Gene Expression

Patient’s DNA May Be Signal to Tailor Drugs:

The colon cancer drugs Erbitux and Vectibix, for instance, do not work for the 40 percent of patients whose tumors have a particular genetic mutation. The Food and Drug Administration held a meeting this month to discuss whether patients should be tested to narrow use of the drugs, which cost $8,000 to $10,000 a month.

To some extent this sort of thing is a gimme; intelligent & proactive patients already “help” their medical professionals by channeling them appropriately in terms of decisions because with the veritable tsunami of data no human can truly keep up. One aspect of personalized medicine is population level data. To give an example for myself, my doctor told me that I wasn’t overweight. Well, actually for my population (South Asian) it seems rather clear that heuristics based on BMI normed to European Americans underestimates the risks of conditions heightened at particular weight thresholds (e.g., Type II Diabetes). Combined with family information I’m always trying to keep my BMI on the low end of normal, because there’s normal for one population, and normal for another.

Personalized medicine takes it to the next level. The example above is an obvious one, but what about drug combinations where the differences are on the margins of effect? If you have risks for illnesses a sum of marginal effects is not trivial, but it is probably not realistic to assume that your personal physician will be aware of all these “moving parts.” Welcome to the world where everyone should have a basic familiar with probability and cost vs. benefit, at least if they want to get the maximum bang from the medicinal buck.

Comments

  1. #1 Clark
    December 30, 2008

    I look forward to the day personalized medicine is here. My wife has an awfully weird biochemistry. Drugs that put most people to sleep absolutely wire her. Stuff that wires most people puts her to sleep. Nothing seems to react on her the way it does the majority. It makes taking medicine a bit of a risky event. (Don’t even get me started on what happened when she tried taking birth control pills — complete personality change and delusions)

    I doubt this sort of thing will be significantly available in my lifetime though. Just the testing of such drugs for FDA approval would be breathtakingly expensive and time consuming.

  2. #2 Kevin
    December 30, 2008

    We like to pretend that medicine isn’t subject to the same economic considerations that drive less social choices but there is and will always be a cost/benefit component to medicine. Advances in technology are however driving down the costs of doing personalized medicine and it is inevitable that at some point, no drugs will be prescribed without a personalized predictive analysis of the benefits and side effects to be expected.

  3. #3 Gregory D. Pawelski
    January 4, 2009

    Personalized Cancer Medicine Is Here, Now!

    As we enter the era of “personalized” medicine, it is time to take a fresh look at how we evaluate treatments for cancer patients. More emphasis is needed matching treatment to the patient. 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.

    Findings presented at the Annual Meeting of the European Society for Clinical Investigation in Uppsala, Sweden and the Annual Meeting of the American Assoication for Cancer Research (AACR) in San Diego, CA concluded that “functional profiling” with cell-based assays is relevant for the study of both “conventional” and “targeted” anti-neoplastic drug agents (anti-tumor and anti-angiogenic activity) in primary cultures of “fresh” human tumors.

    Cell-based Assays with “cell-death” endpoints can show disease-specific drug activity, are useful clinical and research tools for “conventional” and “targeted” drugs, and provide unique information complementary to that provided by “molecular” tests. There have been more than 25 peer-reviewed publications showing significant correlations between cell-death assay results and patient response and survival.

    Many patients are treated not only with a “targeted” therapy drug like Tarceva, Avastin, or Iressa, but with a combination of chemotherapy drugs. Therefore, existing DNA or RNA sequences or expression of individual proteins often examine only one compenent of a much larger, interactive process. The oncologist might need to administer several chemotherapy drugs at varying doses because tumor cells express survival factors with a wide degree of individual cell variability.

    There is a tactic of using biopsied cells to predict which cancer treatments will work best for the patient, by taking pieces of live “fresh” tumor tissue, applying different chemotherapy treatments to it, and examining the results to see which drug or combination of drugs does the best job killing the tumor cells. A cell-based assay test with “functional profiling,” using a cell-death endpoint, can help see what treatments will not have the best opportunity of being successful (resistant) and identify drugs that have the best opportunity of being successful (sensitive).

    Funtional profiling measures the response of the tumor cells to drug exposure. Following this exposure, they measure both cell metabolism and cell morphology. The integrated effect of the drugs on the whole cell, resulting in a cellular response to the drug, measuring the interaction of the entire genome. No matter which genes are being affected, functional profiling is measuring them through the surrogate of measuring if the cell is alive or dead.

    For example, the epidermal growth factor receptor (EGFR) is a protein on the surface of a cell. EGFR-inhibiting drugs certainly do target specific genes, but even knowing what genes the drugs target doesn’t tell you the whole story. Both Iressa and Tarceva target EGFR protein-tyrosine kinases. But all the EGFR mutation or amplificaton studies can tell us is whether or not the cells are potentially susceptible to this mechanism of attack. They don’t tell you if Iressa is better or worse than Tarceva or other drugs which may target this. There are differences. The drugs have to get inside the cells in order to target anything. So, in different tumors, either Iressa or Tarceva might get in better or worse than the other. And the drugs may also be inactivated at different rates, also contributing to sensitivity versus resistance.

    As an example of this testing, researchers have tested how well a pancreatic cancer patient can be treated successfully with a combination of drugs commonly used to fight lung, pancreatic, breast, and colorectal cancers. The pre-test can report prospectively to a physician specifically which chemotherapy agent would benefit a cancer patient. Drug sensitivity profiles differ significantly among cancer patients even when diagnosed with the same cancer.

    The funtional profiling technique makes the statistically significant association between prospectively reported test results and patient survival. It can correlate test results that 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 are a really exciting element of cancer medicine, but do not work for everyone, and a pre-test to determine the efficacy of these drugs in a patient could be the first crucial step in personalizing treatment to the individual.

    Literature Citation:

    Weisenthal, L.M. Functional profiling with cell culture-based assays for kinase and anti-angiogenic agents Eur J Clin Invest 37 (suppl. 1):60, 2007

    Nagourney, R.A. Functional Profiling of Human Tumors in Primary Culture: A Platform for Drug Discovery and Therapy Selection (AACR: Apr 2008-AB-1546)

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