An expensive dream or a vision of the future shared by the cancer community?
New drugs targeting oncogene products activated in several human tumors have been developed over the last 10 years, and some have produced spectacular therapeutic responses in patients resistant to conventional treatments. The variety of genetic and molecular abnormalities found in human cancers has demonstrated their great heterogeneity, even within the same tumor, but has also raised hopes of individualized cancer treatment, with each patient receiving drugs inhibiting the action of the oncogenes involved in his or her own tumor.
The initial results of these therapeutic approaches will be presented and discussed, illustrating some of the successes achieved, but also the current difficulties and limitations. Finally, we will attempt to outline a few avenues for the future.
The most spectacular therapeutic results to date concern :
- Imatinib (Glivec) in chronic myeloid leukemia (CML) containing an activated BCR-ABL fusion protein produced by a t(9-22) chromosomal translocation, and in rare gastrointestinal stromal tumors (GIST) expressing a mutated, activated C-KIT oncogenic receptor on the surface of tumor cells;
- Trastuzumab (Herceptin), whose activity has been demonstrated in breast cancers whose tumor cells overexpress the HER-2 oncoprotein;
- Crizotinib, remarkably effective in rare (3-5%) lung adeno-carcinomas presenting a chromosomal translocation activating the ALK oncogene;
- Vemurafenib , which, for the first time, has achieved major tumor regression in metastatic melanomas whose tumor cells carry the V600E mutation of the B-RAF oncoprotein, present in 50% of patients. Unfortunately, these responses, however spectacular, remain fleeting, and virtually all patients relapse after a few months.
These few successes show that :
- they only concern a very limited number of patients (rare tumours or a small number of patients carrying the target anomaly);
- relapses are frequent, and in some cases constant, due to the emergence of tumor sub-clones resistant to the drug used;
- human tumors do not contain a single genetic event involved in oncogenesis (so-called " driver " mutations), but several (from 5 to 15), with a high frequency of rare anomalies for which the production of future targeted drugs remains highly uncertain. In addition, tumor cells contain many other genetic anomalies (from 50 to 150) which, although not necessary for the survival of malignant cells (so-called " passenger " mutations), may play a role in drug resistance as well as in the relationship between the tumor and its environment (immune system, neo-angiogenesis).
