Method for treating hematopoietic neoplasms

Abstract

This invention relates to methods for treating a hematopoietic neoplasm comprising administering a therapeutically effective amount of a combretastatin compound, or a pharmaceutically acceptable salt thereof, to a subject having a hematological malignancy, wherein the combretastatin compound comprises a catechol or quinone moiety and is capable of forming a reactive oxygen species (ROS) in vivo. The method may further comprise co-administering a second 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]Cancer is a leading cause of death in the industrialized world and despite years of research, many types of cancer lack an effective therapeutic treatment. Although chemotherapy induces remission in the majority of adult patients with acute myeloid leukemia (AML), only a 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 vascular cells, 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 ...

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Benefits of technology

[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, α4α1) 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]Combretastatin A-1, a novel tubulin-destabilizing agent, was isolated from the South African tree Combretum caffrum. Combretastatin A-1 binds to tubulin at the same site as colchicine, but with higher affinity. Its phosphate pro-drug, combretastatin A-1 phosphate (CA1dP) induces rapid microtubule depolymerization and vascular shutdown in subcutaneous solid tumors causing tumor necrosis at concentrations well below the maximum tolerated dose. Combretastatin A-1 comprises a single ortho-catechol moiety and is known to be capable of generating an enhanced antitumor response by forming reactive oxygen species (ROS) in the locality of the tumor in addition to selectively reducing the flow of blood to at least a portion of a tumor. This results in both direct inhibition of the proliferation of tumor cells, and tumor selective induction of hypoxia and subsequent necrosis in a portion of the tumor tissue without substantial necrosis of adjoining non-tumor tissue. Other catechol- and quinone-containing vascular disrupting agents have been shown to have enhanced therapeutic activity, relative to vascular disrupting agents that act solely through interaction with tubulin, particularly against sold tumors (see co-pending U.S. Ser. No. 10 / 790,662, U.S. Patent Publication No. 2004-024696, incorporated herein by reference in its entirety).

[0005]In this report, we show that combretastatin compounds that comprise a catechol or quinone moiety induce rapid cell death of non-adherent leukemic cells, at low, non-toxic doses. We also demonstrate that single-agent treatment with a catechol- or quinone-containing combretastatin compound is effective in eradicating both circulating, and vascular-adherent leukemic cells in subcutaneous mouse models of AML, without affecting normal hematopoiesis. CA1dP-treated mice had significantly prolonged survival and significantly decreased tumor load. Co-administration of an additional chemotherapeutic agent, e.g. AraC, decreases tumor load even further. Therefore, catechol- or quinone-containing combretastatin compounds delivered alone or in combination with chemotherapeutic agents represent a promising novel therapeutic approach to eradicate hematopoietic neoplasms.III. SUMMARY OF THE INVENTION

Problems solved by technology

Cancer is a leading cause of death in the industrialized world and despite years of research, many types of cancer lack an effective therapeutic treatment.

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

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