The main research goals of my laboratory are: (1) to identify and study the biology of novel cancer selective targets whose enzymatic function can be exploited for therapeutic and diagnostic purposes; (2) to develop methods to target novel agents for activiation by these cancer selective targets while avoiding or minimizing systemic toxicity; (3) to develop novel agents for imaging cancer sites at earliest stages. To accomplish these objectives the lab has originally focused on the development of prodrugs or protoxins that are inactive when given systemically via the blood and only become activated by tumor or tissue specific proteases present within sites of tumor. Using this approach, we are developing therapies targeted for activation by the serine proteases prostate-specific antigen (PSA), human glandular kallikrein 2 (hK2) and fibroblast activation protein (FAP) as well as the membrane carboxypeptidase prostate-specific membrane antigen (PSMA). One such approach developed in the lab consists of a potent bacterial protoxin that we have reengineered to be selectively activated by PSA within the Prostate. This PSA-activated toxin is currently being tested clinically as treatment for men with recurrent prostate cancer following radiation therapy. In a related approach, a novel peptide-cytotoxin prodrug candidate that is activated by PSMA has been identified and is this prodrug candidate is now entering early phase clinical development. In addition, we have also identified a series of potent inhibitors of PSA that are now under study as drug targeting and imaging agents to be used in the treatment and detection of prostate cancer.

Our lab is focused on using comprehensive gene expression, methylation and sequencing and metabolomics analysis to identify alterations in breast cancer, and exploiting these for early detection and therapy. Among deferentially expressed genes, our lab has focused on the HOX genes. HOX genes are intimately involved in the development of resistance to both chemotherapy and to agents targeting the estrogen receptor. Our work explores the alternate pathways that are activated by HOX proteins leading to this resistance and novel treatments to overcome resistance in both tissue culture and xenograft models. In addition, epigenetically silenced genes and a metabolic reprogramming in tumors also trigger novel early detection and therapeutic strategies. We are testing the utility of differentiation therapy through reactivating RAR-beta in breast cancer using histone deacetylase inhibitors with great success. Also, we are targeting enzymes involved in gluconeogenesis and glycolysis with small molecule FDA-approved antimetabolites to achieve antitumor effects.

The Systems Biology Lab applies methods of multiscale modeling to problems of cancer and cardiovascular disease, and examines the systems biology of angiogenesis, breast cancer and peripheral artery disease (PAD). Using coordinated computational and experimental approaches, the lab studies the mechanisms of breast cancer tumor growth and metastasis to find ways to inhibit those processes. We use bioinformatics to discover novel agents that affect angiogenesis and perform in vitro and in vivo experiments to test these predictions. In addition we study protein networks that determine processes of angiogenesis, arteriogenesis and inflammation in PAD. The lab also investigates drug repurposing for potential applications as stimulators of therapeutic angiogenesis, examines signal transduction pathways and builds 3D models of angiogenesis. The lab has discovered over a hundred novel anti-angiogenic peptides, and has undertaken in vitro and in vivo studies testing their activity under different conditions. We have investigated structure-activity relationship (SAR) doing point mutations and amino acid substitutions and constructed biomimetic peptides derived from their endogenous progenitors. They have demonstrated the efficacy of selected peptides in mouse models of breast, lung and brain cancers, and in age-related macular degeneration.

Our scientists pursue out-of-the-box approaches at the very edge of knowledge to: 1) Elucidate the molecular/cellular/physiological landscapes of ovarian and uterine cancers. 2) Understand the earliest events in their development and mechanisms of tumor evolution/dormancy and drug resistance. 3) Deliver promises for better prevention, detection and treatment to women who have diseases or are at an increased risk to have these cancers.

Dr. Hua's research has centered on the development of novel MRI technologies for in vivo functional and physiological imaging in the brain, and the application of such methods for studies in healthy and diseased brains. These include the development of human and animal MRI methods to measure functional brain activities, cerebral perfusion and oxygen metabolism at high (3 Tesla) and ultra-high (7 Tesla and above) magnetic fields. He is particularly interested in novel MRI approaches to image small blood and lymphatic vessels in the brain. Collaborating with clinical investigators, these techniques have been applied 1) to detect functional, vascular and metabolic abnormalities in the brain in neurodegenerative diseases such as Huntingdon's disease (HD), Parkinson's disease (PD), Alzheimer's disease (AD) and mental disorders such as schizophrenia; and 2) to map brain functions and cerebrovascular reactivity for presurgical planning in patients with vascular malformations, brain tumors and epilepsy.

Dr. Zhou's research focuses on developing new in vivo MRI and MRS methodologies to study brain function and disease. His most recent work includes absolute quantification of cerebral blood flow, quantification of functional MRI, high-resolution diffusion tensor imaging (DTI), magnetization transfer mechanism, development of chemical exchange saturation transfer (CEST) technology, brain pH MR imaging, and tissue protein MR imaging. Notably, Dr. Zhou and his colleagues invented the amide proton transfer (APT) approach for brain pH imaging and tumor protein imaging. His initial paper on brain pH imaging was published in Nature Medicine in 2003 and his most recent paper on tumor treatment effects was published in Nature Medicine in 2011. A major part of his current research is the pre-clinical and clinical imaging of brain tumors, strokes, and other neurologic disorders using the APT and other novel MRI techniques. The overall goal is to achieve the MRI contrast at the protein and peptide level without injection of exogenous agents and improve the diagnostic capability of MRI and the patient outcomes.

We are interested in how immune responses occur in the cervix. The focus of our translational research is on developing immune therapies for disease caused by human papillomavirus (HPV). HPV infection causes more cancers than any other virus in the world. Cervical cancer is the most common cancer caused by HPV, and although we have known how to screen for it for over half a century, it remains the second most common cause of cancer death in women. Although the preventive vaccines are a public health milestone, they prevent HPV infections, but are not designed to make immune responses to treat HPV. We are testing different strategies to make immune responses that could treat HPV disease. Our dedicated researchers are working to extend the techniques used in HPV vaccine development to the creation of vaccines targeting other cancers with defined tumor antigens.

Johns Hopkins is a member of the Specialized Program of Research Excellence (SPORE) in Cervical Cancer. With a $11.5 million grant from the National Cancer Institute, we are conducting lab, translational and clinical studies to prevent and treat cervical cancers. Previous studies have identified connections between immune system genes and HPV16. Current projects include the development of next-generation HPV vaccines to control HPV-associated precursor lesions and invasive cancer. Our dedicated researchers are working to extend the techniques used in HPV vaccine development to the creation of vaccines targeting other cancers with defined tumor antigens.

The Greider lab uses biochemistry to study telomerase and cellular and organismal consequences of telomere dysfunction. Telomeres protect chromosome ends from being recognized as DNA damage and chromosomal rearrangements. Conventional replication leads to telomere shortening, but telomere length is maintained by the enzyme telomerase. Telomerase is required for cells that undergo many rounds of divisions, especially tumor cells and some stem cells. The lab has generated telomerase null mice that are viable and show progressive telomere shortening for up to six generations. In the later generations, when telomeres are short, cells die via apoptosis or senescence. Crosses of these telomerase null mice to other tumor prone mice show that tumor formation can be greatly reduced by short telomeres. The lab also is using the telomerase null mice to explore the essential role of telomerase stem cell viability. Telomerase mutations cause autosomal dominant dyskeratosis congenita. People with this disease die of bone marrow failure, likely due to stem cell loss. The lab has developed a mouse model to study this disease. Future work in the lab will focus on identifying genes that induce DNA damage in response to short telomeres, identifying how telomeres are processed and how telomere elongation is regulated.