Recent advances in the therapy of CML have resulted in a very high remission rate, including hematologic and cytogenetic responses in the vast majority of patients. However, minimal residual disease can be detected in most patients by PCR monitoring. Levels of Bcr/Abl mRNA detected by reverse transcriptase PCR probably underestimate the residual leukemia burden, as transcriptionally inactive, quiescent CML cells cannot be detected by this technique. Bcr/Abl signaling negatively regulates the expression ofthe chemokine receptor CXCR4 on CML cells. CXCR4 is the receptor for SDF-1, a major chemokine produced by the bone marrow microenvironment. Downregulation of CXCR4 results in release of CML cells/progenitor cells from the bone marrow into the circulation and may explain the characteristic leucocytosis of CML. We have recently demonstrated that Bcr/Abl kinase inhibitors such as imatinib upregulate CXCR4 expression and may therefore favor the survival of CML progenitor cells in the bone marrow niche. Pharmacological inhibition of CXCR4 by a specific small molecule inhibitor (AMDSIOO/Plerixafor) in leukemia patients resulted in striking release of malignant cells from the bone marrow into the circulation and in the CXCR4-mediated inhibition of pro-survival signaling in the leukemic cells, independent of their mobilization. Our in vitro and in vivo data in myeloid leukemias demonstrated that disruption ofthe CXCR4/SDF1 axis results in pronounced sensitization to signal transduction inhibitors and chemotherapy thus overcoming microenvironment-mediated resistance. A clinical trial is ongoing and has provided proof-of-concept, i.e. that CXCR4 inhibition results in preferential mobilization of Ph+ leukemia cells. In addition, integrins mediate anchoring of leukemic cells in their microenvironment and inhibition of VLA-4 resulted in disruption of leukemia/stroma cell interactions and chemosensitization. We therefore propose:
Specific Aim 1. To test the hypothesis that inhibition of CXCR4 and/or VLA-4 results in disruption of CML/stroma interactions and thus reverses microenvironment-mediated protection of CML progenitor cells to tyrosine kinase inhibitors.
Specific Aim 2. To test the hypothesis that non-genotoxic activation of p53 by Nutlin-3a in chronic phase and blast crisis CML disrupts leukemia/stroma interactions via SDF-1/CXCR4 inhibition.
Specific Aim 3. To investigate the potential of combined tyrosine kinase and Bcl-2 inhibition on the survival of quiescent CML progenitor cells in the bone marrow microenvironment in vitro and in vivo. We expect these studies to improve our understanding of the complex interactions between CML cells and their microenvironment and provide mechanism-based rationale for eliminating residual CML progenitor cells.
Chronic myeloid leukemia (CML) therapy has been revolutionized by the use of Gleevec. However, the majority of patients remain positive for CML cells that will cause relapse once the drug is discontinued. This proposal is based on our observation that Gleevec will induce leukemic cells to hide in the bone marrow by upregulation of chemokine receptor CXCR4. Inhibition of CXCR by a specific inhibitor or by p53 activation is then proposed to sensitize leukemia progenitor/stem cells to agents inhibiting Bcl-2 and thus inducing cell death in residual leukemia cells protected by the bone marrow microenvironment.
|Eiring, A M; Page, B D G; Kraft, I L et al. (2015) Combined STAT3 and BCR-ABL1 inhibition induces synthetic lethality in therapy-resistant chronic myeloid leukemia. Leukemia 29:586-97|
|Zhang, Weiguo; Gao, Chen; Konopleva, Marina et al. (2014) Reversal of acquired drug resistance in FLT3-mutated acute myeloid leukemia cells via distinct drug combination strategies. Clin Cancer Res 20:2363-74|
|Tao, Wenjing; Leng, Xiaohong; Chakraborty, Sandip N et al. (2014) c-Abl activates janus kinase 2 in normal hematopoietic cells. J Biol Chem 289:21463-72|
|Thall, Peter F; Nguyen, Hoang Q; Zohar, Sarah et al. (2014) Optimizing Sedative Dose in Preterm Infants Undergoing Treatment for Respiratory Distress Syndrome. J Am Stat Assoc 109:931-943|
|Mak, P Y; Mak, D H; Mu, H et al. (2014) Apoptosis repressor with caspase recruitment domain is regulated by MAPK/PI3K and confers drug resistance and survival advantage to AML. Apoptosis 19:698-707|
|Jin, Ick Hoon; Liu, Suyu; Thall, Peter F et al. (2014) Using Data Augmentation to Facilitate Conduct of Phase I-II Clinical Trials with Delayed Outcomes. J Am Stat Assoc 109:525-536|
|Benjamini, Ohad; Kantarjian, Hagop; Rios, Mary Beth et al. (2014) Patient-driven discontinuation of tyrosine kinase inhibitors: single institution experience. Leuk Lymphoma 55:2879-86|
|Havelange, Violaine; Ranganathan, Parvathi; Geyer, Susan et al. (2014) Implications of the miR-10 family in chemotherapy response of NPM1-mutated AML. Blood 123:2412-5|
|Ohanian, Maro; Kantarjian, Hagop M; Quintas-Cardama, Alfonso et al. (2014) Tyrosine kinase inhibitors as initial therapy for patients with chronic myeloid leukemia in accelerated phase. Clin Lymphoma Myeloma Leuk 14:155-162.e1|
|Zabriskie, Matthew S; Eide, Christopher A; Tantravahi, Srinivas K et al. (2014) BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia. Cancer Cell 26:428-42|
Showing the most recent 10 out of 220 publications