Combining medical training as a hematologist with a doctoral degree, Dr. Wiestner’s goal is to align his research in lymphoid malignancies as closely as possible with clinical translation. Using samples of blood, bone marrow, and lymph nodes collected from patients during clinical trials for chronic lymphocytic leukemia (CLL) and the related mantle cell lymphoma (MCL), he aims to improve therapeutic strategies by identifying the critical molecular drivers of disease pathogenesis and understanding the impact of existing therapies on tumor cell stress responses and the development of drug resistance.
Using gene expression profiling of cells from MCL patients undergoing bortezomib treatment, Dr. Wiestner and his colleagues demonstrated that bortezomib, through inhibition of proteasome function, causes an abnormal accumulation of proteins. This results in two overlapping stress responses in these tumors; one due to the increased protein load in the endoplasmic reticulum (ER) and the other due to the generation of reactive oxygen species (ROS). Patients who respond well to the drug show a very strong antioxidant response, suggesting that tumor cells are overwhelmed rather than incapable of fighting back. Resistant cells appear to have a higher basal level of antioxidant gene expression, suggesting that they are more competent in handling ROS stress. Complementary insights into bortezomib resistance came from the generation of MCL cell lines that are 50-100 times less sensitive to the drug. Dr. Wiestner and his colleagues have shown that the acquisition of bortezomib resistance, which is a slow and reversible process, correlates with an increase in the expression of genes that are typically expressed in plasma cells, including genes coding for protein chaperones and antioxidant functions. This “partial plasma cell program” endows cells with the capacity to handle high protein load and could be the key to MCL drug resistance. Clinically, a subset of bortezomib-resistant MCL indeed does show features of plasma cell differentiation, and is less sensitive to bortezomib.
For CLL, a number of studies using in vitro models have put forth candidate pathways that may be important for disease progression. Using gene expression profiling and analysis of signaling proteins, Dr. Wiestner and his colleagues demonstrated that CLL cells in the lymph node appear to be activated through a few distinct pathways, one of which operates through the B cell receptor. B cell receptor signaling inhibitors have been developed and have potent activity in certain lymphoid malignancies including CLL and MCL. Based on these observations, Dr. Wiestner’s team designed a clinical trial to study CLL cells isolated from the lymph node before and after treatment with B-cell receptor inhibitors. The goal is to study and contrast the impact of these inhibitors on the B-cell receptor pathway in patients that respond to therapy or develop resistance.
Dr. Wiestner’s group has also investigated the anti-tumor effects of lenalidomide in CLL and found that the drug induces a strikingly potent immune response that results in tumor shrinkage. Learning more about the biological action of single therapeutics allows for the design of rational combination therapies that have the potential to overcome the resistance that often develops with single agent therapies over time.
Dr. Wiestner’s group has several ongoing clinical studies being conducted at the NIH clinical center (www.clinicalcenter.nih.gov) in Bethesda, MD that are open to patients from all over the United States. These clinical trials range in scope from observational studies for untreated CLL patients (NCT00923507) to treatment trials using novel and emerging drugs such as the BTK inhibitor ibrutinib (formerly PCI-32765; NCT01500733) or the fully humanized anti CD20 antibody ofatumumab (NCT01145209). For participant information please refer to www.clinicaltrials.gov, and enter the NCT identifier into the search field.