Myeloma and Lymphoma

Posted by James

Multiple Myeloma: Oncogenomics for Targeting Tumor Cells in the Microenvironment

Speaker: Kenneth Anderson, Dana-Farber Cancer Institute, Boston, Massachusetts

Recent progress in the research on multiple myeloma (MM) demonstrates the tumor-promoting influence of the micro-environment. Growth factors promote tumor cell proliferation and survival, and cytokines and chemotactic factors promote tumor cell migration and invasion. Proteases break down the basement membrane, alter the architecture of tissue structures, and promote migration and invasion by tumor cells. The vasculature of tumor cells is composed of endothelial cells that are uniquely altered in different tumors. Tumors produce growth factors, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), which recruit endothelial cells, thus affecting the growth of the tumor vasculature.

Gene modulation (up-regulation) occurs after the binding of MM cells to bone marrow stem cells, causing an increase in tumor growth potential and the release of adhesion molecules, cytokines, and proteasomes that affect the microenvironment. When myeloma sets up residence in the bone marrow, the myeloma cells activate cytokines, promoting drug resistance as well as molecules that affix tumor cells to receptor sites, making them almost impossible to eradicate with conventional treatments.
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Some emerging drugs, however, appear to be able to overcome intrinsic drug resistance, inhibit angiogenesis (blood vessel growth), prevent tumor cells from adhering to bone marrow, and augment the patient’s own immune defenses by increasing the number of circulating natural killer T cells.

Lenalidomide. Lenalidomide (Revlimid®, Celgene) is an oral thalidomide analogue that targets both tumor cells and their microenvironment. Early clinical trials indicate that it overcomes conventional drug-resistance mechanisms in a few patients with relapsed or refractory MM. In a phase 3 trial of 700 patients, there was a significant increase in response rates, in disease-free periods, and in time to disease progression in the lenalidomide/dexamethasone treatment arm, compared with the dexamethasone (control) arm. After 20 months, rates of clinical remission were 20% with lenalidomide/dexamethasone and 4% with dexamethasone; rates of partial remission were 60% with lenalidomide/dexamethasone and 22% with dexamethasone.

A New Drug Application for lenalidomide/dexamethasone for the treatment of MM is near approval.

Bortezomib. Bortezomib (Velcade, Millennium), a pro-teasome inhibitor, targets MM cells in the bone marrow micro-environment and milieu. Proteasome inhibitors are a new class of targeted therapies that may be more effective in patients with relapsed or refractory blood cell cancers such as MM. They block MM cells to the stroma and inhibit angiogenesis.
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The drug received accelerated approval for the treatment of relapsed refractory MM. The initial therapy for MM patients may eventually include combinations of bortezomib/thalido-mide/dexamethasone, lenalidomide/dexamethasone, bortezomib/lenalidomide, or bortezomib alone. Bortezomib/ doxorubicin combinations showed activity in patients with advanced MM.

I Kappa B Kinase (IKK) and SCIO-469. Novel therapies targeting the bone marrow microenvironment include IKK inhibitors and the p38 mitogen-activated protein (MAP) kinase inhibitor SCIO-469, which blocks interleukin-6 (IL-6) and VEGF secretion from bone marrow stem cells. An ongoing clinical study is being conducted to determine whether SCIO-469 will have a positive impact on the microenvironment in patients with MM.

NPI-0052. NPI-0052 is an oral proteasome inhibitor that kills all three bortezomib-resistant cells (beta 1, beta 2, and beta 5). Clinical trials are expected to be under way soon.

Vatalanib. PTK 787 (vatalanib), a tyrosine kinase inhibitor, prevents VEGF-induced effects in MM cells and in bone marrow. It is indicated for angiogenesis, to inhibit the maturation of dendritic cells, and to increase bone-resorbing activity.

Telomestatin. Telomerase is found in the nucleus of MM cells and is overexpressed in MM. Telomestatin, an intramolecular G-quadruplex intercalating drug with specificity for telomeric sequences, will be studied in MM patients. prescription drugs from canada

Deacetylase. The histone deacetylase (HDAC) inhibitor of cell signaling HDAC6 (tubacin), one of 11 known human HDACs, may have therapeutic value in treating MM. Aside from deacetylating tubulin, HDAC6 has a fascinating function; it binds both polyubiquinated proteins (those marked for degradation by attached ubiquitin “flags”) and dynein (a protein motor associated with microtubules), bringing the two together to help the cell “clean house.” This takes place through a cell structure called the aggresome. Studies of tubacin, in combination with bortezomib, are under way.