conventional therapy is palliative treatment for an unknown etiology without a cure.
My wife had I.C. Her doctor allowed me to offer a therapy that promotes the production of mucin, a protective glycoprotein on the bladder membrane. Most over the counter products for menstrual discomfort can inhibit mucin production. The trade name drug Cytotec, prostaglandin agonist for gastric ulcer, was chosen because it can increase mucin production. I designed the drug protocol for my wife. After nine months of treatment, she has remained asymptomatic for five years.
It is possible for a drug or drugs to interfere with mucin secretion. An interruption of glycoprotein secretion may expose the lipid bilayer to strong hydrophilic forces. An occurrence of a breach will trigger VEGF and inflammatory mediators’ response or an inflammatory lining disease. One of the downstream signals of VEGF is PI (3) K. Using a prostaglandin agonist to stimulate glycophorin A dimmer will increase mucin secretion. An over expression of g-protein couple receptors will send deactivation signals to VEGF and over expressing PPAR, using nicotinic acid to utilize PLC-γ to increase endothelial nitric oxide synthesis, will downgrade transport for inflammatory mediators. The affected cells will return to normal cell noise, both extrinsic and intrinsic cell noise. Where the actin cytoskeleton is not re-arranged then normal transduction and cargo transport will resume.
The control over VEGF and inflammatory mediators in inflammatory lining disease has potential for other metabolic disorders including cancer. In the situation of cancer, the cells have abandon social-cooperation for self-survival. Cancer cells, probably coerce, have activated a conserved evolutionary gene(s) that allowed the cells to survive when environmental conditions are harsh and toxic. Although independent, the cancer cell still possesses the ability to respond to signals from the community. Therefore, a high frequency signaling induction will arrest VEGF and cytokines, and reestablish normal modulation of extrinsic and intrinsic cell noise, an eventual return to the community.
Drug regiment that I developed for treating I.C. is available upon request.
Sincerely,
Norman A. Smith
normanasmith@cox.net
Posted by: norman a smith | June 7, 2007 07:15 AM
Most cellular and in vivo model systems in anti-cancer drug discovery are everything but predictive for the effect of a drug candidate in patients. This is a widely acknowledged fact in the pharma industry.
Researchers have realized that they may be missing potentially efficacious compounds which have not shown activity in primary in vitro HTS screens in which an isolated protein is targeted. Compounds which are active against isolated proteins in such tests may have completely different activities in cells in which they are facing thousands of different proteins not previously encountered. That is why the industry is moving towards cellular high-content assays as primary screens and worrying about drug targets later. In such assays no single protein is targeted.
It is wrong to believe that on-target automatically means efficacy and off-target toxicity in patients. There is also on target (mechanism-based) toxicity and off-target efficacy (benefitial side effects) possible. Most targeted anti-cancer drugs currently available unfortunately only prolongue life by a few months in a small minority of patients. This is one of the reasons why agencies such as NICE (National Institute for Clinical Excellence) which makes recommendations concerning the reimbursement of drugs by the British National Health Service has in a number of cases recommended that the NHS does not pay for such drugs. They are just not cost effective in their opinion. The message to the industry is: YOU HAVE TO DO BETTER THAN THAT!!! And this is exactly what we are trying to do using innovative new drug discovery strategies and getting away from reductionist dogmas and paradigms which have long passed their sell-by date.
Posted by: Burkhard Haefner | June 7, 2007 12:12 PM
Targeting treatment directly to the tumor cells, sparing healthy cells the worst of chemotherapy's damage. A push in oncology toward protecting patients against drugs and treatments, although successful for some patients, won't work for most others.
However, the tactic of using biopsied cells to predict which cancer treatments can work best for the patient, by taking pieces of "fresh" tumor tissue, apply different chemotherapy treatments to it and examine the results to see which drug or combination of drugs do the best job killing the tumor cells.
Older technology assays failed because scientists looked to see which drugs inhibited the cancer cells' growth (cell-growth), not which chemotherapies actively killed the tumor cells (cell-death). Cancer wasn't growing faster than other cells, it was just dying slower. The newer assay technology connects drugs to patients by what "kills" their cells, not by what "slows" them down.
The "functional profiling" technique is a cell-death endpoint assay system in which drug effect upon cancer cells is visualized directly. Photomicrographs of actual tumor cells show the condition of the cells as they are received and enriched in the lab, and also the condition of control cells post-culture.
This discriminates tumor from nontumor cells. The entire contents of each microliter plate well of tumor cells, including controls and each drug at each concentration, are spun onto glass slides, stained cytologically, and retained as a permanent archival record.
In this visualization, the microscopic slides sometime show that the exact same identical individual culture well, shows some clusters have taken up vast amounts of the drug, while right next door, clusters of the same size, same appearance, same everything haven't taken up any of the drug.
So it doesn't matter if there is a "target" molecule in the cell that the targeted drug is going after, if the drug either won't "get in" in the first place or if it gets pumped out/extruded or if it gets immediately metabolized inside the cell, drug resistance is multifactorial. The advantage of "functional profiling" is that it can show this in the "population" of cells.
"Functional profiling" uses a variety of metabolic and apoptotic measurements to determine if a specific drug was successful at killing the patient's cancer cells. The method differs from other tests in that it assesses the activity of a drug upon combined effect of all cellular processes, using combined metabolic (cell metabolism) and morphologic (structure) endpoints, at the cell "population" level, measuring the interaction of the entire genome.
Other tests, such as those which identify DNA, RNA sequences, or expression of individual proteins often examine only one component of a much larger, interactive process. "Functional profiling" measures genes before and after drug exposure. Gene expression profiles measures the gene expression only in the "resting" state, prior to drug exposure.
The "functional profiling" method makes the statistically significant association between prospectively reported test results and patient survival. It can correlate test results which are obtained in the lab and reported to physicians prior to patient treatment, with significantly longer or shorter overall patient survival depending upon whether the drug was found to be effective or ineffective at killing the patient's tumor cells in the laboratory.
This could help solve the problem of knowing which patients can tolerate costly, new treatments and their harmful side-effects. These "smart" drugs do not work for everyone, and a test to determine the efficacy of these drugs in a patient could be the first crucial step in personalizing treatment to the individual.
Posted by: Gregory D. Pawelski | September 18, 2007 06:28 AM
Older technology assays failed because scientists looked to see which drugs inhibited the cancer cells' growth (cell-growth), not which chemotherapies actively killed the tumor cells (cell-death). Cancer wasn't growing faster than other cells, it was just dying slower. The newer assay technology connects drugs to patients by what "kills" their cells, not by what "slows" them down.
Posted by: rapidshare search | March 22, 2009 12:26 PM