Methods and compositions for inhibiting the growth of hematopoietic malignant cells

Abstract

Disclosed herein are compositions and methods for reducing the growth of hematopoietic malignant cells (e.g., B-cell leukemia cells). The methods involve reducing the growth of hematopoietic malignant cells by contacting hematopoietic malignant cells with GP88 antagonists. GP88 is an 88 KDa autocrine growth factor that promotes the growth of hematopoictic malignant cells. Antagonists to GP88 are provided which inhibit its expression or biological activity. The antagonists include antisense oligonucleotides and antibodies. Also provided are methods for determining if a patient is responding or is responsive to anti-cancer therapy (e.g., glucocorticoid therapy). Increased levels of GP88 in hematopoietic cells indicates a patient is not responding or responsive to anti-cancer therapy.

Description

[0001] This application is a continuation-in-part of U.S. application Ser. No. 09 / 456,886, filed Dec. 8, 1999, which is a divisional of U.S. application Ser. No. 08 / 991,862, filed Dec. 16, 1997, now U.S. Pat. No. 6,309,826, which is a continuation-in-part of U.S. patent application Ser. No. 08 / 863,079, filed May 23, 1997, now abandoned.[0002] This invention relates to cell biology, physiology and medicine, and concerns an 88 kDa glycoprotein growth factor ("GP88" or "PCDGF") and compositions and methods which affect the expression and biological activity of GP88. These compositions and methods are useful for diagnosis and treatment of diseases including cancer.REFERENCES[0003] Several publications are referenced herein by Arabic numerals within parenthesis. Full citations for these references may be found at the end of the specification immediately preceding the claims.[0004] The proliferation and differentiation of cells in multicellular organisms is subject to a highly regulated p...

AI Technical Summary

Benefits of technology

[0014] The inventor has further discovered that GP88 is overexpressed in hematopoietic malignant cells such as leukemia cells of B-cell lineage (e.g., acute lymphocytic leukemia, B cell lymphoma, and multiple myeloma). GP88 stimulates the tumorigenic properties of hematopoietic malignant cells while inhibition of GP88 expression and biological activity greatly reduces the tumorigenic properties of hematopoietic malignant cells. An embodiment of the invention provides methods of inhibiting the growth or viability of hematopoietic malignant cells. In one embodiment of the invention, a GP88 antagonist inhibits multiple myeloma cell growth. In another embodiment of the invention, a composition for inhibiting the growth or viability of hematopoietic malignant cells comprising a GP88 antagonist (e.g., an anti-GP88 antibody, or anti-GP88 nucleic acid) is provided. In yet another embodiment, a method of diagnosing B-cell leukemia is provided comprising detecting GP88 (e.g., GP88 protein, or nucleic acids encoding GP88) in a tissue sample containing B cells (e.g., tissue suspected of containing myeloma cells including, but not limited to blood, bone marrow, lymph, liver, and spleen) and diagnosing multiple myeloma by determining whether GP88 protein is present in the tissue sample. The presence of GP88 in B cells indicates multiple myeloma. Alternatively, detecting GP88 in B-cells indicates the presence of leukemia cells of B-cell lineage. Thus, the presence of GP88 serves as a prognostic marker for B-cell leukemia.

[0087] FIG. 31 shows the effect of dexamethasone on PARP cleavage in ARP-1 cells overexpressing GP88. ARP-1 cells overexpressing GP88 have significantly reduced levels of PARP cleavage.

Problems solved by technology

A distinguishing feature of cancer cells is the absence of control over this process; proliferation and differentiation become deregulated resulting in uncontrolled growth.

Malignant cells which observe this autocrine behavior circumvent the regulation of growth factor production by other cells and are therefore unregulated in their growth.

Plasma cells produce immunoglobulins and have a limited life span.

However, uncontrolled growth of plasma cells in a clonal lineage of B cells may lead to accumulation of plasma cells producing monoclonal immunoglobulins or immunoglobulin fragments (e.g., M protein).

The few available therapies for treatment of MM have severe side effects and are of limited efficacy.

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