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Laboratory of Molecular Biology

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Overview

The Laboratory of Molecular Biology uses genetics, molecular biology, cell biology, and molecular modeling to examine and solve a broad range of important biological problems.

The Molecular Biology Section carries out research directed at designing, producing, and testing new agents (recombinant immunotoxins) to treat cancer. Recombinant immunotoxins (RIT) are genetically modified forms of Pseudomonas exotoxin A that are targeted to cancer cells by Fv portion of antibodies. Three recombinant immunotoxins that have been developed in the LMB are now in clinical trials. The most advanced of these is moxetumomab pasudotox that targets CD22 on B cell malignancies. It has produced many complete and partial remissions in drug resistant Hairy Cell Leukemia, several in children with ALL and is being evaluated in multi-center trials in other B cell malignancies. A second RIT is named SS1P and is directed at mesothelin expressing cancers, which include mesotheliomas, cholangiocarcinomas and cancers of the lung, ovary and pancreas. SS1P has shown activity in phase 1 trials and is now being evaluated in combination with chemotherapy in mesothelioma patients. Based on information gained in clinical trials, we use protein engineering to make these proteins more useful in patients by increasing their activity, decreasing their side effects and decreasing their immunogenicity so more treatment cycles can be given before antibodies develop.

The Clinical Immunotherapy Section directs clinical trials of recombinant immunotoxins for hematologic malignancies, most prominently hairy cell leukemia, and develops new agents and combinations for this disease. The section also conducts laboratory research using new agents, as well as clinical samples obtained from patients, to better understand the mechanisms of immunotoxin toxicity and efficacy, ultimately to improve clinical targeting. LMB-2, targeting CD25, is being used in phase II trials in patients with hairy cell leukemia (HCL), adult-T-cell leukemia (ATL) and cutaneous T-cell lymphoma (CTCL). Moxetumomab pasudotox, also called HA22 or CAT-8015, targeting CD22, is being tested in phase I/II studies in patients with HCL, chronic lymphocytic leukemia (CLL) and non-Hodgkins lymphoma (NHL). Randomized trials are also conducted testing the anti-CD20 MAb rituximab given simultaneously or sequentially after cladribine for early HCL, and comparing rituximab with either bendamustine or pentostatin for multiply relapsed/refractory HCL. The lab tests samples from patients with HCL to 1) study minimal residual disease, 2) better understand the origin and biology of HCL, and 3) determine toxicity against the normal B- and T-cell repertoire. HCL and CLL samples are tested in the lab to determine their sensitivity to recombinant immunotoxins including new agents. The lab also conducts animal studies to model combinations of chemotherapy and immunotoxins, to improve response and decrease the ability of the immune system to make antibodies which neutralize the effect of immunotoxins.

The Solid Tumor Immunotherapy Section conducts translational research for treatment of mesothelioma and lung cancer. A major focus of this section is to exploit the tumor differentiation antigen mesothelin for treatment of mesothelioma. There are ongoing clinical trials of an anti-mesothelin immunotoxin (SS1P) as well as an anti-mesothelin monoclonal antibody (MORAb-009) in combination with chemotherapy for treatment of pleural mesothelioma. In addition, research in this section is focused on targeting the insulin growth factor receptor-1 (IGF-1R) for treatment of mesothelioma and there is an ongoing clinical trial of the anti-IGF1-R monoclonal antibody, IMC-A12 in patients who have failed standard therapies for mesothelioma. Laboratory research conducted in this section is also directed at better understanding the biology of mesothelioma using tumor and serum samples from patients.

The Biotherapy Section studies the structure and function of Pseudomonas exotoxin (PE) and applies this knowledge to the design of recombinant antibody-toxin fusion proteins (immunotoxins). An immunotoxin directed to CD22 is currently being evaluated for the treatment of patients with B cell malignancies. Because immunotoxins exhibit limited cell killing activity against certain cancers, we are exploring strategies to enhance toxin-mediated apoptosis. Currently, this effort is focused on the use of chemical compounds that neutralize prosurvival proteins and/or enhance toxin delivery to the cell cytosol. A second toxin, an exotoxin from V. cholerae, is also being developed as an immunotoxin component. This toxin appears structurally similar but immunologically distinct when compared with PE.

The Antibody Therapy Unit conducts mechanistically-based research leading to the generation of novel monoclonal antibodies and immunoconjugates directed at potential cancer therapy targets. One project involves studying the molecular mechanisms underlying the role of glypican-3 in the pathogenesis of hepatocellular carcinoma in addition to developing therapeutic monoclonal antibodies. Another major project focuses on monoclonal antibodies and immunocytokines targeting mesothelin in mesothelioma, cholangiocarcinoma and ovarian cancer. We have established an in vitro tumor spheroid model for the purpose of analyzing antibody penetration in solid tumors. We have also developed an innovative method (called mammalian cell display) to isolate functional single-chain Fv antibodies on human cells by flow cytometry.

Researchers in the Molecular Modeling Section conduct studies in structural bioinformatics and molecular and mathematical modeling. Our main current interest is in detecting inherently symmetric proteins in the protein structure database and characterizing their symmetry and structure. We are also refining a mathematical model built earlier for the process by which the administered immunotoxin is delivered through the tumor tissue into the cancer cells to kill them. Recently, we have began to build models of the structure of the transcription factor STAT tetramer in complex with DNA.

In the Gene Regulation Section, investigators have created mouse models of human diseases-including resistance to thyroid hormone, thyroid cancer, pituitary tumors, and dwarfism-by targeting mutations of thyroid hormone receptors to the gene locus. Using these knock-in mice, we investigate molecular events in the development and progression of these diseases. Current efforts are focused on elucidating aberrant molecular signaling pathways of mutant receptors underlying the carcinogenesis of thyroid cancer and on identifying molecular targets for prevention, diagnosis, and treatment.

In the Developmental Genetics Section, mechanism and control of gene transcription are studied with emphasis on structure, function, and dynamics of the transcription intermediates and their regulatory complexes. The latter include regulatory DNA-multiprotein complexes containing bifunctional transcription factors (gene activators and repressors), for example, cAMP receptor protein (CRP), Gal repressor (GalR) and histone like protein (HU). Another set of studies is focused on developing bacteriophage strains as agents in the diagnosis and curing of infections diseases in animals and humans.

The Biochemical Genetics Section is focused on studies of novel regulatory mechanisms and their use in complex regulatory circuits in bacteria. In particular, the lab is currently focusing on small regulatory RNAs and regulated proteolysis. Novel methods for identifying regulatory RNAs and studying their mechanism of action and roles in regulation are all of interest. In studies of regulated proteolysis, we study ways in which proteins are delivered to the protease and how this process is perturbed by small protein regulators.

Investigators in the DNA Molecular Biology Section study the mechanisms by which ATP-dependent molecular chaperone machines reactivate damaged proteins, solubilize protein aggregates and target irreversibly inactivated proteins for proteolysis. Chaperones function during non-stress conditions to promote folding, stability and activation of many essential proteins and to facilitate the degradation of misfolded proteins. Following cell stress, chaperones disaggregate and reactivate damaged proteins. Understanding how molecular chaperones function and how they interact with proteases is providing the foundation for the development of drugs that target chaperones for use in treating cancer and diseases of protein aggregation and misfolding, such as Alzheimer's disease, Parkinson's disease and cystic fibrosis.

Researchers in the Cell Biology Unit study how proteins localize to particular regions within the cell and how they subsequently assemble into large structures. Currently, the lab is investigating how a cell's shape can drive the localization and function of proteins during development and cell division. The lab employs cytological, genetic, and biochemical approaches in order to understand how a cell ultimately assumes its proper morphology.

This page was last updated on 1/7/2013.