About the Program
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. Follow the link below to view our most recent publications on PubMed.
Immune-checkpoint blockade (ICB) therapies have revolutionized the field of Cancer Immunotherapy. However, the low response rate in a majority of patients indicates the urgent need to identify and target additional checkpoint regulators. The Wang laboratory is among the first groups to demonstrate that the immune-checkpoint protein “V domain Immunoglobulin Suppressor of cell Activation” (VISTA) is a promising target for cancer immunotherapy. Current projects are multi-disciplinary and involve elucidating the epigenetic and metabolic regulations by novel inhibitory receptors expressed in tumor-associated cytotoxic T cells, macrophages, or myeloid-derived suppressor cells (MDSCs). Additional projects include investigating the mechanisms of resistance following cell-based immunotherapies and investigating novel immune signatures governing clinical outcomes for myeloid leukemia, lung cancer, and other cancers. These projects have a balanced basic and clinical research aspects and provide excellent training opportunities for translational researchers.
The main focus of our research is novel target discovery and small molecule therapeutic development against myeloid malignancies and hematological disorders. We are heavily invested in understanding the fundamental mechanism of the gain of survival function in cancer cells upon therapeutic treatment. We study cellular innate immunity and transcriptional reprogramming in cancer cells upon treatment with DNA damaging agents. We use structure guided small molecule design and synthesis to target oncogenic factors responsible for aberrant activation of cell survival. We use various state-of-the-art techniques in structural biology, biochemistry and molecular biology to tease out the detailed mechanism of cancer cell survival. Our long term goal is to develop a new generation of therapeutics against myeloid malignancies and hematological disorders.
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 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.
- View Dr. Maciejewski's Physician Profile.
- View Dr. Maciejewski's Lab Profile.
- Dr. Maciejewski on ConsultQD.
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.
Clinical Focus: Genitourinary Cancers (e.g., Bladder, Prostate, Urethra, Kidney)
Research Mission: To improve outcomes and minimize treatment related toxicity through a better understanding of the interaction between radiation, the tumor environment, and the epigenome.
Research Overview: Cancer is fundamentally a genetic and epigenetic disease characterized by pervasive genomic disorganization. Epigenetic therapies are poised to change the landscape of cancer treatment and we have a unique opportunity in Radiation Oncology to harness these breakthroughs. In my laboratory we are interested in addressing two areas of clinical need in radiation oncology: 1) the utilization of epigenetic therapies (e.g., DNA methylation inhibitors, bromodomain inhibitors, HDAC inhibitors) and global modifiers of epigenetic programs (e.g., Methyl-CpG binding Proteins, Steroid hormone inhibitors) to enhance the efficacy of radiation therapy and 2) the need for reliable epigenetic biomarkers of disease burden, response to radiation therapy, early relapse, risk of radiation related normal tissue injury, and the underlying biology that distinguishes indolent from lethal phenotypes.
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.
Clinical Focus: Sarcoma
Research Mission: To understand how cancers acquire resistance to targeted biological agents and radiation and to harness this knowledge to design better therapeutic strategies for our patients.
Research Overview: Cancer is a complex disease that is an aberration of our own tissues, but it still obeys fundamental biological rules. Our greatest challenge in the clinic is the emergence of resistance to our therapies, a process which is governed by Darwinian evolution. Using a suite of mathematical and experimental models, my laboratory seeks to deconvolute the complexity of the evolutionary process into fundamental principles. We aim to use this knowledge to then curtail the evolutionary process to increase the efficacy of targeted therapies and radiation. This same knowledge can be further harnessed to understand the differences in disease progression and therapy response on a personalized basis, so that the right treatment can be given to the right patient at the right time.
John Pellecchia, Department Administrator
Kristine Cencia, Department Secretary
Sherri Gatto, Research Administrative Coordinator
THOR primary investigators
Jaroslaw Maciejewski, MD, PhD, FACP, Chairman
Li Lily Wang, PhD, Associate Staff
Babal Jha, PhD, Associate Staff
Daniel Lindner, PhD, Associate Staff
James Philips, PhD, Project Staff
Valeria Visconte, PhD, Project Staff
Yogen Saunthararajah, MD, Staff
Jacob Scott, MD, DPhil, Staff
Omar Mian, MD, PhD, Staff
THOR secondary investigators
Anjali Advani, MD, Staff
Keith McCrae, MD, Staff
Roberto Vargas, MD, Staff