We are investigating molecular bases of drug resistance as markers of clinical outcome in acute myeloid leukemia (AML) and testing various drug-sensitizing strategies in hopes of improving cure rates for patients with this disease. Relevant chemotherapeutics induce apoptosis and leukemic blasts become drug resistant by downregulating apoptotic responses to these drugs. As a result of anti-apoptotic activities, expression of Bcl-2 family proteins is associated with failure to achieve remission, with short disease-free survival, and with drug-resistant relapse in AML. Bcl-2 proteins are constituents of mitochondrial pore complexes (PTPC) where they block apoptosis by antagonizing mitochondrial pore dissolution that otherwise occurs after lytotoxic treatments. Like Bcl-2, peripheral benzodiazepine receptors (pBzR) reside in PTPC of normal and leukemic blood cells and can protect transfected leukemia cells from apoptosis. However, the association of pBzR expression with clinical outcome has not been directly tested. If high pBzR expression predicts clinical failures in AML, pBzR would be a rational target for molecular anti-leukemia therapies. PK11195 is a high-affinity pBzR antagonist that can block the PTPC protection afforded by Bcl-2 proteins, and can thereby overcome drug resistance. However, whether pBzR or Bcl-2 expresson levels determine the efficacy of PK11195 is unknown. We propose laboratory analyses that will determine the variability of BzR expression in a large number of cell samples collected from AML patients in IRB-approved clinical trials from which complete clinical data is available. We will use standard statistical analyses to determine whether pBzR is an independent prognostic marker in AML. We also propose laboratory analyses of PK11195 efficacy in primary AML cell samples treated with different relevant drugs and in isogenic cell lines over-expressing different anti-apoptotic proteins. NOD/SCID mice will be used as an in vivo model to further test PK11195 efficacy in sensitizing engrafted AML cells. In vitro analyses of normal bone marrow samples and of non-leukemia cells in engrafted mice will examine possible PK11195 toxicities: Data collected in these studies will improve our understanding of the molecular bases of drug resistance in AML. Furthermore, if drug-sensitizing by PK11195 is documented and low toxicity is confirmed in these experiments, novel treatment strategies that include PK11195 will be warranted for AML.
| Walter, Roland B; Pirga, Jason L; Cronk, Michelle R et al. (2005) PK11195, a peripheral benzodiazepine receptor (pBR) ligand, broadly blocks drug efflux to chemosensitize leukemia and myeloma cells by a pBR-independent, direct transporter-modulating mechanism. Blood 106:3584-93 |
| Banker, Deborah E; Mayer, Sasha J; Li, Henry Y et al. (2004) Cholesterol synthesis and import contribute to protective cholesterol increments in acute myeloid leukemia cells. Blood 104:1816-24 |
| Walter, Roland B; Raden, Brian W; Cronk, Michelle R et al. (2004) The peripheral benzodiazepine receptor ligand PK11195 overcomes different resistance mechanisms to sensitize AML cells to gemtuzumab ozogamicin. Blood 103:4276-84 |
