Translational Hematology & Oncology Research
The Department of Translational Hematology and Oncology Research (THOR) conducts cancer research to develop and make available novel diagnostic tools, targeted therapies and clinical trials for direct use in patient care.
Based on the most current scientific standards, THOR researchers apply advances in the laboratory to provide the highest level of care for patients.
An important part of the Taussig Cancer Institute research efforts, THOR is engaging a new generation of physician scientists to develop scientific advances and translational research that is internationally recognized.
Scientific Areas of Emphasis
- Cancer Genomics and Cytogenetics
- Cancer Stem Cell Biology
- Cancer Immunology and Tumor Surveillance
- Drug Design
- Cancer Pharmacology/Pharmacogenetics
- Signal Transduction
Department physician scientists are available for consultation regarding second or third opinion evaluations, participation in clinical trials and referrals to subspecialists. Some diseases targeted in the department’s research include but are not limited to the following:
- Acute Leukemia
- Bone Marrow Failure including:
- Aplastic Anemia
- Paroxysmal Nocturnal Hemoglobinuria
- Myelodysplastic Syndrome
- Large Granular Lymphocytic Leukemia
- Lung Cancer
- Multiple Myeloma
- Myeloproliferative Syndromes
- Ovarian Cancer
- Renal Cancer
The Department of Translational Hematology & Oncology Research has a substantial list of Journal Publications that help to further our research efforts. To view our complete list of publications, please download the PDF below.
Research News & Articles
Taussig Cancer Institute has been awarded more than $2 million from the American Recovery and Reinvestment Act (ARRA) for the renovation and expansion of its translational cancer research facilities. The National Center for Research Resources, part of the National Institutes of Health, awarded the grant, which will create 17 new jobs.
Dr. Lindner Receives Department of Defense Exploration-Hypothesis Development Award for MDS Research
Dr. Daniel Lindner, M.D., Ph.D. received the Exploration-Hypothesis Development Award for a study titled "Complementation of Myelodysplastic Syndrome Clones with Lentivirus Expression Libraries."
In this study, bone marrow cells from patients with Myelodysplastic syndrome (MDS) will be infected with engineered lentivirus that carries a genetic library. That is, each virus caries a single normal human gene. Infection of the patient's MDS cells with virus in culture will result in overexpression of a single, random normal human gene in each of the MDS cells.
If the experiment works, some lentivirus-infected MDS cells will recover the ability to grow and differentiate normally. Researchers will screen for these “recovered” MDS cells and hope to identify the gene(s) that “correct” the behavior of the abnormal MDS cells.
In September 2009, Jaroslaw Maciejewski, MD, PhD, Chairman of the Department of Translational Hematology and Oncology Research, received a five-year, $1.9 million grant from the National Institutes of Health (NIH) to help fund his research of viruses as a potential cause of certain types of bone marrow cancers and other blood disorders.
Our research focuses on identifying the genomic abnormalities which give rise to therapeutic resistance in cancers and using this information to develop personalized therapies in a new strategy of biologically-guided treatment. As a Radiation Oncologist with training in radiation science, genomics, and cellular and molecular biology, Dr. Abazeed uses his experience in both patient care and basic science to develop a clinically relevant research program to study cancers and to translate laboratory discoveries into potential improvements in clinical care. The goal of our efforts, through a highly integrative and collaborative research program, is to nominate therapeutic targets in cancer and to motivate an evolution in the use of therapy from a generic approach to one in which therapies are selected based on the molecular alterations identified in a patient’s tumor. This approach allows us to enhance efficacy and limit toxicity in the context of a new approach of precision therapy. We have recently developed a large body of data annotating the radiogenomic landscape of cancer and we are focused on studying recently discovered genomic alterations in order to better understand and therapeutically target cancers.
Our research broadly focuses on identifying novel targets for therapy and studying the mechanisms of action of experimental therapeutic agents using a combination of primary patient cells, cell lines, and mouse models. We collaborate closely with our clinical colleagues to develop hypothesis-driven early phase clinical trials based on our preclinical findings. Specific areas of interest include investigating the roles of key regulators of protein homeostasis in disease pathogenesis and therapeutic resistance and developing novel small molecule inhibitors of epigenetic modulators with potential applications for the treatment of MDS, AML, and other hematological malignancies.
We have an interest in inositol polyphosphate kinases, their enzymatic products, and the pathways by which they affect cell growth and apoptosis. Ongoing studies with IP6K2 knockout mice suggest that they are predisposed to development of head and neck carcinoma.
We are also utilizing a genetic approach to identify genes that may alter the phenotype of myelodysplastic syndrome and resultant bone marrow failure syndrome. Another focus of the laboratory is tumor induced angiogenesis. Utilizing murine models, we have shown that myeloid derived suppressor cells are early promoters of angiogenesis in renal cell carcinoma.
Our laboratory focuses on investigations of pathogenesis, cancer signaling, molecular targeted therapy, and cancer genomics in thoracic/aerodigestive oncology. Our disease studies include small cell and non-small cell lung cancer, mesothelioma, neuroendocrine carcinoma. Our research effort is highly translational and multidisciplinary, with the ultimate goal of developing novel and highly effective targeting strategies of molecular therapeutics to improve long term survival outcome of thoracic malignancies.
The research areas include:
- human kinome oncogenic signaling and cross-talk network studies
- oncogenic driver mutations
- cancer stem cell and single cell biology analysis
- circulatory tumor cells (CTC)
- molecular determinants of targeted therapy sensitivity and resistance (as in inhibitors against EGFR, MET, ALK)
- tumor-stromal interaction
- cancer metabolism
- cancer target imaging
- mechanisms of adaptive early tumor resistance and acquired resistance regulation in targeted therapy
- tumor molecular profiling to understand cancer biology and progression
We adopt cross-disciplinary research methods and platforms to achieve the research goals, including molecular and cell biology, signaling studies, flow cytometry, nanofluidic PCR, CTC isolation and molecular assays, genomics/proteomics/metabolomics, multimodal in vivo molecular imaging (PET/CT, bioluminescence imaging), radiosynthetic in vivo molecular imaging probe, and next-gen high throughput cancer genome sequencing. We aim to optimize the strategies in combination targeted therapy to ultimately impact on personalized cancer care.
Our laboratory investigates pathogenesis of several hematopoietic disorders including aplastic anemia, paroxysmal nocturnal hemoglobinuria, myelodysplastic syndrome and chronic and acute myeloid malignancies. The research areas include stem cell biology, molecular pathogenesis of malignant transformation including mutations and DNA damage and immune mechanisms of hematopoietic suppression leading to deficient blood cell production. We apply high density DNA arrays, methylation arrays, high throughput sequencing, flow cytometry and various cell culture systems. All research projects are highly translational and have a goal to identify diagnostic and therapeutic targets in patients.
The McCrae laboratory focuses on vascular cell biology in pathologic disorders through study of endothelial cells in vitro and in vivo. We are primarily interested in two areas. One is the antiphospholipid syndrome (APS), a clinical disorder characterized by thrombosis and recurrent fetal loss. “Antiphospholipid” antibodies are actually not directed against phospholipid, but a phospholipid binding protein, β¬2-glycoprotein I (β2GPI).
We have shown that β2GPI binds to endothelial cells through cell surface annexin A2 (AII) and that cross linking of AII-bound β2GPI by bivalent anti-β2GPI antibodies leads to activation of endothelial cells; our focus is to define the mechanisms by which β2GPI/AII cross-linking leads to transmission of a transmembrane signal. We have also observed increased numbers of endothelial cell and platelet-derived microparticles in plasma of patients with APS.
Our other major interest is in the role of kininogen, a member of the intrinsic coagulation pathway, in regulation of angiogenesis. Upon cleavage, high molecular weight kininogen (HK) is converted to cleaved kininogen (HKa) with the release of bradykinin (BK). We have observed that HKa causes rapid apoptosis of proliferating endothelial cells, and inhibits angiogenesis. We have produced a kininogen deficient mouse, which displays a pro-angiogenic phenotype, and are exploring the mechanisms underlying this phenotype, which contrasts with other animal models of kininogen deficiency. Microarray studies suggest altered expression of a number of genes in tumors from kininogen deficient mice.
Our laboratory’s primary disease focuses include myelodysplastic syndromes, chronic and acute myeloid malignancies, myeloproliferative syndromes, multiple myeloma, and B-cell lymphomas. Our laboratory provides medicinal chemistry expertise. Working collaboratively with the principal investigators in the department of Translational Hematology and Oncology Research, our efforts are focused on using relevant biomarkers discovered within the department to develop more rationally designed small-molecule drugs. Present investigations involve the design and synthesis of LSD1 inhibitors, RNA helicase inhibitors, selective spliceosomal inhibitors, and ubiquitin transfer facilitators.
The goal of our young laboratory is to exploit epigenetic principles for the treatment of cancer in general and cancers of the antibody producing cells (multiple myeloma and related diseases) in particular. We use high throughput screening to identify molecules that selectively reactivate relevant tumor suppressor genes or silence oncogenes, followed by in vitro and in vivo preclinical drug development before translation into clinical study in multiple myeloma. Additionally we want to define the optimal use of already clinically available epigenetic drugs for the treatment of multiple myeloma, like in a clinical trial that uses azacitidine and measures DNA demethylation and tumor suppressor gene re-expression in bone marrow myeloma cells.
A major objective of our work is to develop therapy that selectively destroys malignant cells while sparing normal stem cells. To this end, our work covers a number of aspects: one aspect focuses on understanding the mechanisms by which malignant stem cells self-renew, and finding differences between malignant self-renewal and normal stem cell self-renewal. Another aspect focuses on identifying and developing drug-able compounds that target identified differences between normal and malignant self-renewal. A final aspect studies the pharmacologic properties and considerations of proposed agents to enable the clinical trials for selective malignant stem cell destruction. The other major objective of our efforts is to develop more effective methods for pharmacologic reactivation of fetal hemoglobin expression as a treatment for sickle cell disease and beta-thalassemia.
Our laboratory is interested in identifying prognostic and predictive biomarkers in myeloproliferative neoplasms (MPN) and other bone marrow failure states. The MPN are a diverse group of hematologic cancers that includes diseases including chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), mastocytosis, chronic neutrophilic leukemia, chronic eosinophilic leukemia and MPN unclassifiable.
Diseases like PV, ET and PMF can be complicated by thrombotic events, worsening cytopenia, risk for transformation to acute myeloid leukemia while diseases like mastocytosis and chronic eosinophilic leukemia can be complicated by organ infiltration. With the exception of CML, no effective therapies exist for most cases of Philadelphia chromosome negative MPN.
My laboratory intends to identify novel molecular markers using whole genome scanning technologies, such as single nucleotide polymorphism arrays and next generation genomic sequencing technologies, to help in the elucidation of disease pathogenesis which can subsequently be used to help predict which patients with specific MPNs are more likely to respond to certain biologic treatments.
Conversely, the identification of specific biomarkers may also be prognostic, allowing for improvement of risk stratification schemes. Techniques utilized include flow cytometry, RT-PCR, next generation genomic sequencing, single nucleotide polymorphism arrays and other molecular biology techniques.
Research Administrative Coordinator
THOR Primary Investigators
- Jaroslaw Maciejewski, MD, PhD, FACP
- Mohamed Abazeed, MD, PhD
- Ernest Borden, MD
- Jennifer Carew, PhD
- Daniel Lindner, PhD
- Patrick Ma, MD, MS
- James Philips, PhD
THOR Secondary Investigators
Cancer Answers & Appointments
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