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The Cancer Journal - Volume 9, Number 1 (January-February 1996)


Reappraising the reasons for failure: Gene therapy and cancer

"Everyone agrees that cancer is a genetic disease" is a statement that is frequently heard and that is the major argument put forward in favour of gene therapy. It is also an opinion that has engendered much confusion in many minds.

The opportunity to submit this opinion to an open scientific debate has recently arisen as a result of public disclosure in the US that gene therapy trials have failed and of the National Institutes of Health (NIH) decision to reallocate the funds to basic research. What this return to basic research means is a question that needs to be asked.

The reply that first springs to mind is that we probably do not yet know enough about the techniques of gene therapy to be able to transfer the technology to the treatment of humans. It is thus necessary to continue research to diversify these techniques and to attain a level of performance that will allow clinical trials to be reinitiated. Apparently, we are in need of better transfer vectors, improved gene constructs, higher selectivity organ and cell targetting, and ways of inserting DNA at the best locus on the genome. We also require a more in-depth understanding of the lesions that gene therapy is designed to correct for. Everything seems to indicate that biologists are ready to pursue these goals and that it is only a question of time, means, and effort before they succeed.

The reply takes on a different dimension if, instead of just admitting to inadequate technical knowledge, we question the validity of gene therapy as a means of correcting for malignant genetic lesions and basically refute the assertion that cancer is due to genetic lesions. Under these circumstances, we need not only to improve the technique, but also to reevaluate the rationale for gene therapy of cancer.

Let's analyze the reasoning :
1. Are cancers due to deleterious genetic alterations ?
2. If 'yes', will gene therapy be an option to be added to our rather limited list of measures for curing patients or inducing long-term remission ?
3. If 'no', i.e., even if genetic lesions are not the cause of all or, at least, of some cancers, will gene therapy nevertheless remain an option ? This proposition may at first sight seem illogical but it should not be ignored.

No informed reader today is surprised when told that the causes of cancer are multifactorial, that among these causes genetic alterations (somatic mutations, deletions, translocation ....) have a role that differs with cancer type and individual, and that the effects of any gene alterations depend upon associated factors (environment, more or less genotoxic carcinogens, the endocrine, immune, neurologic, and nutritional status of the individual). He will also have heard that the disease progresses by stages over a long time before the appearance of the first clinical signs. All these statements are extremely commonplace.

But, let's take a somewhat less traditional view by saying :
1. Among all the associated causal factors leading to cancer, gene alterations are factors that sometimes play a predominant role and sometimes only a negligible role. In most instances, however, their relative role in carcinogenesis remains totally unknown.
2. At the end of a long, complex, and multifactorial process leading to progressive chronic illness, it is uncertain whether any remedial action on the initial lesion would actually have any effect on the disease. This is because either the initial lesion may no longer be present or because the dynamics of the process are independent of the etiological factors that trigger it.

However, ineffective action on the trigger mechanism does not eliminate other types of action on the pathological process in order to slow down, palliate, or cure the disease. Thus, gene therapy targetted to sites other than the initial lesion may prove to be an effective measure.

These logical hypotheses outside the bounds of the traditional realm of the physiopathology of cancer and therapeutical research can be tested through experimental investigation. As they are falsifiable, they should therefore be included in any proposed research strategy.

Jean-Claude Salomon