2018 Research at the Blumberg Institute
In the clinic:
- Hepatitis B Virus (HBV) Capsid inhibitor drug successfully finishes Phase I clinical trials (with Arbutus BioPharma)
- HBV RNA degrading drug we are studying, getting readied for Phase I trials (with Arbutus BioPharma)
- Liver Cancer early detection marker better than AFP in >200 person blinded study (with Glycotest)
- FDA approves a clinical trial for CCR5 inhibitors (based on work from R Pestell’s lab) in triple negative breast cancer (with Prostagene/CytoDyne)
In the pipeline, as basic science:
- Compound with novel activity against HBsAg identified (Lead: T Zhou Lab)
- Cellular proteins HBV needs to produce “cccDNA” identified (Lead: J. Guo Lab)
- Cellular proteins that “repress” HBV cccDNA expression identified (Lead: J Guo Lab)
- HBV’s unusual process of producing its “mRNA” discovered ( Lead: Zhou et al lab)
- unique role of cytoplasmic DNases in regulation of HBV cccDNA synthesis and activation of STING-mediated innate immune response in HBV-infected cells (Leads: J Chang & J Guo lab)
- STING agonist as therapeutics for cancers and chronic viral infectious diseases (Leads: J Chang & J Guo Lab, with Kulp)
- Antiviral drug candidate against yellow fever virus, with a new mechanism of action, identified and characterized (Lead: J Chang lab)
- Identified prodrugs of ER glucosidase inhibitor and determined their safety and antiviral profiles against hemorrhagic fever viruses such as dengue, yellow fever, zika and Ebola viruses (lead: J Chang, with Y. Du)
- New “biomarker” analyte family to detect liver cirrhosis and liver cancers identified (Lead: Sayeed lab)
- Selective Killing of hepatocellular carcinoma cells (HCC) by exploiting HBV surface antigen expressed in HCC cells (Thapa lab)
- identified a novel compound, KPD10, through our cell-based high-throughput compound screening, which selectively kills HCC cells expressing HBV surface antigen (Lead: Zhou, with Thapa labs)
- Selective Killing of Hepatocellular Carcinoma Cells by exploiting HBV surface antigen expressed on HCC cells (lead: R Thapa Lab)
- For use as a new, non invasive marker of HCC, identified HBV sequences integrated adjacent to cell oncogenes from the urine of people with HCC (Lead: Y. Su Lab)
2017 Research at the Blumberg Institute
New Strategies to Treat Chronic Hepatitis B
- Human trials for the capsid inhibitor
The lab of Ju-Tao Guo, MD, the Thomas London Distinguished Professor, has identified several HBV antivirals that have unique targets. One of them, a “capsid inhibitor” has completed Phase I safety trials, and is expected to enter the next phase in 2018. This is licensed to Arbutus BioPharma, which is the trial sponsor. Dr. Guo has been studying the compound’s mechanism of activity in detail (Guo, F, 2017; Wu et al, 2017). He is also exploring new targets and details about the molecular biology of HBV. For example, his lab has shown that HBV cccDNA synthesis has been shown to depend upon cellular repair enzymes (Cui 2016, Qi 2016).
- Unique HBV antiviral target
Another compound that causes the selective destruction of HBV RNA in the infected cell, is being studied by Blumberg scientists, led by Tianlun Zhou, MD, PhD, MPH. Dr. Zhou has been characterizing the compound’s unusual mechanism of action. The mechanism appears to be a first for HBV, and has enormous therapeutic potential. Most exciting is that compounds of this class could be in human trials within the next 12 months.
- Immune stimulation
The lab of Jinhong Chang, MD, PhD, working with Prof. J. T. Guo, has developed new antiviral assay systems. Dr. Chang and colleagues identified first-in-class ‘agonists’ of stimulator of interferon genes (see Guo, 2015; Chang, 2015; Zhang 2016). They are also working with new faculty member, Roshan Thapa, MD, an expert in cancer death pathways, to understand if and how “death” signals are activated by STING agonists. This is intended to be way of activating the body’s own self defense systems to repress the virus. It also has potential as a cancer therapeutic.
Detecting Cancer Early
Early Detection Biomarkers is exciting work being conducted by our Translational Medical Research and Cancer Biomarker Discovery group. They have focused on identification and development of liver cancer biomarkers to assist early detection and guide therapies.
- It’s in the proteins
Based on work with Patrick Romano, PhD and Anand Mehta, DPhil, one liver cancer biomarker, GOLPH 2 (GP73), has been studied in thousands of people, resulting in more than 150 publications from many institutions. When used with other markers, in an algorithmic value, our biomarkers provide a very compelling non-invasive system to detect liver cancer early (Wang 2017).
- It’s in the DNA
Ying-Hsiu Su took a genetic approach and determined that human urine contains small DNA fragments from the blood that come from virtually every organ. She has collaborated with our industrial partner, JBS Science Inc, to develop a panel of tests to detect specific cancer associated mutations in DNA isolated from human urine, allowing for non-invasive detection of colorectal cancer, polyps, and of course, liver cancer.
- It’s in the blood
Aejaz Sayeed, PhD, is studying if and how liver cancer cells spill their contents into the blood stream. The hope is that this will lead to new cancer treatments, and new biomarkers to detect cancer early.
Discovering Drugs that Inhibit Pathogens Other Than HBV
The Blumberg Institute research accomplishments transcend hepatitis B and liver cancer. Some of the assays we design, and consequently drugs we find, have activity against other viruses. One important parallel line of work involves development of drugs active against hemorrhagic and other hepatitis fever viruses of public health concern. This year, Dr. Chang’s lab, working closely with Medicinal Chemistry Director, Yanming Du, PhD, reported new Yellow Fever virus and Ebola virus active drugs, with efficacy alone and in combination, in animal studies, carried out with collaborators at the NIH and USAMRIID (Ma, 2017).
This group searches for new drugs using our natural products collection, led by Matt Todd, PhD, with Jason Clement, PhD and Sung Park, PhD. Working with colleagues from Virginia Technology University and U Georgia, they identified compounds with anti-malarial activity (Presley et al, 2017) isolated from a K. spinosia plant. They also reported compounds isolated from plants from Australia and Indonesia (Clement et al, 2017).
Understanding and Treating Cancer
Richard Pestell, MD, PhD, world renowned cancer biologist, recently joined our faculty and has invigorated our cancer therapeutics and biology programs, establishing the Blumberg Institute’s Pennsylvania Center for Cancer and Regenerative Medicine. He and his colleagues Xuanmao Jiao, PhD; Gabriele DiSante, PhD; and Agnese Di Rocco, PhD have expressed provocative theories and ground-breaking observations. They recently reported that the co-receptor for HIV is found on a small population of cells within human breast cancers and provided experimental evidence, in tissue cultures, that that breast cancer might be treatable with existing medicines that block the HIV co-receptor and dramatically enhanced the killing by chemotherapy or radiation (Jiao 2018).
Liver Cancer Drug Update
Blumberg Institute professors Yanming Du, PhD, and John Kulp, PhD, collaborated with doctors from Mt. Sinai Hospital in New York and found that the aminothiozole compound, found to be highly selective against liver cancer cells in our labs, retained excellent activity against primary liver cancers taken right out of patients. This is very encouraging and future study of these compounds is underway.