Somewhat along the same line Kenneth Andersson will present an overview at the upcoming AACR conference.
Targeting the myeloma cell in its bone marrow microenvironment
Kenneth C. Anderson, Dana-Farber Cancer Institute, Boston, MA
We have developed both in vitro systems and in vivo animal models to characterize mechanisms of MM cell homing to BM, as well as factors (MM cell-BM stromal cell interactions, cytokines, angiogenesis) promoting MM cell growth, survival, drug resistance, and migration in the BM milieu . These model systems have allowed for the development of several promising biologically-based therapies which can target the MM cell and the BM microenvironment including (thalidomide/revamid (2-5), velcade (6-13), vascular endothelial growth factor receptor kinase inhibitor PTK787 (14-17), histone deacetylase inhibitors SAHA (18-19) and LAQ 824 , 2 methoxyestradiol (21-22), arsenic trioxide , and LPAAT inhibitor) ; those which target MM cells including telomestatin (25-26), heat shock protein 90 inhibitor 17 AAG , TRAIL (28-29), statins , insulin growth factor receptor inhibitor ; and those which target only the BM microenvironment including IκB kinase inhibitors and p38MAPK inhibitors . It is our hypothesis that drugs in these classes will need to be combined to achieve complete eradication of MM cells, and we are presently studying their mechanisms of action at a gene and protein level in order to provide the framework for rational combination clinical trials to overcome drug resistance and improve patient outcome . Having demonstrated preclinical promise of these novel agents, we have rapidly translated our laboratory studies to phase I, II, and III clinical trials to evaluate their clinical utility and toxicity, and to move them rapidly from the bench to the bedside. Most excitingly, velcade (38-39) and Revamid have already demonstrated marked clinical anti-MM activity even in patients with refractory relapsed MM, confirming the utility of our preclinical models to identify and validate novel therapeutics. Importantly, gene array and proteomic studies have helped to identify in vivo mechanisms of action and drug resistance, as well as aiding in their clinical application. For example, gene microarray profiling of velcade treated MM cells reveals induction of heat shock protein 90 stress response , providing the rationale for the combined clinical use of velcade and 17-AAG to enhance anti-MM activity. Study of proteomics also forms the basis for clinical application. For example, protein profiling of velcade treated MM cells demonstrated cleavage of DNA repair enzymes, providing the rationale for combining velcade with DNA damaging agents to enhance sensitivity or overcome resistance to these conventional therapies . Ultimately it may be possible to carry out gene and protein profiling both to select cocktails of targeted therapies for specific patients, and to define targets of sensitivity and resistance in order to develop next generation, more potent and less toxic, therapeutics . Our studies have therefore demonstrated the critical role of host BM-tumor cell interactions both in MM pathogenesis and as targets for novel therapies. They have provided the framework for a new treatment paradigm targeting MM cell-host BM stromal cell interactions and their sequelae in the BM milieu to overcome drug resistance and improve patient outcome in MM.
References:
Presenter: Kenneth C. Anderson
Affiliation: Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; E-mail: n/a
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