Preclinical studies of novel targeted therapies

Abstract

The bone marrow (BM) milieu confers drug resistance in multiple myeloma (MM) cells to conventional therapies. Novel biologically based therapies are therefore needed. Preclinical studies have identified and validated molecular targeted therapeutics in MM. In particular, recognition of the biologic significance of the BM microenvironment in MM pathogenesis and as a potential target for novel therapeutics has already derived several promising approaches. Thalidomide, lenalidomide (Revlimid), and bortezomib (Velcade) are directed not only at MM cells but also at the BM milieu and have moved rapidly from the bench to the bedside and United States Food and Drug Administration approval to treat MM.

Figure 1

Novel biologically-based therapies targeting MM cells and the BM microenvironment. Novel agents A. directly inhibit MM cell growth; B. inhibit angiogenesis; C. inhibit MM cell adhesion to BM accessory cells; D. decrease cytokine production and sequelae in the BM microenvironment; and E. enhance host anti-MM immunity.

Figure 2

Cell surface and intracellular targets of novel therapeutic agents. Novel agents block signaling cascade triggered by MM cell-BM accessory cell interaction and induce growth inhibition in the BM microenvironment. Novel agents; inhibit interaction of cytokines/growth factors and their receptors expressed on MM cell; inhibit receptor tyrosine kinase activity; intracellular molecules (kinases, anti-apoptotic proteins, molecular chaperons, transcription factors).