From genes to treatments targeted on oncogenic events
Hopital St Louis
The activity of all trans retinoic acid (ATRA) in acute promyelocytic leukemia (APL) is the first model of the new drugs targeting major oncogenic events leading to reversion of malignancies. Fresh cell cultures from patients demonstrated the differentiation effect, allowing maturation of malignant leukemic cells to polymorphonuclear cells. Randomized clinical trials confirmed in vivo differentiation of malignant cells, dramatically improving prognosis of the disease (25% and 75% of cured patients using chemotherapy or chemotherapy and ATRA, respectively). Subsequent to clinical results, the molecular basis of ATRA activity was explored on gene and cell levels. The specific translocation of APL t(15;17) damaged two genes i.e. retinoic acid receptor alpha (RARA) on chromosome 17 and a gene cell PML (for ProMyelocytic Leukemia) on chromosome 15. The breakpoint joins the two genes, constructing a new fusion gene PML-RARA coding for a non natural protein PML-RARA with oncogenic properties. RARA is the natural receptor of retinoic acid and play a role as a transcription factor involved in the myeloid differentiation. When ATRA binds to its nuclear receptor RARA, exchange of corepressor (repressing the expression of genes needed for the myeloid differentiation) to coactivators (activating of the expression of these myeloid differentiation genes) occurs. The presence of a fusion protein PML-RARA needs pharmacological dose of ATRA, the physiological concentration being inefficient. Arsenic trioxyde was also used successfully in this disease. Both arsenic and ATRA clear the oncogenic protein PML-RARA through its sumoylation and destruction in the proteasome. Arsenic targets the sumoylation on the PML moiety and ATRA on RARA moiety. A trial demonstrated the synergistic effect of the two drugs in mice. Conversely to the ATRA treatment in APL where studies started by clinical results followed by molecular explanation of mechanism, the second example of targeted drug i.e. GLIVEC in chronic myeloid leukemia, comes from the studies of molecular knowledge leading to the construct of specific inhibitors of tyrosine kinase (bcr-abl). While Farnesyl Transferase Inhibitors (FTI) de-activating Ras protein gave promising results in AML, the relationship between clinical response and Ras mutation status is not clear. Another example of ambiguous results is the absence of clinical response of FLT3 inhibitors used as monotherapy in AML patients with FLT3 tandem duplication. Targeted drugs have to be applied to the major defect of myeloid malignancy such as differentiation therapy in acute types, antiproliferative in chronic types and anti apoptotic in follicular lymphomas. Differentiation process is governed mainly by transcription factors while proliferation is due to an excess of transduction, and adenomegaly to apoptotic defects. Prognostic factors are not similar to those considered when chemotherapy was given. Targeted treatments need combination of drugs in order to avoid the selection of resistant clones.
Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in plenary session 701 (Molecular oncogenesis).