The leukemic clone in virtually all of the patients with chronic myeloid leukemia with blast crisis (CML-BC) and approximately one-third of the adults with acute lymphoblastic leukemia (ALL) expresses the bcr-abl fusion gene encoded p210 and p185 Bcr-Abl tyrosine kinase (TK), respectively. Although the chemotherapeutic regimens or bone marrow stem cell transplantation employed against acute leukemias can also produce complete remissions in Bcr-Abl positive ALL and CML-BC, these remissions are not durable and the overall clinical outcome remains dismal. This creates a strong rationale to test novel strategies in this clinical setting. Arsenic Trioxide (As2O3 or AT) is clinically active against relapsed or refractory acute promyelocytic leukemia (APL), where it downregulates the levels of the fusion protein PML-RARdelta causing partial differentiation and apoptosis of APL cells. Recently, we have demonstrated that clinically achievable levels of AT can also reduce p210 or p185 Bcr-Abl fusion protein levels and induce apoptosis of CML-BC cells. Based on these findings, we propose to conduct a Phase II clinical-pharmacologic trial of AT (NCI/CTEP sponsored) as the induction therapy for relapsed and refractory; Bcr-Abl positive adult ALL and CML-BC. In vitro studies on the patient derived leukemic blasts are proposed to determine the molecular correlates of the clinical response and apoptosis induced by AT. We have also shown that STI571, a relatively specific inhibitor of Bcr-Abl TK activity, induces differentiation and apoptosis of Bcr-Abl positive leukemic cells. Therefore, we also propose to investigate the in vitro apoptotic and differentiation effects of a combination of AT and STI571 in Bcr-Abl positive leukemic blasts.
The specific aims of this proposal are:
AIM 1 : To determine the clinical efficacy, i.e., the rate and duration of clinical and hematologic response and overall survival, secondary to treatment with daily intravenous AT in adult patients with Philadelphia chromosome (bcr-abl fusion gene) positive relapsed or refractory ALL or CML-BC.
AIM 2 : To determine the pharmacokinetic parameters of AT, i.e., AUC and Css and correlate these with the clinical and cytogenetic response in patients with Bcr-Abl positive ALL or CMLBC.
AIM 3 : To correlate the clinical response to AT with the decline in the bcr-abl mRNA levels determined by real-time RT-PCR.
AIM 4 : To correlate the clinical and in vivo molecular response to AT with AT-induced in vitro downregulation of Bcr-Abl and Akt protein levels, histone hyperacetylation as well as differentiation and apoptosis, utilizing the pre-treatment samples of leukemic blasts.
AIM 5 : To determine the in vitro differentiation and apoptotic effects of STI-571 alone and in combination with AT in the pre-treatment samples of Bcr-Abl positive leukemic blasts. These in vitro and in vivo studies are designed to evaluate AT-based novel strategies against Bcr-Abl positive human leukemias.
| Rasheed, Zeshaan; Wang, Qiuju; Matsui, William (2010) Isolation of stem cells from human pancreatic cancer xenografts. J Vis Exp : |
| Nimmanapalli, Ramadevi; Bali, Purva; O'Bryan, Erica et al. (2003) Arsenic trioxide inhibits translation of mRNA of bcr-abl, resulting in attenuation of Bcr-Abl levels and apoptosis of human leukemia cells. Cancer Res 63:7950-8 |
