Dr. Paul Keim of TGen and NAU is Named a Fellow of the American Association for the Advancement of Science

AAAS recognizes Dr. Keim for contributions to microbiology, genetics, genomic analysis, evolution, forensics and public health

Dr. Paul Keim, Director of the Pathogen Genomics Division of the Translational Genomics Research Institute (TGen) and the Cowden Endowed Chair of Microbiology at Northern Arizona University (NAU), has been named a Fellow of the American Association for the Advancement of Science (AAAS).

Election as a Fellow of AAAS is an honor bestowed upon members by their peers for meritorious efforts to advance science or its applications.

Dr. Keim’s peers recognized him for “distinguished contributions to the fields of microbiology, evolution and genetics through the use of genomic analysis for applications in forensics, biology and public health,” according to the AAAS, which will formally announce this year’s Fellows in the Nov. 27 issue of the organization’s journal Science.

Dr. Keim and other new Fellows also will be recognized Feb. 13 at the AAAS Fellows Forum during the 2016 AAAS Annual Meeting in Washington, D.C.

Dr. Keim is a world-renowned expert in anthrax and other infectious diseases. At TGen and NAU he directs investigations into how to bolster the nation’s biodefense, and to prevent outbreaks — even pandemics — of such contagions as flu, cholera, E. coli, salmonella, and even the plague.

“There is no question that AAAS’s recognition of Dr. Keim is extremely well deserved,” said Dr. Jeffrey Trent, TGen President and Research Director. “Paul’s achievements in revealing the genomes of microbial pathogens — both natural and those made into weapons — are of profound worldwide importance. His research, along with his dedication to his students and to the cause of public health, place him in the upper echelon of premier scientists, and cements Arizona’s place on the map in this critical and growing area of research.”

“Thousands of NAU students have participated in research organized by Dr. Keim, and from there have launched successful scientific careers,” said NAU President Rita Cheng. “His research group has forged a strong partnership between the university and TGen North, generating an important economic impact and producing health benefits for Arizona and beyond.”

Dr. Keim is Director of TGen’s Pathogen Genomics Division, also known as TGen North in Flagstaff, which aims to protect human health though genomic investigations of some of humankind’s most deadly microbes.

Dr. Keim also is Director of NAU’s Microbial Genetics & Genomics Center, also in Flagstaff, a program that works with numerous government agencies to help thwart bioterrorism and the spread of pathogen-caused diseases.

“I’m gratified to know this honor also brings recognition to everyone in the lab, including the students who work with us,” said Dr. Keim, a Professor at TGen and Regents Professor of Microbiology at NAU. “Their contributions, achieved through dedication and talent, are meaningful and well deserving of the attention.”

Dr. Keim is a former member and chair of the federal government’s National Science Advisory Board for Biosecurity (NSABB), where he helped draft national research policy guidelines for blunting bioterrorism while elevating ethical standards and improving the quality of scientific research.

“Our science has been completely transformed by the rapid advancements of technology. Now, TGen’s job is to use these advancements to make positive impacts on human health. We have that ability, therefore, we feel that we have that responsibility to mankind,” Dr. Keim said.

His lab was involved in the investigation of the 2001 anthrax-letters attacks. Anthrax samples from the U.S. House and Senate buildings were rushed under heavy guard to Dr. Keim’s laboratory in Flagstaff for analysis. At the time, the FBI didn’t have a biosafety Level 3 lab. Dr. Keim’s lab became the major repository for anthrax samples gathered for comparison by the FBI from across the globe.

TGen North collaborates with local, national and international universities, biotech companies, security agencies, health care providers, public health departments and other institutions in its quest to protect human health.

Dr. Daniel D. Von Hoff, TGen Physician-In-Chief and Distinguished Professor, was named an AAAS Fellow in 1992 for his work in Medical Sciences.

Dr. Thomas Witham, NAU Regents Professor of Biology, was named an AAAS Fellow in 2011 for his research in Ecological Sciences.

The tradition of AAAS Fellows began in 1874. Fellows are elected by the AAAS Council, which is the policymaking body of the Association, chaired by the AAAS president, and consisting of the members of the board of directors, the retiring section chairs, delegates from each electorate and each regional division, and two delegates from the National Association of Academies of Science.


TGen Identifies Drug That Could Limit the Spread of Deadly Brain Tumors

Study funded by Ivy Foundation shows PPF could help treat glioblastomas by sensitizing tumors to chemotherapy and radiation treatments

In a significant breakthrough, the Translational Genomics Research Institute (TGen) has identified a drug, propentofylline or PPF, that could help treat patients with deadly brain cancer.

In a study published today in the Journal of NeuroOncology, TGen researchers report that PPF works to limit the spread of glioblastoma multiforme, or GBM — the most common primary tumor of the brain and central nervous system — by targeting a protein called TROY.

In addition, TGen laboratory research also found that PPF increases the effectiveness of a standard-of-care chemotherapy drug called temozolomide (TMZ), and radiation, to treat glioblastoma.

“We showed that PPF decreased glioblastoma cell expression of TROY, inhibited glioma cell invasion, and made brain cancer cells more vulnerable to TMZ and radiation,” said Dr. Nhan Tran, Associate Professor and head of TGen’s Central Nervous System Tumor Research Lab.

An advantage of small-molecule PPF — which has been previously used in clinical trials in an attempt to treat Alzheimer’s disease and dementia — is that it can penetrate the blood-brain barrier and reach the tumor. And, the FDA has already approved it.

“Our data suggests that PPF, working in combination with TMZ and radiation, could limit glioblastoma invasion and improve the clinical outcome for brain tumor patients,” said Dr. Tran, the study’s senior author.

This study was funded, in part, by The Ben & Catherine Ivy Foundation.

“GBM is one of the most aggressive of all cancers and it affects people of all ages,” said Catherine (Bracken) Ivy, founder and president of The Ben & Catherine Ivy Foundation. “Funding research focused on helping patients survive longer is critical, and studies such as this advance our goal of not only improving treatments for brain cancer, but eventually finding a cure.”

One of the primary treatments for glioblastoma is surgical removal of the tumor. However, because of the aggressive way glioblastomas invade surrounding brain tissue, it is impossible to remove all parts of the tumors, and the cancer eventually returns and spreads. This insidious cancer invasion also limits the effectiveness of chemotherapy drugs and radiation therapy.

TGen found that PPF works to limit the spread of glioblastomas by targeting and knocking down the expression of the TROY protein. TGen researchers have linked TROY to the cellular mechanisms that enable glioblastomas to invade normal brain cells, and resist anti-cancer drugs.

“New therapeutic strategies that target the molecular drivers of invasion are required for improved clinical outcome,” said Dr. Harshil Dhruv, a TGen Research Assistant Professor and lead author of the study. “Propentofylline may provide a pharmacologic approach to targeting TROY, inhibiting cell invasion and reducing therapeutic resistance in glioblastomas.”

One of the fundamental challenges in treating brain cancer with drugs is what is known as the blood-brain barrier that separates circulating blood from the brain extracellular fluid in the central nervous system. This barrier works to protect the brain from toxins. However, this security system is so effective at protecting the brain that it prevents many life-saving drugs — all but some small molecules — from being able to treat cancer and other diseases of the brain.

As a result, there has been little progress in recent decades in finding new effective treatments for GBM. Median survival for newly diagnosed GBM patients is only 14.6 months. Only 5 percent of patients survive more than 5 years.

“Clinical trials revealed that PPF can cross the blood-brain barrier, and has minimal side effects,” Dr. Tran said. “PPF could be easily translated to the clinic as an adjuvant therapy in combination with standard of care treatment for GBM patients.”

This study — Propentofylline inhibits glioblastoma cell invasion and survival by targeting the TROY signaling pathway — also was funded by the National Institutes of Health under grants NS86853 and P50 CA108961. To read the abstract, visit: http://link.springer.com/article/10.1007/s11060-015-1981-0.

‘Liquid Biopsy’ Promotes Precision Medicine by Tracking Patient’s Cancer

Circulating tumor DNA in blood could inform physicians on best treatments for individual patients

A team of researchers, including scientists from the Translational Genomics Research Institute (TGen), has reported that analyzing circulating tumor DNA (ctDNA) can track how a patient’s cancer evolves and responds to treatment.

In a study published today in Nature Communications, Dr. Muhammed Murtaza of TGen and Mayo Clinic, and colleagues, describe an extensive comparison between biopsy results and analysis of ctDNA in a patient with breast cancer.

The researchers followed the patient over three years of treatment.

“When patients receive therapy for advanced cancers, not all parts of the tumor respond equally, but it has been difficult to study this phenomenon because it is not practical to perform multiple, repeated tissue biopsies,” said Dr. Murtaza, Co-Director of TGen’s Center for Noninvasive Diagnostics, and one of the study’s lead authors.

“Our findings empirically show that ctDNA analysis from blood samples allows us to detect cancer mutations from multiple different tumor sites within a patient and track how each of them responds,” Dr. Murtaza said.

This type of blood test — known as a liquid biopsy — is less invasive, less costly and less risky than conventional tissue biopsies, which essentially are minor surgeries. Obtaining liquid biopsies could occur more frequently, too, thus providing physicians with up-to-date information about how a patient’s cancer might be changing. This, in turn, could help in the selection of the best possible treatments to combat the cancer.

The researchers followed a 42-year-old woman diagnosed with invasive ductal carcinoma — the most common type of breast cancer — that had spread to other parts of her body, including her backbone, chest and liver. Eventually, it spread to her brain and left ovary.

Over the course of her illness, the researchers obtained eight tissue biopsies and nine blood samples for study, including samples obtained at a research autopsy. Their analysis revealed that ctDNA in blood samples tracked mutations that occurred in her cancer as it spread to various parts of her body and identified the tumor sites that developed resistance to therapy.

“Our results show that ctDNA, collected through liquid biopsies, provides a dynamic sampling of cancer cell alterations, reflecting the size and activity of distinct parts of the tumor,” Dr. Murtaza said.

Further, the study results suggest that precise and up-to-date genetic monitoring of changes in a patient’s cancer, through ctDNA analysis, could help inform physicians what type of targeted treatment might be best at each stage of the disease.

“The potential of using circulating DNA for estimating just how well a patient may respond to targeted therapies and for tracking the development of resistant clones in real-time, heralds a new era for precision medicine,” said Dr. A. Keith Stewart, Carlson and Nelson Endowed Director, Mayo Clinic Center for Individualized Medicine. Dr. Stewart was not involved in the research.

While the study, Multifocal clonal evolution characterized using circulating tumor DNA in a case of metastatic breast cancer, resulted from deep genomic analysis of a single patient, the observations have important implications for future ctDNA studies.

Contributing to and supporting this study were: Mayo Clinic in Arizona, the University of Cambridge, the Human Research Tissue Bank at Addenbrooke’s Hospital, the NIHR Cambridge Biomedical Research Centre, Cancer Research UK, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge Experimental Cancer Medicine Centre, Illumina Inc., Peter MacCallum Cancer Centre, the Australian National Breast Cancer Foundation and Victorian Cancer Agency Early Career Fellowship, and Science Foundation Arizona’s Bisgrove Scholars Early Tenure Track Award.