Penn Vet’s Boris Striepen Receives $1.8M Grant to Find Drugs against Deadly Diarrheal Disease in Infants

Penn Vet’s Boris Striepen Receives $1.8M Grant to Find Drugs against Deadly Diarrheal Disease in Infants

By Martin Hackett
Published: Jan 2, 2018

[January 2, 2018; Philadelphia, PA] – Boris Striepen, PhD, Professor of Pathobiology at the School of Veterinary Medicine at the University of Pennsylvania, has received a $1.8-million, three-year grant from the Bill & Melinda Gates Foundation to enable the development of drugs for cryptosporidiosis, a diarrheal disease caused by microscopic parasites.

According to the Centers for Disease Control and Prevention, cryptosporidiosis sickens approximately 750,000 people each year in the United States. Caused by Cryptosporidium, a microscopic parasite that is typically transmitted through contaminated water, the disease is the second leading cause of severe diarrhea in small children. Globally, diarrheal diseases claim the lives of over 800,000 children under the age of five each year. The disease can be particularly serious in children who are malnourished and in individuals who are immunocompromised either due to illness or medical treatments.

Striepen is a leader in the study of Cryptosporidium. Under the grant, he and his team will use a variety of molecular genetic approaches to support drug development efforts, focusing on the identification and validation of therapeutic targets to guide medicinal chemistry. The project will build upon the team’s breakthrough in establishing techniques for genetic manipulation of Cryptosporidium to produce parasites suitable for drug testing in vitro and in vivo. Striepen will seek to link drug candidates with their targets within the parasite. Understanding how drugs work is very helpful to further enhance their potency and to anticipate and avoid unwanted toxicity and side effects.

“We will develop rigorous tests to establish whether drug candidates truly act on the target they were designed to,” Striepen said. “We will establish how the metabolism of the parasite interacts with that of its human host cell and assemble a catalog of those functions that are essential to the survival of the parasite and thus good targets for intervention.”

To accomplish these goals, Striepen and his researchers will conduct several activities. Initially, they will focus on those parasite functions for which drug candidates are already available and under study. Next, they will establish a model of the parasite’s metabolism and identify biochemical vulnerabilities within that model. They will seek to understand the metabolites the parasites uses at different points in its lifecycle and whether those are made by the parasite or taken from the host. Lastly, they will use genome-wide knock out approaches to discover all those activities that are essential to the parasite’s viability.

“This information will allow us not only to understand the lifecycle in much greater detail,” said Striepen, “but also open the door to more sophisticated manipulation of the parasite, to support drug development, but also to potentially generate weakened strains that may be suitable for vaccination.”

Striepen joined Penn Vet’s faculty in July 2017. His research program is supported by the National Institutes of Health, the Bill & Melinda Gates Foundation, and the Wellcome Trust. Striepen serves on numerous scientific advisory and editorial boards including the Bernhard Nocht Institute for Tropical Medicine, Keystone Conferences, PLoS Biology, and MBio, and he was the director of the Biology of Parasitism summer research course at the Marine Biological Laboratories in Woods Hole. Striepen received his PhD at Philipps-Universität in Marburg, Germany and was a Post-doctoral Fellow at the University of Pennsylvania.

Improving oral cancer diagnosis on many fronts

Improving oral cancer diagnosis on many fronts

Text by Katherine Unger Baillie

A Penn Dental expert is increasing oral cancer awareness by helping to improve ADA recommendations, editing scholarly journals, and partnering with Penn Nursing.

A comprehensive dental visit includes more than a cleaning and X-rays; well-trained dentists know they must also take a thorough look inside the oral cavity to spot any potentially unusual lesions that could signal oral cancer.

Recently, the American Dental Association (ADA) reviewed its recommendations on what dentists should do when they spot a potentially malignant lesion in the mouth. Thomas Sollecito, chair of the Department of Oral Medicine in Penn’s School of Dental Medicine and chief of the Division of Oral Medicine in the Perelman School of Medicine, was part of an expert panel charged with reviewing and updating the ADA’s guidelines regarding oral cancer diagnostics.

“Our review sought to answer the question, ‘What is the best way of evaluating potentially malignant oral disorders?’” says Sollecito. “This is set against a background of oral cavity cancer diagnoses still being made at a relatively late stage.”

The team, which included members with expertise in epidemiology, oncology, and head and neck surgery, as well as oral medicine, reviewed high-quality scientific studies to come up with their recommendation. Among the evidence they considered were studies evaluating the effectiveness of what are known as “adjuncts,” diagnostic tests that can help dentists determine whether a lesion is potentially malignant.

Thomas Sollecito, chair of the Department of Oral Medicine at Penn Dental. Photo by Penn Dental

“These adjuncts are being marketed to dentists, and some are probably using them in their practices,” Sollecito says. “This review is intended to provide clarity to dentists as to what is the best evidence at this time for the use of adjuncts.”

Some diagnostics use biomarkers in the saliva to test for the presence of cancerous or precancerous cells. Others use a method akin to a Pap smear, where cells are lightly scraped from the oral cavity and then evaluated for signs of dysplasia or malignancy.

But after a rigorous scientific review, Sollecito and his co-panelists found that the evidence supporting the use of these adjuncts was low in quality. If a dentist spots a suspicious lesion, the panel’s recommendation remains the same as it had been at the time of their last review in 2010: to biopsy the tissue.

“The biopsy is the gold standard,” Sollecito says.

But it is invasive, especially if the same lesion must be biopsied repeatedly to test whether it has become malignant over time.

“Ultimately, we’ll have to improve our ability to determine and predict whether a lesion’s behavior over time can be obtained without re-biopsying frequently,” he adds.

The ADA review is only one way that Sollecito is trying to increase awareness of oral cancer and early detection. Along with Eric Stoopler, director of the Oral Medicine Residency Program at Penn Dental, Sollecito edited an issue of Dental Clinics of North America focused on oral cancer, with chapter contributions from other colleagues within Penn’s Dental and Medical schools.

And on Penn’s campus, Sollecito is part of an effort to grow the pool of health care providers who possess the knowledge to recognize suspicious oral lesions and perform head and neck exams. Through a partnership with the School of Nursing, nurse practitioner students are spending time in the oral diagnosis clinic at the Dental School.

“The more people who feel comfortable looking at all of the nooks and crannies of the oral cavity in a systematic fashion, as difficult as it is, will only help in detecting a potentially malignant lesion earlier,” says Sollecito.

While the Dental students help instruct the Nursing students in how to perform oral cancer screenings, the Nursing students share their expertise in looking beyond the dental and medical conditions, and understanding the psychosocial dimensions of their patients.

“I’m really excited about this partnership,” Sollecito says. “We have a robust inter-professional interaction with the Nursing School, and it’s beneficial for everyone involved.”

Originally published on .

Drs. Charles Bradley and Elizabeth Grice Receive 2017 One Health Award

Drs. Charles Bradley and Elizabeth Grice Receive 2017 One Health Award

By John Donges
Published: Nov 22, 2017

[November 22, 2017; Philadelphia, PA] – Charles W. Bradley, VMD, of the School of Veterinary Medicine (Penn Vet), and Elizabeth A. Grice, PhD, of the Perelman School of Medicine (Penn Medicine), have been named the 2017 recipients of Penn’s One Health Award, recognizing their exemplary interdisciplinary collaboration in improving health care for the benefit of humans, animals, and the environment. The One Health Award was established in 2013 by the deans of the four health schools at Penn: the Perelman School of Medicine (Penn Medicine), the School of Nursing Science (Penn Nursing), the School of Dental Medicine (Penn Dental Medicine), and the School of Veterinary Medicine (Penn Vet).

The award ceremony took place on Wednesday, November 8 at Penn Vet as part of the 2017 Microbiome Symposium.

Research conducted by Bradley and Grice has uncovered important insights about the skin microbiome of atopic dermatitis (AD) in dogs compared to humans. Canine AD shares important features of the human version, making dogs an excellent clinical model. The research revealed that there is a correlation between the skin’s barrier function, the immune system, and the composition and diversity of bacterial colonization during flares. The hope is that insights gained from this and future studies will enable clinicians to treat AD by altering the skin’s microbiome without antibiotic use.

“We are delighted to recognize the extraordinary research collaborations throughout the University that advance the One Health initiative,” said Joan C. Hendricks, VMD, PhD, the Gilbert S. Kahn Dean of Veterinary Medicine at the University of Pennsylvania. “Drs. Bradley and Grice exemplify the spirit of One Health by working to advance the knowledge base for the same skin disease across species. They are also superb in their focus on publicizing the One Health approach in their presentations at scientific and medical conferences.”

Charles W. Bradley, VMD, is an assistant professor of pathology in the Department of Pathobiology at Penn Vet. His research interests are focused on dermatopathology and the role of the microbiome in skin disease, particularly canine atopic dermatitis.

“This award is a true honor, and symbolizes the interdisciplinary support and friendships that have grown out of our work, across campus and health systems,” said Bradley. “Elizabeth and her lab continue to be tremendous colleagues and partners in advancing our research goals. I am thankful for Penn leading in the One Health paradigm where these far-reaching collaborations can take root and flourish.”

Elizabeth A. Grice, PhD, is an assistant professor of dermatology and microbiology at Penn Medicine. Her research focuses on host-microbe interactions of the skin and elucidating their roles in skin health, disease, and wound healing. Grice is on the Board of Directors of the Wound Healing Society and chairs the Admissions Committee for the Genomics and Computational Biology PhD program at Penn.

“The collaboration between my lab and Charles and Penn Vet has been extremely productive, and has also brought to light the values with which we approach our research,” said Grice. “We strive to embrace ‘One Health’ in all lines of research in the lab, recognizing its impact on not only human medicine, but animals and the environment.”

About Penn Med

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $6.7 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 20 years, according to U.S. News & World Report’s survey of research-oriented medical schools. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2016 fiscal year.

The University of Pennsylvania Health System’s patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center — which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report — Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital — the nation’s first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2016, Penn Medicine provided $393 million to benefit our community.

Unpacking the forces that drive health disparities

Unpacking the forces that drive health disparities

Four Penn Integrates Knowledge Professors will discuss health disparities through an interdisciplinary lens.

From top, Penn Integrates Knowledge Professors Karen Glanz, Dorothy Roberts, Sarah Tishkoff, and Ezekiel Emanuel. Photo by Penn Integrates Knowledge Program

Look to almost any major disease and you’ll find disparities in how it affects different groups. African Americans and Hispanics have higher rates of HIV/AIDS infection than white Americans. Women, particularly African-American women, have lower survival rates following a heart attack than men. And many cancers are diagnosed at later stages in African Americans than in whites, leading to poorer outcomes.

While these differences are sometimes attributed to variations in biology between groups, the reality is more complicated. On Wednesday, Nov. 29, from 4 to 5:30 p.m. in the Jordan Medical Education Center Law Auditorium, three Penn Integrates Knowledge (PIK) ProfessorsKaren GlanzDorothy Roberts, and Sarah Tishkoff, will participate in a panel discussion—moderated by a fourth PIK Professor, Ezekiel Emanuel—to sift through the biological, social, and even legal and regulatory forces that may either be supporting or working to dismantle these disparities. Provost Wendell Pritchett will offer introductory remarks, and each of the three speakers will give a brief talk before the panel is opened up for audience interaction.

“I think this event will be of interest to anybody who uses health care, who is a health care provider or might be one someday, anyone in public policy or who is affected by public policy,” Glanz says. “Really, this is aimed at a very general audience as these issues affect everyone.”

The discussion, “Health Disparities: Integrating Knowledge from Genomics, Social Sciences and the Law,” will be the second annual PIK Seminar organized and sponsored by the PIK Professors, a group of 22 faculty members whose expertise crosses disciplines and who have appointments in multiple schools at the University. Last year’s PIK Seminar, “PIK-ing on the Brain,” dealt with the subject of neuroscience and featured PIK Professors whose areas of focus ranged from mathematics, to ethics, to epigenetics, to brain science.

Glanz, a public health scholar with appointments in the School of Nursing and the Perelman School of Medicine, whose efforts to identify and reduce health disparities has informed policy and organizational change, sees natural areas of overlap between her own work and that of her co-panelists Roberts and Tishkoff.

Roberts, who has appointments in the Department of Sociology in the School of Arts & Sciences (SAS) and Penn Law School, has worked to illuminate ways in which the perception of race as having a biological basis has led to poorer care for minority groups and a failure to account for the social factors that lead to health disparities. Genomics studies of African populations led by Tishkoff, a geneticist with appointments in the Perelman School of Medicine and the Department of Biology at SAS, have further underscored the fallacy of a biological notion of race, highlighting the immense diversity present within one so-called racial group.

Glanz is hopeful that the dialogue that emerges will be fruitful and multi-dimensional, true to the philosophy of the Penn Integrates Knowledge professorships.

“There is a richness that emerges from looking at major public policy and social issues through the lens of multiple disciplines,” she says.

Register for the seminar here.

Originally published on .

Targeting Enzyme in ‘Normal’ Cells May Impede Pancreatic Cancer’s Spread, Penn Vet Team Shows

Targeting Enzyme in ‘Normal’ Cells May Impede Pancreatic Cancer’s Spread, Penn Vet Team Shows

By Katherine Unger Baillie | Kbaillie@Upenn.Edu | 215-898-9194
Published: Oct 27, 2017

Cancer of the pancreas is a deadly disease, with a median survival time of less than six months. Only one in 20 people with pancreatic cancer survives five years past the diagnosis. The reason is the cancer’s insidiousness; tumor cells hide deep inside the body, betraying no symptoms until late in the disease, when the cancer has almost invariably spread to other organs.

New findings from a University of Pennsylvania-led team offer a promising target for future therapies that could potentially root out even well-hidden metastatic cancer lesions. When they deleted the gene encoding this protein in mice with the disease, the animals lived longer, and the cancer’s spread to other organs was reduced.

Dr. Ellen Puré“We thought that by targeting this protein we would see a big change in the primary tumor, and, while we do see a delay, the big change was in the metastasis,” said Ellen Puré, the study’s senior author and chair of the Department of Biomedical Sciences in Penn’s School of Veterinary Medicine. “It looks like this protein might be a druggable target, so we’re hoping that with some additional follow-up work, it’s something that we’ll see go into patients.”

Puré, who is also director of Penn Vet’s Cancer Center, collaborated on the work with Penn Vet’s Albert Lo, Elizabeth L. Buza, Rachel Blomberg, Priya Govindaraju, Diana Avery and James Monslow; Chung-Pin Li of Taipei Veterans General Hospital and National Yang-Ming University School of Medicine; and Michael Hsiao of the Academia Sinica Genomics Research Center in Taipei.

Their paper was published in the Journal of Clinical Investigation Insight.

To gain a clearer understanding of cancer biology and expand the range of potential therapeutics, researchers such as Puré and her colleagues have increasingly expanded their research focus, from examining the tumor cells in isolation to a fuller picture of how tumors interact with their surrounding tissues. This investigation of the so-called “tumor microenvironment” has revealed that seemingly “normal” tissues that envelop the tumor, known as the stroma, can impede, allow or even encourage tumor growth, depending on a host of factors.

The stroma is sometimes referred to as the “soil” in which cancers grow; the right conditions will either allow a tumor to grow or keep it from rooting.

“If you take a tumor cell and put it on normal stroma,” Puré said, “it will typically inhibit tumor growth. You need to have a permissive stroma to let a neoplastic cell grow out of control and eventually metastasize.”

Many elements contribute to whether a stroma is tumor-permissive or not, but one that has been shown to be important is the tissue’s density and stiffness. Stroma can hold in tumor cells and prevent them from growing on the one hand, but, on the other, reorganized, tightly packed or dense stroma can promote tumor growth and make it difficult for immune cells or drugs to reach the tumor itself.

In earlier studies of the role of the tumor microenvironment, Puré and colleagues discovered a protein that plays a role in shaping the physical nature of the stroma, a protein-cleaving enzyme called FAP, for fibroblast activation protein. In a 2016 publication, the researchers demonstrated that this enzyme digests collagen, a primary component of the stromal extracellular matrix, by snipping intermediate-sized pieces of collagen into degradable fragments. This FAP-dependent turnover of stroma enhances tumor growth. When the team deleted or inhibited FAP in mouse models of lung and colon cancer, it led to an accumulation of matrix material and inhibited tumor growth because the undigested collagen restrained the tumor and prevented it from receiving an adequate blood supply.

“Collagen is something we have to understand a lot more about in the context of the tumor microenvironment,” Puré said. “A lot of people think it’s just the amount of collagen present, but we’re showing that it’s more complicated; the architecture and structure play a critical role.”

In the current work, the researchers looked to pancreatic cancer, a tumor type that is dominated by connective tissue, to see whether modulating FAP could make a dent in the primary tumor growth and, importantly, whether it played a role in making other organ’s tissue more susceptible to metastatic lesions.

First the researchers looked to tissues samples from human patients and found that FAP levels correlated with prognosis. Those patients with high levels of FAP expression in their stromal cells had shorter survival times compared with patients with lower FAP levels.

In a mouse model of pancreatic cancer, abolishing FAP expression delayed the onset of disease by five weeks and prolonged the animals’ overall survival by 36 days.

Drilling down into how FAP affected the disease course, the researchers found that FAP-depleted tumors had more signs of necrosis, a form of cell death, and greater infiltration of white blood cells, suggesting that FAP may normally act to prevent the immune system from controlling tumors.

Perhaps the more significant effect of FAP, however, was to reduce the cancer’s spread from the pancreas to other organs.

“This is the first time we’ve shown that FAP is important for promoting metastasis,” Puré said. “By targeting FAP with a drug, we may be able to slow down the spread of the cancer by treating distal tissues that you don’t even realize are getting ready to accept tumor cells, a phenomenon referred to as treating premetastatic niches. That is the hope.”

In future work, Puré’s group will be narrowing down what aspect of FAP is responsible for promoting disease progression. Inhibitors to its protein-cleaving activity already exist, so, if that is found to be responsible for its role in driving cancer, the path to a human therapy may be alluringly in reach.

The research was supported by the National Institutes of Health (grants CA169741, CA141144 and CA172921), Academia Sinica and Taiwan’s Ministry of Science and Technology.