Methods for Treating Hematopoietic Neoplasms

Abstract

This invention relates to methods for treating, preventing and / or managing hematopoietic neoplasm in a subject by administering to the subject combretastatin A-4 phosphate, or a pharmaceutically acceptable salt thereof. The method may further comprise co-administering a chemotherapeutic agent.

Description

I. CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. provisional patent application No. 60 / 989,786, filed 21 Nov. 2007.II. INTRODUCTION[0002]Although chemotherapy induces remission in the majority of adult patients with acute myeloid leukemia (AML), only small percent are cured with conventional chemotherapy. Relapse of leukemias is in part due to the persistence of minimal residual leukemias that remain viable within specialized niches, such as vascular niches. Hence, novel treatment strategies are urgently needed to block the interaction of hematopoietic neoplasms with activated vasculature, interfering with the establishment of pro-leukemic niches in various organs and to eradicate resistant disease.[0003]Adhesion of leukemic cells to stromal cells has been shown to confer increased resistance to chemotherapeutic agents and diminish the rate of apoptosis of the leukemic cells. This process, named cell adhesion-mediated drug resistance (CAM-D...

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[0002]Although chemotherapy induces remission in the majority of adult patients with acute myeloid leukemia (AML), only small percent are cured with conventional chemotherapy. Relapse of leukemias is in part due to the persistence of minimal residual leukemias that remain viable within specialized niches, such as vascular niches. Hence, novel treatment strategies are urgently needed to block the interaction of hematopoietic neoplasms with activated vasculature, interfering with the establishment of pro-leukemic niches in various organs and to eradicate resistant disease.

[0003]Adhesion of leukemic cells to stromal cells has been shown to confer increased resistance to chemotherapeutic agents and diminish the rate of apoptosis of the leukemic cells. This process, named cell adhesion-mediated drug resistance (CAM-DR), depends on the interaction of integrins with their ligands. Adhesion of VLA4 (very late antigen 4, α4β1) integrin-positive myeloid cells, to VCAM-1+ stromal cells is an important mediator of CAM-DR. Indeed, expression of VLA4 by leukemic cells portends a poor prognosis and a decreased five-year survival rate. Therefore, identification of novel anti-leukemic agents that inhibit interaction of leukemic cells with vascular cells provides novel strategies to target organ-infiltrating, angiogenesis-dependent leukemias.

[0004]Within the marrow or in circulation, hematopoietic neoplasms are closely associated with endothelium, supporting establishment of neo-vessels by elaboration of angiogenic factors. In addition, leukemic cells may activate endothelial cells by releasing pro-inflammatory factors, including interleukin-1 (IL-1), facilitating invasion into tissues and formation of infiltrative organ disease or subcutaneous tumors, namely chloromas, thereby establishing chemotherapy-refractory leukemic minimal residual disease.

[0005]One approach to destabilize interactions of hematopoietic neoplasms with endothelium is through disruption of the cytoskeletal organization of the neoplastic cells. Indeed, disruption of cytoskeletal stability of hematopoietic neoplasms may not only promote cell death directly, but also diminish the cellular interaction of the hematopoietic neoplasms with vascular cells, thereby increasing sensitivity to chemotherapy.

[0006]Combretastatin-A4, a novel tubulin-destabilizing agent, was isolated from the South African tree Combreturn caffrum. Combretastatin-A4 binds to tubulin at the same site as colchicine does, but with even higher affinity. Its pro-drug, combretastatin-A4 phosphate (CA4P) induces rapid microtubule depolymerization and vascular shutdown in subcutaneous solid tumors causing tumor necrosis at concentrations well below the maximum tolerated dose. CA4P also can induce apoptosis of the endothelial cells by disengaging VE-cadherin interaction. Thus, CA4P may not only target rapidly proliferating leukemic cells directly, but also diminish interaction of the leukemic cells with activated endothelial cells, thereby preventing establishment of a perivascular nidus for leukemic chloromas.

[0007]The inventors demonstrate that CA4P at low, non-toxic doses, surprisingly induces rapid cell death of non-adherent leukemic cells through caspase activation, mitochondria destabilization and accumulation of reactive oxygen species (ROS), accompanied by the release of pro-apoptotic mitochondrial membrane proteins. Additionally single-agent CA4P treatment is effective in eradicating both circulating, and vascular-adherent leukemic cells in subcutaneous and systemic mouse models of AML, without affecting normal hematopoiesis. CA4P-treated mice had significantly prolonged survival and showed a drastic reduction of detectable leukemic cells in the marrow and peripheral circulation, and significantly decreased leukemic organ infiltration. In addition, CA4P decreases expression of VCAM-1 on endothelial cells both in vitro and in vivo, thereby decreasing leukemic cell adhesion to the vascular cells, thereby reversing drug resistance. Therefore, CA4P delivered in combination with chemotherapeutic agents represents a promising novel therapeutic approach to treat hematopoietic neoplasms.III. SUMMARY OF THE INVENTION

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Indeed, expression of VLA4 by leukemic cells portends a poor prognosis and a decreased five-year survival rate.

Indeed, disruption of cytoskeletal stability of hematopoietic neoplasms may not only promote cell death directly, but also diminish the cellular interaction of the hematopoietic neoplasms with vascular cells, thereby increasing sensitivity to chemotherapy.

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