MOLECULAR DETERMINANTS OF CHEMOTHERAPY RESISTANCE

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Although induction combination chemotherapy regimens for acute myelogenous leukemia (AML) are associated with a complete remission induction frequency of 75 %, only about 20% of the total number of AML patients per year are cured of their disease with conventional dose combination chemotherapy alone. AML with balanced translocations [inversion l6 and t(8;21)] have been associated with cures in excess of 60%. The t(15; 17) has been associated with an intermediate prognosis. The poor prognosis subsets have been associated with monosomies of chromosomes 5 and 7, t(9;22), and trisomy 8. Almost none of these patients can be cured with conventional dose combination chemotherapy. The genes at the translocation breakpoints in the good prognosis subsets include the MIL RARalpha in t(15;17), and the chimeras of CBF alpha and beta in the t(8;21) and the inversion 16 subsets, respectively. These subsets, especially inversion 16, are among the most sensitive diseases of all the neoplastic states. A single drug, cytosine arabinoside (Ara-C), can cure patients with this subset, while not eradicating the normal myeloid cells. This suggests that these inversion 16 AML cells are more vulnerable to chemotherapy-induced cell death than are normal cells, whereas the poor prognosis subsets are among the most resistant of all of the neoplasms, often surviving even super lethal levels of chemotherapy. This project is designed to identify the molecular changes in AML cells which exert a dominant effect on response to chemotherapy and on survival, and to apply that information to the development of novel approaches to therapy of this disease. This project is based on the following data: (I) Work in prior funding years of the grant revealed changes in the levels and functional states of proteins in the growth factor induction pathway (Rb, p53 and WAF- 1) which are predictive of decreased response to therapy and survival; (2) WAF-1 is activated by P53 suppresses proliferation in AML cells, and is associated with resistance to chemotherapy induced apoptosis; (3) The combination of the cytogenetic changes and the molecular changes in the cells of AML patients define a set of markers which can be used to not only predict sensitivity or resistance to therapy but also to understand the mechanisms of this resistance; (4) The identity of genes at the breakpoints of the majority of balanced translocations have been identified; and (5) Genetic modification can be used to develop therapeutic interventions based on the reversal of these genetic changes in the AML cell so as to either suppress the neoplastic phenotype of the AML cell or to increase their sensitivity to chemotherapy. On the basis of these findings, we have proposed to use therapy outcome data and molecular analysis of genetic changes in responders and nonresponders to identify the changes within AML cells that are exerting a dominant effect in generating a high and low sensitivity to chemotherapy. We will also study ways of using molecular and genetic methods to modify AML cells so as to suppress the resistance phenotype as a primary means of therapy. The ultimate application of this information is to use these surrogate markers of response to allocate patients to the most appropriate therapy.