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 41st 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:

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

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

I've spent 35 years of my career in cancer care, beginning at St. Jude Children's Research Hospital in the early days of clinical research into childhood cancers.  The successful treatment of childhood cancers should be a model for future efforts in adults.  The reason that we've not been successful in adult cancers is two-fold.  The first is that less than 5 percent of adults are on clinical trials; the second is that clinical trials have been trial and error rather than targeted.  A greater emphasis on basic science research so that de novo trials can be developed rather than just adding new drugs to existing drug regimens is critical.  

I've spent 35 years of my career in cancer care, beginning at St. Jude Children's Research Hospital in the early days of clinical research into childhood cancers.  The successful treatment of childhood cancers should be a model for future efforts in adults.  The reason that we've not been successful in adult cancers is two-fold.  The first is that less than 5 percent of adults are on clinical trials; the second is that clinical trials have been trial and error rather than targeted.  A greater emphasis on basic science research so that de novo trials can be developed rather than just adding new drugs to existing drug regimens is critical.  

This article harked me back some years. Brother was diagnosed in 1982 with oat cell cancer, lung, succeeding the death of our mother  in 1973 of lung cancer, oat cell. Both were tortured with chemotherapy for a year and died anyway, brother dying in 1983. Both were sicker than dogs on and off from the poisonous chemotherapy, guinea pigs, I have concluded. Nothing worked. It was said in 1982 that marijuana could relieve the symptoms of the treatments, but the law prohibited the use. I had mixed emotions about whether brother would want to smoke the weed after getting the cancer from smoking. Neither of us wanted to tangle with the law and have to make bail under such dire circumstances, so he never tried it. Died, mercifully after the year of treatment, just like the article above says. Cancer is smarter than we are. Nothing works. I have waited 25 years for my turn. Nothing happens. No cancer. It is mysterious.

I have noticed that the same year seems to prevail in the duration of the chemotherapy torture before the inevitable death. I have wondered why this continues as a recommended treatment. Money doesn't seem to make a difference in the quest for a solution to this disease. I don't even want to ask why this is still done. The only justification could be that the treatment somehow is less painful than not administering it. I don't want to know the answer, because if it is less painful to avoid the treatment, I don't believe that I could stand the thought of my loved ones having been needlessly tortured for a year before they died. Forget about the marijuana. It is probably not a good idea to make it available to everybody.