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January 26, 2005

QUALITY: Pawelski's out of line in accusing the NCI by Oren Grad

Oren Grad, a physicians and an independent consultant whose work focuses on policy and strategy in the health sciences, didn't think much of what Greg Pawelski said yesterday on THCB about cancer research being aimed at the wrong things. Nor did he much appreciate the way that he said it. Again, I'm no expert in these issues and, although I have some sympathy with the position that we do too much at the margin in oncology that promotes the profit of the oncologists rather than of the patients, I understand that this is a very, very delicate area. Greg has good reasons for holding his positions, but here's Oren's explanation of why he's wrong.

I have to say that Greg Pawelski's post today on cancer research was annoying. I think he's out of line in both tone and substance, and his "expose" is in fact pretty stale by now.

It's not as if the leadership of NCI aren't very well aware of the issues Greg raises, as well as many more that he doesn't. The CTWG initiative described in these links is but one of several being pushed vigorously by NCI director Andrew von Eschenbach. A lot of very smart, very busy people both within and outside NCI are currently chewing up substantial time figuring out how to adjust NCI's approach to meet today's challenges rather than yesterday's.

From a scientific perspective as well, the implication that Greg's found magic answers that are being scandalously overlooked is way off base. Both metastasis and ways of individualizing treatment are very much on people's minds, and will, appropriately, see increased research effort in coming years. Only time will tell whether the insights brought by these efforts will in fact pan out in improved patient outcomes. Cancer is fundamentally a very hard problem.

It's certainly difficult to redirect a large public agency like NCI quickly. But as a long-time observer of cancer research policy and bureaucratic politics, I do think that as the current initiatives play out we can expect to see changes that will help NCI respond more effectively to new scientific findings and opportunities.

January 26, 2005 in Quality | Permalink


In an era of ever increasing numbers of partially effective cancer treatments, there is an obvious need for technologies to better match treatment to a patient. In the field of chemosensitivity testing, there is substantial literature that has not been recently reviewed and which the vast majority of clinical oncologists are not familiar. Clearly, more effective therapies are desperately needed; we should look for other avenues of study.

It is time to set aside empiric one-size-all treatment in favor of recognizing that various forms of cancer represent heterogenous diseases, where the tumors of different patients have different responses to chemotherapy. It requires individualized treatment based on testing the individual properties of each patient's cancer.

Posted by: Gregory Pawelski | Mar 6, 2005 9:56:45 PM

Dr. Andrew C. von Eschenbach was tapped as the new acting chief of the FDA. It is Dr. von Eschenbach's belief that now, doctors treat illnesses based on how well other people have responded to a given treatment. However, soon they will develop a tailored response built around specific understandings of the patient, the treatment and the disease.

"We are discovering so much about diseases like cancer at the molecular level," he says, "which will lead us to a new kind of health care." He feels much of what has been done, has been based on a model of "empiricism." He goes on to say, "doctors will be able to intervene with medical treatments more effectively matched to a specific patient's illness." Dr. von Eschenbach says he will prepare the FDA for this transformation, as one of his goals.

More and more physicians and patients are turning to individualized therapies to treat cancers. 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.

Treatments need to be individualized based on the unique set of molecular targets produced by the patient's tumor, and these important treatment advances will require individualized cell culture assay testing which can improve patient survival in chemotherapy for cancer. Assay-directed chemotherapy is an individualized approach to killing cancer.

It is time to set aside "empiric" one-size-fits-all treatment in favor of recognizing that breast, lung, ovarian and other forms of cancer represent heterogenous diseases, where the tumors of different patients have different responses to chemotherapy. It requires individualized treatment based on testing the individual properties of each patient's cancer.

Posted by: Gregory D. Pawelski | Sep 26, 2005 11:47:43 PM

I revisit this posting by Oren Grad that still shows up on Google, to express not only wasn't I out of line then, but I'm still not out of line now, three years later.

The headlong rush to develop pre-tests (companion diagnostics) to identify molecular predisposing mechanisms still does not guarantee that a cancer 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 cancer agents of the same class.

The drug discovery model over the last three years or so has been limited to one gene (protein), one target, one drug. The "cell" is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyse the systems' response to drug treatments, not just one target or pathway.

With all the hoopla of decoding the human genome in 2000, sparked hopes that a new era of tailored medicine was just around the corner. However, uncovering the genetic differences that determine how a person responds to a drug, and developing tests, or biomarkers, for those differences, is proving more challenging than ever. As a result, patients with cancer are still being prescribed medicines on a trial-and-error basis.

The key to understanding the genome is understanding how cells work. The ultimate driver is "functional" pre-testing (is the cell being killed regardless of the mechanism) as opposed to "target" pre-testing (does the cell express a particular target that the drug is supposed to be attacking).

While a "target" test tells you whether or not to give "one" drug, a "functional" pre-test can find other compounds and combinations and can recommend them from the one test.

The core of "functional" testing is the cell, composed of hundreds of complex molecules that regulate the pathways necessary for vital cellular functions. If a "targeted" drug could perturb any one of these pathways, it is important to examine the effects of the drug within the context of the cell. Both genomics and proteomics can identify potential new thereapeutic targets, but these targets require the determination of cellular endpoints.

Cell-based "functional" pre-testing is being used for screening compounds for efficacy and biosafety. The ability to track the behavior of cancer cells permits data gathering on functional behavior not available in any other kind of testing.

Gene profiling tests, important in order to identify new therapeutic targets and thereby to develop useful drugs, are still years away from working successfully in predicting treatment response for "individual" patients. Perhaps this is because they are performed on dead, preserved cells that were never actually exposed to the drugs whose activity they are trying to assess.

It will never be as effective as the cell "function" methodology, which has existed for the last twenty years and is not hampered by the problems associated with gene expression tests. That is because they measure the net effect of all processes within the cancer, acting with and against each other in real-time, and it tests "living" cells actually exposed to drugs and drug combinations of interest.

It would be more advantageous to sort out what's the best "profile" in terms of which patients benefit from this drug or that drug. Can they be combined? What's the proper way to work with all the new drugs? If a drug works extremely well for a certain percentage of cancer patients, identify which ones and "personalize" their treatment. If one drug or another is working for some patients then obviously there are others who would also benefit. But, what's good for the group (population studies) may not be good for the individual.

Patients would certainly have a better chance of success had their cancer been chemo-sensitive rather than chemo-resistant, where it is more apparent that chemotherapy improves the survival of patients, and where identifying the most effective chemotherapy would be more likely to improve survival above that achieved with "best guess" empiric chemotherapy through clinical trials.

It may be very important to zero in on different genes and proteins. However, when actually taking the "targeted" drugs, do the drugs even enter the cancer cell? Once entered, does it immediately get metabolized or pumped out, or does it accumulate? In other words, will it work for every patient?

All the validations of this gene or that protein provides us with a variety of sophisticated techniques to provide new insights into the tumorigenic process, but if the "targeted" 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, it just isn't going to work.

To overcome the problems of heterogeneity in cancer and prevent rapid cellular adaptation, oncologists are able to tailor chemotherapy in individual patients. This can be done by testing "live" tumor cells to see if they are susceptible to particular drugs, before giving them to the patient. DNA microarray work will prove to be highly complementary to the parellel breakthrough efforts in targeted therapy through cell function analysis.

As we enter the era of "personalized" medicine, it is time to take a fresh look at how we evaluate new medicines and treatments for cancer. More emphasis should be put on matching treatment to the patient, through the use of individualized pre-testing.

Upgrading clinical therapy by using drug sensitivity assays measuring "cell death" of three dimensional microclusters of "live" fresh tumor cell, can improve the situation by allowing more drugs to be considered. The more drug types there are in the selective arsenal, the more likely the system is to prove beneficial.

Posted by: Gregory D. Pawelski | Feb 10, 2008 2:12:12 PM

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