The University of Chicago Hematology/Oncology section conducts a wide range of cutting edge research for advancements in the treatment of cancer in both the laboratory and clinical setting. Some of our basic research includes the following fields: developmental biology and genetics, cellular biology including intracellular pathways and signal transduction, drug resistance and development, cytogenetics, tumor immunology, transplant biology, and protein targeting. Much of our basic research carries over into clinical studies. With our clinical research, the Hematology/Oncology section believes in a multimodality (a combination of treatments) and multi-disciplinary approach that includes laboratory research and clinical research in our pursuit for the best treatment and care for our patients. One of the only institutions to have clinical trials in Phase I, Phase II, and Phase III of drug development, the distinguished faculty have ongoing investigations in each of these phases. By interacting with cooperative research groups like the Alliance for Clinical Trials in Oncology , our cancer program is able to offer advantages to patients with all types of cancer by having access to top research teams across the U.S. and the world.
Dr. Dolan’s research interests include: the modulation of O6-alkylguanine-DNA alkyltransferase (AGT), the role of DNA repair in protection against therapy related leukemia and the pharmacogenetics of anticancer agents. Dr. Dolan research has focused on modulation of O6-alkylguanine-DNA alkyltransferase (AGT), a DNA repair protein responsible for repairing damage at the O6-position of guanine in DNA. Damage at this position by chemotherapeutic methylating or chloroethylating agents results in cytotoxicity, therefore the presence of AGT in tumor cells confers resistance to these agents. She has designed O6-benzylguanine (BG), an inactivator of the AGT protein based on our understanding of the substrate specificity of the protein and the SN2 bimolecular nature of the reaction. The preclinical and clinical development of BG has been a major focus of her laboratory. They have incorporated biochemical, pharmacokinetic, pharmacodynamic and metabolic correlative studies into ongoing clinical trials. Her laboratory has identified the enzymes responsible for conversion of BG to its metabolites and studied drug-drug interactions. Research has recently found that BG enhances the toxicity of other bi-functional agents (i.e. cisplatin, carboplatin, cyclophosphamide) not known to produce an O6-guanine adduct. Enhancement is independent of AGT status indicating a separate and novel mechanism possibly within nucleotide excision repair (NER) or homologous recombination repair (HR). Modulation of repair pathways acting on the damage produced by cisplatin represents a novel route for improving its clinical efficacy.
Cyclophosphamide is an anticancer agent that is converted to PM, the metabolite responsible for antitumor activity and acrolein, a toxic byproduct thought to be responsible for bladder carcinogenesis and secondary leukemia. Dr. Dolan’s laboratory demonstrated an important role for AGT in protecting against the mutagenic effects of cyclophosphamide. Although there were some conflicting reports regarding the importance of AGT and cyclophosphamide activity, their data indicated that AGT protected against the toxic byproduct, acrolein, not PM. The implications of this finding are 1) AGT may play a role in the protection of therapy related leukemia associated with this agent; 2) AGT may protect against bladder toxicity and carcinogenesis; 3) Overexpression of AGT in hematopoietic stem cells or bladder may be a means to protect against these devastating side effects. They are currently identifying the acrolein-DNA lesion(s) in DNA repaired by the AGT protein. Using Nf1 mice crossed with AGT-knockout mice we are establishing the role of this DNA repair protein in therapy related leukemia induced by cyclophosphamide and other alkylating agents.
Dr. Dolan’s laboratory is also investigating the pharmacogenetics of anticancer agents. In order to identify genetic variables responsible for differences among individuals in drug efficacy and/or host toxicity, they are involved in the discovery of genetic polymorphisms (genotype) responsible for differences in the rate of metabolism of chemotherapeutic agents to their active or inactive metabolite (phenotype). The objective is to determine whether polymorphisms within genes are responsible for differences in metabolism of drugs that ultimately affect response or toxicity. They are evaluating human carboxylesterase, an enzyme responsible for conversion of CPT-11 to its active component, SN-38. There are 2 known isoforms of human carboxylesterase, hCE1 and hCE2. They have demonstrated that hCE2 was primarily responsible for the conversion of CPT-11 to its active component SN-38. Her laboratory has now identified a number of single nucleotide polymorphisms in human carboxylesterase 1 and 2 and is working on the promoter structure of hCE2 and correlating phenotype to genotype.
Dr. Lucy Godley
Dr. Godley’s laboratory focuses on elucidating molecular mechanisms of tumorigenesis. Specifically, they work in two general areas: (1) understanding how cancer cells develop altered DNA methylation and exploring the consequences of the disturbed methylation; and (2) determining the secondary events that occur during leukemogenesis. In project 1, cancer cells exhibit abnormal DNA methylation, although the precise mechanism(s) by which this occurs is not clear. Repetitive sequences are hypomethylated relative to normal cells, and the promoters of particular genes are hypermethylated, causing gene silencing. Both of these aberrations in DNA methylation contribute to the phenotype of cancer cells. Cancer cells are characterized by numerous abnormalities in chromosomal stability, growth control, and apoptosis. The hypomethylated repetitive sequences seen in cancer cells are thought to contribute to the formation of the chromosomal rearrangements found in virtually all cancer cells. Understanding the molecular mechanisms through which DNA methylation is established and maintained in cancer cells is likely to provide important insights that may lead to novel diagnostic strategies and therapeutic interventions.
Dr. Godley’s laboratory has made the initial observation that cancer cells exhibit aberrant splicing of DNMT3b, encoding one of the de novo methylases. Dr. Godley has observed over 20 abnormal splicing events in cancer cells, both in solid as well as in hematopoietic tumors. All of these splicing forms are predicted to encode truncated versions of DNMT3B. They have studied one transcript in particular, DNMT3B7, because it is expressed in virtually all of the tumor cells that we have examined as well as in primary tumor cells from patients with acute myeloid leukemia. They are currently studying how truncated DNMT3B proteins affect the DNA methylation state of cancer cells.
In project 2, leukemia’s, like all cancers, develop from multiple abnormal processes within cells. Dr. Godley is particularly interested in making observations about leukemia that ultimately can be directly translated from the laboratory back to the clinic. She has studied two patients with mast cell leukemia and has demonstrated that they express novel C-KIT transcripts. Her investigations are currently focused on understanding the effects of the abnormal C-KIT proteins produced by these transcripts and determining if these transcripts are seen in any other forms of leukemia. She is also interested in examining unusual cases of bone marrow malignancies by molecular analyses.
Dr. Michelle Le Beau
Dr. Le Beau’s research focuses on the molecular analysis of the recurring chromosomal abnormalities in human leukemia’s and lymphomas. During the past decade, the genes that are located at the breakpoints of a number of recurring chromosomal abnormalities in human tumors have been identified. Molecular analysis has revealed that alterations in the level of expression of these genes, or in the properties of the encoded proteins resulting from the chromosomal rearrangement, play an integral role in the process of malignant transformation. Dr. Le Beau has a long-standing interest in identifying the recurring chromosomal abnormalities in human tumors, and correlating specific chromosomal abnormalities with morphological and clinical features of the neoplastic disease, such as response to therapy and survival.
Dr. LeBeau’s ongoing research projects include the molecular cloning of a myeloid leukemia-related gene involved in the –5/del(5q) characteristic of the major subtype of therapy-related acute myeloid leukemia (alkylating-agent induced); genetic characterization of murine models for acute myeloid leukemia (RUNX1/ETO, PML-RARA, BXH2, NF1+/-, KRAS), and identification of secondary, cooperating mutations and genetic pathways to leukemogenesis; and the determination of the mechanism for the genetic instability characteristic of chromosomal fragile sites (loci which are prone to undergo breakage and rearrangement). These studies involve the analysis of DNA replication, chromatin structure, and cell cycle checkpoints in fragile site instability, as well as the role of DNA repair pathways in mediating repair of damage at fragile sites.
Dr. Mark Ratain
Dr. Ratain’s research is focused on the pharmacogenetics of anticancer agents. Dr. Ratain has investigated the importance of UDP-glucuronosyltransferase transferases, particularly UGT1A1, UGT1A9 and UGT2B7, on the metabolism of anticancer agents. He has demonstrated the critical importance of genetic variants in the UGT1A1 gene in determining variability in the pharmacokinetics and toxicity of irinotecan. His research has also focused on the pharmacogenetics of EGFR-targeting anticancer drugs. This research has become a model for understanding variability in response to the newer targeted drugs, such as angiogenesis inhibitors. The ultimate goal of Dr. Ratain’s research is to help tailor medicines to a person’s unique genetic make-up which will ultimately make medicines safer and more effective.
Dr. Michael Thirman
Dr. Thirman’s laboratory explores the normal functions of the MLL and ELL genes and their aberrant functions in acute leukemia. The MLL gene at chromosome band 11q23 is rearranged frequently in de novo and therapy-related leukemia. His lab cloned the ELL gene at 19p13.1 from leukemia cells with the t(11;19)(q23;p13.1). The consequence of this translocation is the formation of a chimeric protein that contains the amino-terminus of MLL fused in frame to carboxy-terminal sequences of ELL. These leukemias arise as a result of chromosomal recombination event followed by a selective advantage to the cell gained from expression of an MLL-ELL fusion protein. To characterize the pathways that are normally regulated by ELL and the mechanism that disrupts these pathways in acute leukemia, they have sought to identify proteins that interact with ELL. Using a yeast two-hybrid screen, they have isolated and cloned two genes, EAF1 and EAF2, which encode novel proteins that interact with ELL. They have generated specific antibodies to ELL, EAF1, and EAF2, and have demonstrated that these proteins exist in a complex by coimmunoprecipitation. By confocal microscopy, they have determined that ELL, EAF1, and EAF2 colocalize in a nuclear organelle referred to as the Cajal body.
To characterize MLL-ELL leukemias in detail, two alternative strategies have been used to develop mouse models of MLL-ELL leukemia. Using retroviral infection of bone marrow followed by transplantation, recipient mice all develop acute leukemia in 4-6 months. In contrast, in a knock-in model of MLL-ELL generated by gene targeting, chimeric and heterozygous mice do not develop leukemia and exhibit no apparent hematopoietic phenotype, indicating that expression of the MLL-ELL fusion protein is insufficient by itself for the development of acute leukemia. However, treatment of the knock-in mice with ENU induces acute leukemia in 90% of mice that recapitulates the phenotype observed in the retroviral transplant model and human acute leukemias in patients with (11;19)(q23;p13.1) translocations. These data indicate that “second hits” are necessary for the development of MLL-ELL leukemia. Using these mouse models of leukemia and studies on the protein-protein interactions of MLL-ELL as a platform for translational research, we plan to develop novel treatment strategies for MLL-associated leukemias.
Dr. Amittha Wickrema
Dr. Wickrema’s laboratory is investigating the signaling pathways regulating normal and malignant hematopoiesis. In the area of normal hematopoiesis they are currently focused on understanding the signal transduction pathways guiding lineage commitment and terminal differentiation of erythroid cells. They are using a primary human cellular model system where early stem cells and stem cells progenitors commit to erythroid lineage, differentiate and enucleate into reticulocytes during in vitro culture. Using this model they have been able to define the signaling pathways that are vital for erythroid cell viability, proliferation and differentiation. Currently his lab is interested in identifying specific signaling molecules and transcription factors that guide the terminal events including cytoskeletal remodeling and enucleation.
The second major project in the laboratory is focused on growth control of myeloma cells. Multiple myeloma is an incurable disease that affects the plasma B cells. Secretion of Interleukin-6 by autocrine and paracrine mechanisms plays a major role in the pathobiology of the disease. Dr. Wickrema has identified several signaling cascades that are inactivated in myeloma cells contributing to suppression of cell cycle arrest and apoptosis. Current studies are focused on identifying small molecule compounds capable of reactivating these pathways in order to induce apoptosis and/or cell cycle arrest of malignant cells. These studies include identification and selection of candidate small molecule compounds, screening them for effectiveness in modulating the activity of serine/threonine and tyrosine kinases and using a mouse myeloma model to test the efficacy in vivo.
The Section of Hematology/Oncology has a very robust and successful clinical research program. Currently over 250 industry sponsored clinical trials are available to patients with:
- Lung Cancer
- Head and neck cancer
- Breast cancer
- GI Cancer
- Genitourinary Cancer
- Other solid tumors.
In addition, the Section of Hematology/Oncology is one of only a handful of institutions in the country to conduct clinical trials in Phase I, Phase II, and Phase III drug development. A Phase I trial is the first step for physicians to determine whether a potential drug can be tolerated. Presently the Section is the recipient of a Phase I grant that provides novel cancer therapies to patients who have not responded to established therapies. Phase II trials occur after a potential treatment is found to be tolerated in Phase I trials. Our clinical researchers study the effectiveness of the treatment on a specific type of cancer in a small group of patients. Phase III trials occur after Phase II generally in larger groups of patients to compare the experimental treatment’s effectiveness against standard therapy for a particular type of cancer. We are the headquarters for CALGB, Cancer and Leukemia Group B, a national network of 29 university medical centers, over 225 community hospitals and more than 3,000 oncology specialists who collaborate in clinical research studies
The main objective of our clinical research initiative is to identify less toxic and more effective treatment regimens for all types of cancers. As a result, we have discovered many innovative and cutting edge cancer therapies which often are not available at other institutions.
The majority of the faculty is dedicated to clinical research efforts and are assisted by a team of research nurses, data and regulatory coordinators who serve to facilitate data management of ongoing trials, organization of responsibilities of ancillary study staff, and coordination of follow up for patients involved in ongoing clinical trials.