Row 1: P Tang, J Stanek
Row 2: L Miles, J Mortensen, J Mo
Row 3: K Setchell, R McMasters, M Collins, K Wikenheiser-Brokamp, J Yin
Row 4: T Boyd, K Bove, K Stringer, D Witte, A Gupta
Molecular Basis for Lung Disease
Kathryn Wikenheiser-Brokamp, MD, PhD, is a clinical pathologist with research programs in lung development and cancer. Her laboratory studies the genetic and developmental basis of lung disease, with specific interest in identifying the molecular underpinnings of lung cancer and pediatric cystic lung disease. She has identified critical functions for the Rb/p16 and p53 tumor suppressive pathways in pulmonary epithelial cell growth in the context of lung development, injury repair and carcinogenesis. These studies are supported by a National Institutes of Health RO1 grant and funding from the American Cancer Society. Wikenheiser-Brokamp is part of a multi-institutional, interdisciplinary team of physicians and researchers that recently discovered DICER1 mutations in a familial tumor predisposition syndrome that develop pleuropulmonary blastoma (PPB). This work was published in Science in 2009 and represents the first human syndrome associated with DICER1 mutations. She leads the consortium toward elucidating how DICER1, and the microRNAs it generates, controls organogenesis and oncogenesis. In addition to the NIH grant (2011-2015), she received three grants from the St. Baldrick’s Foundation (2009-2016). The most recent St. Baldrick’s Research Consortium Grant supports the basic science studies and development of the International PPB Treatment and Biology Registry.
Targeting Genes for Drug-Resistant Tumors
The introduction of Gleevec (imatinib mesylate) as a targeted therapeutic agent has changed the management of chronic myelogenous leukemia (CML) and played a significant role in developing key concepts for targeting other oncogenic kinases such as EGFR, c-KIT, PDGFRA, PDGFRB and BRAF. Targeted inhibition of these oncogenic kinases by small molecule inhibitors induces hematologic remission in leukemias and tumor regression in solid tumors. Despite this success, most patients retain molecular evidence of residual disease, and emergence of drug resistance limits the prospects for cure. Mohammad Azam, PhD, hypothesizes that a clear understanding of oncogene addiction in imatinib-responsive cells will allow strategies to target the intrinsic resistance of leukemia stem cells (LSCs). Recent work in his lab includes a comparative expression profiling studies of imatinib-responsive and -resistant cells, which suggests c-Fos, Dusp1, Dusp10 and mir-279 are critical mediators of imatinib-mediated therapeutic response. Eradication of these cancer stem cells is probably a critical part of any successful anticancer therapy. This work is aimed to target these identified genes using genetic and pharmacological agents in LSCs of CML. He anticipates engineering the oncogene addiction in LSCs either by genetic or pharmacological means to develop a curative response.
Cancer Biology Program
Cincinnati Children’s is a nationally recognized center for diagnostic evaluation and management of children with malignancies of the hematopoietic system. We are also building a world-class research program in cancer biology to support this clinical program. The focus is to dissect hematopoietic and cancer cell signaling networks at the molecular level. The Division of Pathology has joined with the Hematology /Oncology Research Division under the direction of Yi Zheng, PhD, to build a larger comprehensive joint program of research in leukemia and stem cell biology. An example of this successful joint effort includes the work of Gang Huang, PhD, in the Division of Pathology. He has recently obtained funding from the Ohio Cancer Research Associates to study the “Molecular Mechanisms of Leukemogenesis Mediated by MLL-partial tandem Duplication (MLL-PTD).” MLL-related leukemogenesis has been researched for nearly 20 years. There are still many unknown roles in how MLL causes leukemias. Huang, based on his original study, proposes an elegantly designed step-wise approach to investigate the non-Hoxs MLL downstream targets, the MLL/RUNXl/CBF beta/PU.l network in leukemogenesis. These focuses will potentially provide a scientific foundation in understanding the heterogeneity of MLL-leukemias that may potentially lead to more precise targeting therapy for leukemia patients.