Christopher A. Klug, Ph.D.

One of the major goals of our research efforts is to use animal models to understand the factors that influence the initiation and progression of acute myeloid leukemia (AML) and pancreatic ductal adenocarcinoma (PDAC). AML is a molecularly heterogeneous disease that accounts for about 80% of all acute leukemia cases in adult humans. The two most common AML subtypes are characterized by chromosomal translocations that disrupt the function of the same transcription factor complex, core-binding factor (CBF), which is essential for normal hematopoietic stem cell formation and myeloid lineage development. Animal models of CBF leukemias are readily generated by introducing translocation fusion genes into mouse stem cells using retroviral vectors that co-express green fluorescent protein to allow tracking of cells expressing oncogenic fusion proteins in animals reconstituted with retrovirally transduced cells. These models are ideal for monitoring the pre-leukemic state and for assessing factors that promote tumor progression. They are also very useful for monitoring responses to novel therapeutics in vivo. With respect to pancreatic cancer, a number of inducible mouse models expressing mutant Kras on tp53-mutant backgrounds have become available that histologically recapitulate well-characterized stages of human PDAC, with evidence of early-stage pancreatic neoplasia that is localized to the pancreas, as well as stages where transformed ductal epithelial cells have metastasized to peripheral tissues. We are currently using these mice to identify serum protein and lipid biomarkers that are representative of an early, organ-confined stage of disease to allow for early detection of cancer and to identify pathways that promote chemotherapy resistance in more advanced disease. Pancreatic cancer is one of the most fatal human malignancies, with an overall 5-year survival rate of less than 4 percent, so development of novel therapeutics is essential for improving the prognosis of PDAC.

Frances Lund, Ph.D.

One of the projects in the Lund laboratory evaluates whether drugs that modulate the cellular redox rate can be used to treat lymphoid tumors. Regulation of the cellular redox state is critical for numerous cellular activities including energy metabolism, signaling and transcription. Hematopoietic tumors are prone to intrinsic oxidative stress due to reactive oxygen species (ROS) produced during oxidative phosphorylation. These tumors must constantly rebalance their redox state to survive in the pro-oxidant environment. The cellular redox state is controlled by the NAD/NADH and NADP/NADPH redox partners and tumors are dependent on increased NAD biosynthesis to support their augmented metabolism. In our project we evaluate whether CD38, a NAD(P)-consuming ecto-enzyme expressed by many B cell malignancies, promotes the survival or growth of B cell tumors with the long-term goal of identifying new types of chemotherapy to treat B cell malignancies like multiple myeloma and chronic lymphocytic leukemia.

Guangxiang G. Luo, M.D.

Hepatocellular carcinoma (HCC) is the most commonly diagnosed malignancy of the liver with a poor five-year survival rate (7%) due to its late presentation and resistance to chemotherapy. HCC ranks as the fifth most common cancer type and the third leading cause of cancer death worldwide. In the United States, HCC is the most rapidly increasing type of cancer with annual deaths of more than 14,000. Hepatitis B (HBV) and C (HCV) viruses are the major causes of HCC development, accounting for more than 70% cases. Approximately 400 million people worldwide are chronically infected with HBV and HCV. Therefore, HBV- and HCV-induced HCC represents a major burden of global health. We have developed cell culture systems of HBV and HCV infection and/or replication in both human and mouse hepatocytes. We have also made transgenic mice expressing a functional full-length viral RNA of genotype 2a HCV. Interestingly, HCV replication in transgenic mice resulted in HCC development. However, the underlying molecular mechanism of HCV-induced HCC remains unknown. Over the last decade, compelling evidence has emerged in support of the concept that hepatic cancer stem cells (CSCs) are responsible for initiation and progression of HCC. Through profiling and characterization of hepatic CSCs, we will determine the role and underlying molecular mechanisms of virus-induced hepatic CSCs using multidisciplinary approaches, including cell biological, genetic, genomic, and proteomic technologies. We will also search for reliable biomarkers for diagnosis and/or prognosis of HCC. More importantly, we are interested in identifying safe and efficacious therapeutic agents for treatment of HCC.

Hui Hu, Ph.D.

The Hu laboratory is interested in finding ways to activate T cells under immunosuppressive circumstances. Much of the understanding of molecular mechanisms regulating immune responses is centered on pathways and processes that promote cell activation, division and differentiation. The Hu laboratory has demonstrated that cell-intrinsic signaling pathways are required to maintain mature T cells in a quiescent state (Nat. Immunol. 2011). If these pathways are disrupted, resting T cells become aberrantly activated even in the absence of antigen challenge. The Hu laboratory is interested in identifying regulatory genes and pathways that actively restrain T cell activation, and defining the roles of such negative regulatory pathways in controlling T cell quiescence, effector responses, memory maintenance, and tumor immunology.

Masa Kamata, Ph.D.

The major research foci of our laboratory are understanding a) how viruses or malignant cells establish and maintain prolonged infections or uncontrolled cell division, respectively, in patients under host immune pressure and b) how the host immune system can be mobilized to fight infection or cancer. To this end, we have worked to establish effective strategies using humanized mouse and non-human primate models; our aim is to develop a treatment capable of achieving a state wherein the host immune system decreases levels of virus or cancer in patients to the point where further treatment is not necessary. Our recent efforts using immunotherapeutic strategies have provided potential tools for controlling HIV-1 load as well as aggressive cancers that metastasize to the brain. These studies provide fundamental insight into the basis of host-virus and host- malignant cell interactions and ultimately identify clinically relevant therapeutic targets to augment immune responses and restore antiviral or anticancer immunity in patients.

Jan Novak, Ph.D.

Dr. Novak’s research interests in Cancer include glycoimmunobiology and glycoimmunopathology as they relate to structure and function of antibodies and other glycoproteins in cancer, such as multiple myeloma and different types of adenocarcinoma (e.g., breast cancer).

Jamil S. Saad, Ph.D.

Apoptosis is a strictly regulated process by which abnormal cells are removed from the body without altering the immune system or generating an inflammatory response. Inappropriate apoptosis (enhanced or diminished) is linked to many human diseases including neurodegenerative and autoimmune disorders, AIDS, and many types of cancers. The apoptotic pathway is normally initiated by cell surface death receptors such as Fas. These receptors undergo a conformational change in response to their cognate ligands (FasL), allowing them to interact with adaptor proteins such as Fas-associated death domain (FADD). Fas-FasL interaction leads to activation of caspase 8 (by FADD) and formation of death-inducing signaling complex (DISC). DISC formation and subsequent protein recruitment is a critical initial step in regulating Fas-mediated apoptosis. There is compelling evidence that Fas interacts with various molecules, suggesting that Fas signaling is complex and regulated by multiple proteins. Among these is calmodulin (CaM), which is recruited into DISC in cholangiocarcinoma cells. It has been hypothesized that Fas-CaM interaction may affect Fas-FADD interaction and thus regulates DISC assembly and inhibits apoptosis in cholangiocarcinoma and other cancer cells. Thus, Fas-CaM interaction appears to be an inhibitory component of DISC and may play a vital role in obstruction of caspases activation. Our lab is interested in understanding the structural determinants of Fas-CaM interaction, which will be critical to understanding the precise molecular mechanism of Fas-mediated apoptosis and mechanism of inhibition. These studies will likely lead to developing new strategies to develop inhibitors of these interactions and thus to cancer treatment.