Investigators

Summary

My research as a neurosurgeon-scientist has focused on the translation of new therapies and intraoperative visualization of glioblastoma (GBM). I direct the Brain Tumor Nanotechnology Laboratory in the Hillman Cancer Center studying the use of magnetic iron-oxide nanoparticles (MIONPs) for the targeted imaging and magnetic hyperthermia therapy (MHT) of GBM after convection-enhanced delivery (CED). This collaborative and translational NIH- funded research involves Johns Hopkins University and Penn State University developing a new treatment for GBM. My research is also focused on the study of fluorescence-guided surgery (FGS) and photodynamic therapy (PDT) of GBM. My team was the first to use Gleolan (5-ALA) and perform FGS on a GBM patient in the US in 2011. We also led the FDA effort for approval of 5-ALA (Gleolan) in the US in June 2017.

Summary

My research interests focus on preclinical and clinical development of novel agents from natural products for prevention of prostate and breast cancer in humans and understanding their molecular mechanism of action against cancer using in vitro and in vivo test systems. Natural products include dietary sources (such as garlic, broccoli, watercress, etc.) and traditional Oriental and Indian medicinal plants. Cancer chemoprevention can be defined as the use of natural or synthetic agents to delay, reverse or suppress cancer progression. I am also interested in identifying biomarkers to assess chemopreventive agent response in future clinical trials using cutting-edge Omics technology.

Summary

My research interests focus on the similarities and differences in chromatin structure among different cell types and how chromatin remodeling factors that modulate these differences regulate cell fate. The longterm goals of my laboratory are to comprehensively understand the functions, targets, regulation, and mechanisms of action of non-coding RNAs (ncRNAs) and chromatin regulatory factors with critical functions in the embryonic stem (ES) cell gene regulatory network, through development, and in disease states. Active research areas in my laboratory include: (1) identifying chromatin remodelers that regulate ncRNA expression; (2) determining the function of two uncharacterized classes of ncRNAs in ES cells; (3) characterizing molecular changes occurring in cancer cell lines with chromatin remodeler mutations; (4) optimizing and expanding the utilization of a novel technique for profiling chromatin binding proteins, CUT&RUN. Enabling these studies, my research spans the disciplines of genomics, cell and molecular biology, biochemistry, and genetics.

Summary

Activation of the PI3K pathway, through either oncogenic mutations or loss of tumor suppressors, is arguably the most prevalent transforming event in cancer. Much effort has focused on inhibitors of these pathways, but success to date has been tempered by on-target adverse effects driven by normal physiology that also relies on intact PI3K signaling. My research focuses on the regulatory and homeostatic mechanisms that control PI3K signaling at the level of its central lipid messengers. We aim to uncover how these lipid signals selectively couple to defined signaling outcomes; this basic knowledge will be transformative in predicting how oncogenic PI3K signaling can be selectively targeted while sparing normal physiology.

My lab employs innovative single-cell biochemistry approaches to study lipid signaling in living cells, employing a range of optical biosensors along with gene editing, optogenetic and chemigenetic tools. This approach uniquely empowers us to precisely edit and control cell signaling pathways to model physiology and disease alterations: we can dissect changes away from upstream and downstream pathway components, and notably mimic the effects of potential small-molecule modulators.

Summary

The laboratory of Timothy Hand, PhD, is interested in the immune cells of the intestine and how they respond to the first interactions with colonizing microorganisms. How the immune system deals with newly colonizing bacteria is important, since too little immune response can lead to infection but too much can contribute to damaging inflammation. The intestine is home to the largest and densest group of microorganisms in the body and the intestinal microbiome is required for many host processes, most notably the digestion of complex carbohydrates. Therefore, maintaining a healthy relationship with the microbiome is important for the health of the host. Shifts in the intestinal microbiota and the mucosal immune response have been associated with a variety of important pediatric diseases including colorectal cancer, inflammatory bowel disease and necrotizing enterocolitis.

Our view is that the long- term relationship between the host and the microbiome can be shaped by the results of their initial interaction by the phenomenon of immunological memory. Therefore, we seek to better understand the immune systems ‘first impressions’ of the microbiota and how they are shaped by environmental factors such as diet and inflammation. Our hope is that a better understanding of how the microbiome shapes the host will lead to better therapies for pediatric disease. We also hope to harness this knowledge to improve our ability to use the immune response for therapy and augment anti-tumor immunotherapy.

Summary

Dr. Hempel's research aims to better understand molecular mechanisms that regulate metastasis and tumor progression, with the ultimate goal of identifying novel targets for therapy of advanced-stage disease. Her research efforts have specifically focused on mechanisms by which tumor cells adapt to stress and her past research on the mitochondrial superoxide dismutase SOD2 has significantly contributed to the understanding that antioxidant enzymes have dichotomous roles during tumor progression. Dr. Hempel’s current research efforts focus on ovarian cancer, which remains the deadliest gynecologic malignancy due to its late-stage diagnosis when significant peritoneal metastatic spread has already taken place, high rates of recurrence and chemoresistance development. Currently, Dr. Hempel’s research group uses a variety of molecular, cellular, imaging, and in vivo techniques to focus on several research areas in ovarian cancer biology, including 1. elucidating the regulation and role of antioxidant enzymes and reactive oxygen species in metastatic tumor cells; 2.identifying novel regulators of anoikis resistance during transcoelomic metastasis; and 3. studying the regulation of mitochondrial fission/fusion and mitochondrial metabolism during ovarian cancer progression.

Summary

The Hinterleitner Lab studies mucosal immune responses to gut microbes. Current projects are centered around how gut protists shape immune responses in the context of celiac disease, IBD, and colon cancer.

Summary

My cancer research interests focus on the development of tools designed to make information more useful for translational researchers. Since 2014, I have been a co-investigator and then MPI (with Guergana Savova of Boston Children’s Hospital and Jeremy Warner of Vanderbilt University) on an NCIfunded project “Cancer Deep Phenotyping from Electronic Medical Records”(U24 CA248010-01A1). Known as “DeepPhe”, this project is aimed at extracting longitudinal patient histories from clinical notes via Natural Language Processing and developing visual analytics tools that will facilitate the use of this data for cohort discovery. My role in this effort has been to lead qualitative inquiries into clinician information needs and goals, as needed to guide the design of interactive tools. With additional NCI funding starting in 2019, and with the added collaboration of Eric Durbin of the University of Kentucky/Kentucky Cancer registry, we are working to adapt these tools to facilitate cancer registry data abstraction processes (UG3 CA243120-02).

Summary

Dr. Homa's research is focused on understanding the molecular basis of herpes simplex virus type 1 (HSV-1) capsid assembly and viral genome packaging into the viral capsid. DNA encapsidation and cleavage involves the coordinated interaction of several HSV proteins that are essential for production of infectious virions. How these multi-protein assemblies associate and interact to accomplish this complex task touches on fundamental questions in biology. The HSV-1 genome is translocated into the icosahedral procapsid through a donut-shaped 'portal' that is present at one of the 12 vertices of the procapsid. This process is directed by the terminase complex, which consists of the HSV UL15, UL28, and UL33 proteins that function both as part of the ATP-hydrolyzing pump which drives DNA into the capsid, and also as a nuclease that cuts the concatemeric DNA at specific sites to yield a capsid containing the intact genome. The capsid is then stabilized by the addition of the capsid vertex specific component (CVSC), composed of the UL17 and UL25 proteins, which functions to retain the packaged DNA and to signal for nuclear egress of the mature DNA-filled capsid, as well as for nuclear attachment of the incoming, infecting capsid. Seven viral gene products are required for the stable packaging of viral DNA into the preformed HSV procapsid. Orthologs of these HSV DNA packaging genes are found in all three classes (alpha, beta, and gamma) of herpesviruses. Information obtained about the function of these proteins from these studies should therefore apply to other herpesviruses such as human cytomegalovirus, varicella zoster virus and Epstein-Barr virus.

Summary

I am a physician-scientist whose research efforts have focused specifically on codon usage, tRNA biology, and amino acid metabolism in colorectal and gastric cancers. Using a combination of computational modeling and wet-lab experiments, I found that amino acid availability directly influences tRNA availability and gene expression in a codon-dependent manner, and also potentially affects the evolution of the cancer genome. I plan to better dissect the contribution of the tumor microenvironment towards nutritional stress of cancer cells as well as determine how tRNA synthetases contribute to survival under starvation conditions.

Summary

Dr. Hu's lab focuses on the identification and validation of crucial molecular changes that confer high-risk for tumor progression in mutant BRAF-induced serrated intestinal tumorigenesis. Her lab works to identify novel factors essential for serrated CRC development that can serve as pharmacological targets for the prevention of serrated CRC at an early and curable stage. Dr. Hu's lab also works to identify and validate novel functionally relevant and druggable targets for PDAC.

Summary

In my role as leader in AI for Cancer Research, I work closely with Hillman PIs and Hillman leadership to develop the AI infrastructure and capability to advance clinical operation, clinical research, and basic cancer research. I envision building a robust AI capability at Hillman that can meet the AI needs for cutting-edge cancer research and be adapted to address new challenges. My current cancer-related research includes:

1. Mechanism of infection and oncogenesis by KSHV
Goals: Using a combination of bioinformatics/machine learning, high throughput profiling (scRNA-seq, in-situ-seq, 16s-seq, etc), and bench experiments to delineate the mechanism of KSHV-induced cellular transform and oncogenesis, elucidate the pathogenesis of KSHV-associated cancers, and identify effective therapeutic targets and prognostic biomarkers. Through a long-term collaboration with Dr. SJ Gao, we have identified targets and pathways regulated by KSHV miRNAs (Nat. cell Biology, 2010), delineated the addicted cellular genes and networks by genome-wide CRISPR-Cas9 screening (MBIO 2019), performed the first genome-wide viral and cellular m6A profiling in multiple KSHV-infected systems (Nat. Microbiology 2018), and identified the signatures of oral microbiome in HIV-infected individuals with oral KSHV (PLOS PATHOGENS, 2019).

2. m6A mRNA modification/epitranscriptome and cancer
Goals: 1) Develop bioinformatics/machine learning tools to facilitate the functional study of m6A mRNA methylation and cancer. Using a combination of bioinformatics/machine learning and high throughput profiling technologies to 1) understand the mechanisms by which m6A regulates cancer and viral infection; 2) identify m6A-related clinical makers. m6A/epitranscriptome is a new and rapidly advancing area that studies modifications in mRNAs. My lab leads the development of computation tools for analyzing m6A profiling data and predicting m6A functions. The analysis pipeline for m6A sequencing, exomePeak, has been used widely and cited > 400 times (Google Scholar) by many high impact papers in Cell, Cell Stem Cell, Nature, Nature Cell Biology, Nature Neuroscience, Nature Genetics, and Cancer Cell. Using these tools, we have uncovered the reprogramming of viral and cellular m6A epitranscriptome during the life cycle of Kaposi sarcoma-associated herpesvirus (KSHV) (Nature Microbiology, (2018) 3(1):108-120) and reported common and distinct m6A regulation of innate immune response during bacterial and viral infection (Cell Death & Disease 2022, 13(3)). Besides, I have collaborated with other cancer biologists to uncover a cross-talk among m6A writers, erasers, and readers that regulates cancer progression (Science Advances, 2018 4(10)) and linked the increased activity of ALKBH5 with dysregulation of histone ubiquitination in cancers (Cancer Research, 2022/5).
 
3. Single-cell spatially-resolved transcriptomics (scSRT) analysis
Goals: 1) Develop the analysis and visualization pipeline for scSRT data(Nanostring CosMx, 10X Xenium, and Vizgen MERSCOPE), 2) Develop AI/machine learning tools for modeling tissue structure and disease pathology, and 3) apply scSRT to study immune microenvironment associated with tumor and viral infection. We have recently applied scSRT to reveal the molecular and immune signatures as well as pathological trajectories of fatal COVID-19 lungs (JMV, 2023)

4. Functional interpretable deep learning models and large language models for cancer genomics
Goals: 1) Develop novel deep learning models capable of cancer phenotype predictions and explain the underlying mechanisms. 2) ChatGPT-based prompt engineering for extracting knowledge about molecular regulatory mechanisms from literature. We have developed several genomics-based deep learning/AI tools for cancer prognosis and survival analysis, drug response prediction, and gene dependence prediction (Science Advances, 2021; Cancers, 2023).