Role of NF-κB in Human Malignancies

Numerous studies over the last several decades have been dedicated to understanding how oncogenes (cancer inducing genes) and tumor suppressors (cancer preventing genes) modulate cancer development. Their findings suggest the concept that malignant behaviors may develop by a process of normal cells acquiring autonomy from multiple regulatory signals via genetic or epigenetic alterations of signaling pathways. Thus, malignant cancer cells often display a set of six or seven alterations, referred to as “acquired capabilities”. Each of these attributes could in principle provide a drug target and combined targeting of different acquired capabilities may be required to effectively eradicate cancer cells in each patient. The critical issue is to determine which dysregulated signaling pathways are controlling these attributes in specific types of human cancers. Ideally, this information needs to be defined in individual cancer patients in order to maximally tailor therapy.

We are currently investigating the mechanisms of dysregulated, constitutive (always “on”) activation of NF-kB in several different human cancer types. In particular, we are currently focusing our efforts to understand NF-kB activation mechanisms in two hematologic malignancies, multiple myeloma (MM) and mantle cell lymphoma (MCL), both are lethal diseases and can be difficult to treat. Constitutive NF-kB activity can be detected in a very high percentage (~80% or more) of patient-derived cancer samples but the mechanisms behind this activity are unclear. We also learned that “normal” stromal cells associated with multiple myeloma cells further increase NF-kB activation in myeloma cells to augment drug resistance.  Therefore, not only cancer cells but also normal “microenvironment” cell types appear to promote cancer cell resistance. In collaboration with clinical colleagues and bioengineering experts, we are developing new methodologies (e.g., miniaturized “microchannels”) that enable the analysis of precious patient samples with different anti-cancer drugs to learn the mechanism of NF-kB activity and how to modulate such an activity in these cells.  We are also aiming to learn what other signaling pathways are altered in these cells as they become resistant to different combinations of cancer drugs.  Finally, we are screening chemical compounds to identify potential candidates for new anticancer drugs targeting resistant pathways.  Ultimately, we want to develop a strategy to screen individual patient samples to help tailor personalized treatments.