Clinical Research Unit 216
Characterization of the Oncogenic
Signaling Network in Multiple Myeloma:
Development of Targeted Therapies
funded by DFG
Contact:
Klinische Forschergruppe 216
Heidi Eiselein
Medizinische Klinik und Poliklinik II, Haus E 4,
Versbacher Str. 5
97078 Würzburg
Phone: ++49(0)931-201-45141
09.03.2010
The development of targeted therapies presently marks a paradigm shift in clinical oncology. In addition to traditional approaches - chemotherapy, surgery and radiotherapy - better knowledge on the biology and molecular pathogenesis of malignant diseases has begun to establish molecular therapies as a fourth pillar of tumor treatment. The majority of malignancies are believed to be the result of a number of sequential pathogenetic events leading to illegitimate activation of oncogenic signaling pathways and to defective mechanisms of cell elimination. Consequently, most neoplastic diseases rely on dysregulation of a variety of oncogenes and on activation of a number of oncogenic pathways for expression of the malignant phenotype. A precise description of the molecular heterogeneity is a crucial requirement for the specific development and efficacious application of novel therapeutic approaches.
Multiple myeloma is a neoplastic disease of terminally differentiated, antibody-producing B cells (plasma cells). The majority of these cells are localized within the bone marrow, where they promote bone destruction and impair normal hematopoiesis. Improved methods in stem cell therapies and novel pharmacologic drugs like proteasome inhibitors and derivatives of thalidomide have led to significant improvement in overall survival of myeloma patients, which currently stands at about five years. Nevertheless, multiple myeloma remains incurable and its clinical course is usually characterized by a good initial response to treatment, followed after some time by relapse and an eventual development of general resistance to current therapies.
The pathogenesis of multiple myeloma is considered as a multi-step process. Multiple myeloma is from the outset prone to genetic complexity and to heterogeneity. Whereas some chromosomal aberrations as well as their affected genes have been identified, the functional consequences of most genetic lesions for malignant growth remains largely unclear. Likewise, the oncogenic pathways that are deregulated by mutations are not well understood and how these pathways co-operate is unanswered as well.
Another approach to understand the pathogenesis of MM and to handle its complexity is therefore to analyze functional pathways. In line with this concept major growth-regulatory signaling pathways have been found to be activated or deregulated in MM cells and to contribute to tumor cell survival and proliferation. Signaling systems that have been found to be activated or deregulated in MM include those associated with Raf, NFkB, CD28, heat shock proteins, and the cold shock domain protein YB-1. The precise mechanisms how these pathways co-operate and how they contribute to the malignant phenotype is poorly understood.
Taken together, these observations suggest that different genetic lesions lead to activation and deregulation of a number of oncogenic signaling pathways in myeloma that co-operate to establish an oncogenic signaling network instrumental in the expression of a malignant phenotype. A comprehensive functional, molecular and genetic analysis of this network may therefore lead to a better understanding of the molecular pathogenesis of MM and to the identification of therapeutically relevant targets.