Medical Oncology and Hematology
Research initiatives going on in the University of Louisville Division of Medical Oncology and Hematology, and the James Graham Brown Cancer Center.
The University of Louisville Division of Medical Oncology and Hematology is focused on the conduct of translational research in order to facilitate the rapid transfer of promising scientific discoveries from the laboratory to the patient's bedside. The long-term scientific objective of this highly collaborative group of physicians and scientists is to discover novel cancer preventative strategies, early detection methods and cancer therapeutic agents. Importantly, the division has over eighty open therapeutic trials for patients suffering from cancer and hematological disorders.
Extramural funding from the National Institutes of Health, private foundations (e.g. American Cancer Society), the Congressionally Directed Medical Research Program, the National Center for Research Resources and multiple pharmaceutical industry sponsors exceeds $25,000,000 per year.
Below, we highlight the basic, translational and clinical research programs that are currently underway.
► Paula Bates, Ph.D.: Dr. Bates' laboratory is studying antiproliferative G-rich oligonucleotides as novel anticancer agents. Her group is investigating novel G-rich oligonucleotides (GROs) that strongly inhibit the proliferation of many types of cancer cell lines, including prostate, lung, breast and cervical cancer, malignant melanoma, neuroblastoma, and several types of leukemia. This activity is apparently selective because cells derived from normal tissue are inhibited to a much lesser degree. A protein called nucleolin has been identified as a putative target of GROs. Dr. Bates is presently investigating the molecular mechanisms leading to GRO-mediated proliferation arrest, and evaluating the therapeutic potential of these novel agents in the treatment of cancer.
► Brian Clem, Ph.D.: Dr. Clem's laboratory is focused on cancer cell metabolism as a therapeutic target. He has played a critical role in the development of enzyme-specific inhibitors of 6-phosphofructo-2-kinase and choline kinase, two important enzymes of cancer metabolism. These compounds have now been derivatized and Dr. Clem is actively screening more than 200 new compounds to identify lead drug candidates. Working with the pharmaceutical company, Advanced Cancer Therapeutics, he has strong animal data supporting the clinical utility of his approach and two of these drugs are slated to be tested in a phase I trial at the James Graham Brown Cancer Center.
► J. Brad Chaires, Ph.D.: Research in Dr. Chaires' laboratory uses biophysical chemistry to enhance drug discovery and to design new clinical diagnostic tools. His group is involved in the design of small molecule therapeutic agents that recognize noncannonical DNA structures. Of particular interest are compounds that selectively recognize four-stranded G-quadruplex structures that are emerging as important functional elements within the genome. The lab has invented and implemented an integrated virtual and actual screening platform that permits screening of millions of compounds in silico for specific binding to selected nucleic acid structures, followed by experimental validation of these hits using a novel high-throughput competition dialysis method. He has also become very involved in the development of new diagnostic tools for cancer detection and has developed a new calorimetric assay for characterization of the human plasma proteome. This technology promises to provide a new tool for diagnosis and therapeutic monitoring of cancers.
► Jason Chesney, M.D., Ph.D.: Dr. Chesney's laboratory examines the metabolic properties of transformed cells in order to identify molecular targets that are required for cancer cell survival and proliferation. His group has established the requirement of several enzymes for cancer cell survival and growth and has identified novel competitive inhibitors with potent anti-tumor activities in mice that are being advanced to phase I clinical trials. Dr. Chesney also has a robust immunotherapeutic clinical trials program and recently completed an investigator-initiated trial of Denileukin Diftitox (Ontak) in advanced melanoma patients that has resulted in several long-term survivors. This agent targets a small subset of lymphomas but was found by his group to activate melanoma-specific immunity by depleting a subset of lymphocytes that suppress the immune system. Based on these results, a randomized national study with 15 separate cancer centers is currently open.
► Alfred Cunningham, Ph.D.: Dr. Cunningham is a structural biologist who is using molecular modeling to identify novel molecular targets of tissue-specific chemical-induced carcinogenesis. He plans to use this information to discover pharmacophores for new anticancer therapies that will “interact” with these targets. His group is using structure-activity relationship (SAR) modeling to define groups of tissue-specific carcinogens followed by comparative toxicogenomics and proteome analyses to identify the molecular targets they interact with or influence. He believes that new drugs based on this work will therefore predominately interact with, and be toxic only to (cancer) cells possessing the particular molecular target.
► Geoffrey J. Clark, Ph.D.: Dr. Clark studies downstream signaling pathways of the oncogene Ras which is mutated and/or activated in human cancers. He is currently attempting to determine if using small molecules to reactivate RASSF inhibitory pathways at the same time as using novel small molecules to inactivate the transforming RalGEF pathway will provide synergistic inhibition of Ras mediated transformation.
► John Eaton, Ph.D.: A primary focus of Dr. Eaton's research is biological oxidation/reduction reactions, particularly as they affect cytotoxicities caused by iron overload, xenobiotics and hyperoxia. Within this area, recent work has focused on the importance of progressive oxidant-mediated damage to mitochondrial DNA, which latter may explain the slow and insidious onset of organ failure in patients with hemochromatosis and of heart failure in patients treated with anthracycline drugs. Additionally, Dr. Eaton is testing the feasibility of the prevention of all types of cancer through vaccination against a broad spectrum of early stem cell antigens.
► Dharamvir Jain, M.D. and Elizabeth Riley, M.D.: Drs. Jain and Riley are medical oncologists who focus their clinical research programs on the testing of novel chemotherapeutics for breast cancer patients. Examples of clinical trials that they are conducting include: Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation Study; A Randomised, Multi-centre, Open-label, Phase III Study of Adjuvant Lapatinib, Trastuzumab, Their Sequence and Their Combination in Patients with HER2/ErbB2 Positive Primary Breast Cancer; A randomized Phase III, double-blind, placebo-controlled multicenter trial of daily everolimus in combination with tratuzumab and vinorelbine, in pretreated women with HER2/neu over-expressing locally advanced or metastatic breast cancer A randomized, 3 arm, multicentre, phase III study to evaluate the efficacy and the safety of T-DM1 combined with Pertuzumab or T-DM1 combined with Pertuzumab-Placebo, versus the combination of Herceptin plus taxane, as 1st line treatment in HER2 positive progressive or recurrent locally advanced or metastatic breast cancer.
► Goetz H. Kloecker, M.D.: Dr. Kloecker is a medical oncologist who is Director of the Brown Cancer Center Thoracic Oncology Program. He has had an interest in the early diagnosis of lung cancer and is currently working to develop exosomal phospholipid signatures of non-small cell lung cancer. Dr. Kloecker has developed the Brown Cancer Center Lung Cancer Biorepository which will serve as an important resource for lung cancer researchers. He also has a very active lung cancer clinical research program with over 10 trials open at the Brown Cancer Center.
► Andrew N. Lane, Ph.D.: Understanding functional aspects of molecular interactions that drive biological recognition requires a determination of the structure and dynamics of the isolated interacting components and the changes that occur on forming the complex. Dr. Lane is using nuclear magnetic resonance (NMR) on proteins and DNA labeled with stable isotopes, both for spectral simplification (13C and 15N) and for reducing dipolar relaxation (by deuteration). He is also studying the regulation of metabolism in cancer cells and tissue via stable isotope analysis. In this approach, 13C-labeled precursors such as glucose or glutamine are provided to cells or injected into pre-operative cancer patients, and individual atoms are traced through metabolic pathways to provide a detailed picture of the metabolic changes in cancers.
► Chi Li, Ph.D.: Dr. Li's research interest is on the molecular basis of reduced programmed cell death in malignant cells. He has shown that intracellular organelles possess sensors that detect specific cell death-inducing signals and activate different signal transduction pathways. His work is elucidating the detailed molecular mechanisms regulating the ER-dependent cell death signaling pathways, including the mechanisms of the disruption of the ER membrane during cell death, the death signaling pathways mediated by released ER lumen proteins, the profile of released ER lumen proteins in response to different death stimuli and the mechanism by which ER-specific death pathway interacts with the mitochondria-dependent death signaling pathway. These studies should lead to the development of novel classes of chemotherapeutic agents.
► Donald M. Miller, M.D., Ph.D.: Dr. Miller's laboratory group has discovered a unique tumor suppressor gene, MBP-1, which appears to play a role in the development of breast cancer and other endocrine-related tumors. Interestingly, when they sequenced this gene it was found to represent a truncated form of α-enolase, an important enzyme in the glycolytic pathway. Work underway in the laboratory is studying the potential utility of this bifunctional gene as a therapeutic target. Dr. Miller's group also discovered the antiproliferative properties of quadruplex-forming oligonucleotides and phase I clinical trials revealed no toxicity and surprising effectiveness in two patients with renal cell carcinoma. The agent (named AS1411) is now being developed by the British biotech company, Antisoma, which is conducting phase II clinical trials in renal cell carcinoma and acute myeloid leukemia.
► Robert A. Mitchell, Ph.D.: Dr. Mitchell's research focuses on the pro-inflammatory cytokine, macrophage migration inhibitory factor (MIF). Their recent investigations show important roles for MIF in modulation of cell cycle regulatory pathways central to oncogene-mediated malignant transformation, hypoxic adaptation and tumor-associated angiogenesis. Dr. Mitchell is currently examining the precise contribution of MIF to hypoxia-inducible factor 1 alpha (HIF-1α) stabilization and subsequent modulation to hypoxic adaptation within a tumor's micro-environment. In a second area, they are establishing several in vivo models of tumorigenesis to determine the precise role of MIF in the development of different human malignancies. Dr. Mitchell's laboratory, in collaboration with Dr. John Trent, also has a very active program in anti-MIF drug discovery that has recently resulted in discovery of the most effective small molecule inhibitor of MIF.
► Mariusz Z. Ratajczak M.D., Ph.D., D.Sci.: Dr. Ratajczak is investigating the role of CXCR4 positive very small embryonic-like (VSEL) stem cells in tissue and organ regeneration. Recently, he identified these CXCR4+ circulating pluripotent VSEL stem cells that seem to compete for SDF-1 positive niches. He is developing new strategies to isolate those cells from bone marrow, mobilized peripheral blood, cord blood and peripheral tissues. Dr. Ratajczak also is pursuing the hypothesis that the metastasis of cancer stem cells and trafficking of normal stem cells involve similar mechanisms, and he is elucidating the common molecular mechanisms involved in these processes. Dr. Ratajczak also is working on the biological effects of microvesicles. Recently, microvesicles, isolated from embryonic stem cells, were used by his group to improve ex vivo expansion and survival of hematopoietic stem/progenitor cells.
► Guilherme Rabinowitz, M.D.: Dr. Rabinowitz is a Medical Oncologist who has recently joined the faculty as Medical Director of the Multidisciplinary Head and Neck Cancer Clinic. Dr. Rabinowitz has received an ASCO Career Development award for his work in exosomal microRNA as a biomarker for malignancy. As a Medical Oncology fellow, he completed a study which demonstrated differences in exosomal microRNA in patients with lung cancer. He is now extending that study to patients with squamous cell carcinoma of the head and neck. Additionally, he is sponsored to conduct the following clinical trial: A Phase 3 Randomized Trial of Concurrent Cisplatin and Radiotherapy with or without OncoVEX in Previously Untreated Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck.
► Brad K. Rodu, D.D.S.: Dr. Rodu's research focus has been on tobacco harm reduction, involving the substitution of safer tobacco products for smokers who are unable or unwilling to quit smoking with conventional cessation methods. His published research includes epidemiologic models regarding life expectancy of tobacco users, prevalence studies of tobacco use and adverse health consequences in Sweden, and laboratory analyses of tobacco products. For more information about this research, visit www.smokersonly.org.
► Vivek R. Sharma, M.D. and Rebecca Redman, M.D.: Drs. Sharma and Redman are medical oncologists who are collaborating to develop novel approaches for the treatment of gastrointestinal malignancies. Examples of their sponsored clinical trials include: A Phase III Trial of Irinotecan / 5-FU / Leucovorin or Oxaliplatin / 5-FU / Leucovorin with Bevacizumab, or Cetuximab (C225), or with the Combination of Bevacizumab and Cetuximab for Patients with Untreated Metastatic Adenocarcinoma of the Colon or Rectum; A Phase III Trial Evaluating the Addition of Cetuximab to Paclitaxel, Cisplatin, and Radiation for patients with Esophageal Cancer who are treated without surgery; and Phase I Clinical Trial Investigating the Ability of Plant Exosomes to Deliver Curcumin to Normal and Malignant Colon Tissue; A Randomized, Double-blind, Multi-center Phase III Study of Brivanib versus Sorafenib as First-line Treatment in Patients with Advanced Hepatocellular Carcinoma.
► Sucheta Telang, M.B.B.S.: Dr. Telang is funded by the National Cancer Institute and the American Cancer Society to study the regulation of glycolysis in lung cancer and breast cancer. She has found that an enzyme (PFKFB4), previously thought to be only expressed in the testes, is over-expressed in human cancers. She is currently developing knock-out mice to examine the function of this enzyme in cancer development and progression. Her research program recently expanded to include the targeting of glucose metabolism for the development of novel T cell inhibition strategies in auto-immune disorders.
► John O. Trent, Ph.D.: Dr. Trent's research centers around the structure-based drug design of anticancer agents targeting both DNA and protein. Target structures are elucidated using state-of-the-art molecular modeling techniques often in conjunction with X-ray crystallographic and/or NMR data or biophysical data. This has led to the first small molecule inhibitors of telomerase, the first truly allosteric DNA-binding small molecule, design and structure of DNA-drug complexes, rational design of inhibitors for calmodulin, structural rationalization of components of HIV-entry, and investigations into protein structure and drug design in DNA duplex, triplex, and quadruplex. The two main current areas of research involve the design of quadruplex DNA aptamers and of inhibitors of membrane proteins. Dr. Trent's group also has developed virtual screening techniques to directly target nucleolin with small molecules. Dr. Trent has used the virtual screening methodologies to successfully find small molecule inhibitors against more than 30 targets.
► Brian Wattenberg, Ph.D.: Dr. Wattenberg's laboratory is focused on the lipid signaling enzyme Sphingosine Kinase which has recently gained considerable attention as both an intracellular second messenger and an extracellular ligand for a novel group of receptors. Sphingosine-kinase activity is regulated by an interesting array of extracellular ligands including tumor necrosis factor, interleukin-1, and growth factors. His recent studies have demonstrated that the signaling function of sphingosine kinase depends as much on where in the cell the enzyme is located as its degree of enzymatic activation. Dr. Wattenberg is currently exploring how changes in localization of this critical signaling enzyme occur and why localization is such an important aspect of its signaling function.
► Jun Yan, Ph.D.: Dr. Yan, with Dr. Gordon Ross, discovered the remarkable ability of β-glucan, a dietary food supplement that can be purchased at health food stores, to inhibit growth of a variety of tumor cell types. Dr. Yan has extensively characterized the immune mechanism of this effect in tissue culture and in animal models. In fact, he has shown that intravenous treatment with this compound can eradicate lung cancer in nude mice in 80% of instances. Most recently, he has begun work on a new strategy for eradicating existing cancers in murine models using adoptive transfer of normal syngeneic mouse granulocytes with impressive early results.
► Kavitha Yaddanapudi, Ph.D.: Dr. Yaddanapudi is a cancer immunologist who is developing novel vaccination strategies for the prevention of lung cancer. She is collaborating with Drs. Eaton and Mitchell to develop embryonic stem vaccines as well as the use of MIF inhibitors to modulate the immune system. She has particular expertise with flow cytometric analyses and is funded by the National Center for Research Resources.
► Hong Ye, Ph.D.: Dr. Ye's laboratory is focused on understanding the structural and molecular mechanism of Notch signaling regulation in cancer primarily with X-ray crystallography combined with a variety of biophysical and biochemical methods. She is interested in the activation and regulatory processes involving different proteins, and uses thermodynamics as well as structural methods to define the interactions.
► Wolfgang Zacharias, Ph.D.: Dr. Zacharias' group is determining the roles of lysosomal proteases, as well as cystatins, the natural cathepsin inhibitors of these proteases, and of altered cathepsin protease/cystatin inhibitor balances, in the malignancy and metastatic potential of tobacco-related oral carcinomas and lung cancers. They are also investigating the contributions of tumor microenvironment (hypoxia, cell-matrix interactions) on such protease and/or inhibitor expression profiles. RNA-mediated ribozyme gene therapy approaches are being developed for the selective inhibition of such cathepsin proteases in targeted tumor cells.