Apoptotic and Survival Signaling in tumor cells: Therapeutic Implications
Multiple Myeloma (MM) is diagnosed in 15,000 new individuals annually. The median survival has been prolonged from 3-4 to 7 years, especially in patients less than age 50. However, despite important advances including biological agents bortezomib, thalidomide, and lenalidomide, MM remains incurable due to the development of drug resistance, which manifests as relapsed/refractory disease. The molecular mechanisms whereby MM cells evade drug-induced cytotoxicity and acquire drug-resistant phenotypes include interaction of MM cells with their bone marrow (BM) microenvironment. The BM milieu contains stromal cells (BMSCs), osteoclasts, myeloid cells, and immune effector cells. BMSCs promote growth and drug resistance in MM cells; however, the functional significance of other BM cellular components is unclear. Our recent study showed increased numbers and more frequent localization of plasmacytoid dendritic cells (pDCs) in MM patient BM than normal BM. Functional analysis using in vitro and in vivo models of human MM in the BM milieu shows that pDCs confer growth, survival, chemotaxis, and drug resistance. Importantly, targeting Toll-like receptors with CpG ODNs improves immune function of pDCs and abrogates pDC-induced MM cell growth. These findings identify an integral role of pDCs in MM pathogenesis and provide the basis for targeting pDC-MM interactions as therapeutic strategy to improve patient outcome.
Genomics and proteomics studies have identified therapeutic targets to interrupt growth and/or amplify apoptotic signaling in MM cells to enhance cytotoxicity and overcome drug resistance. Our recent studies have utilized novel drugs that target molecules on the MM cell surface, cytoplasm, mitochondria, endoplasmic reticulum, and nucleus. In addition, preclinical studies are examining the combination of biochemical inhibitors of growth/survival signaling pathways with standard therapeutic agents to increase overall MM cell apoptosis. Many of these new agents are currently being evaluated in clinical trials.
Another major area of research in our laboratory is the ubiquitin-proteasome pathway (UPP). Previous reports have established that UPP modulates intracellular protein degradation. Specifically, the multi-enzyme protease 26S proteasome degrades misfolded or redundant proteins, while blockade of the proteasomal degradation pathways results in the accumulation of unwanted proteins and cell death. Because cancer cells proliferate more than normal cells, the rate of protein translation and degradation is also higher in cancer cells. This discovery led to the development of proteasome inhibitors as therapeutics in cancer. The FDA recently approved the first proteasome inhibitor bortezomib (Velcade), formerly known as PS-341, for the treatment of relapsed/refractory MM. However, prolonged treatment with bortezomib is associated with toxicity and the development of drug resistance.
Our recent study shows that the novel proteasome inhibitor NPI-0052 induces apoptosis even in bortezomib-resistant MM cells. NPI-0052 is distinct from bortezomib in its chemical structure, effects on proteasome activities, mechanisms of action, toxicity profile against normal cells, and bioactivity. In animal model studies, NPI-0052 cured 57% of treated mice, was well tolerated, and prolonged survival. Combining NPI-0052 and bortezomib induces synergistic apoptosis in MM cells; therefore, our study provides rationale for clinical protocols evaluating NPI-0052, alone or in combination with bortezomib.