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Grants Foster a Climate of Innovation

Fox Chase Cancer Center has long been a shining example of how passion and determination can foster a climate of innovation. But while these qualities will take researchers far, scientists and clinicians at Fox Chase and Temple Health also depend on grants from outside organizations to help translate their work into real-world applications.

One example is Lucia Borriello, PhD, an Assistant Professor in the Department of Cancer and Cellular Biology at the Lewis Katz School of Medicine at Temple University. She was awarded a $450,000 grant from the Susan G. Komen Foundation, funding that will allow her to not only establish a translational breast cancer research program but leverage her discoveries to develop therapies that may ultimately save lives.

Additionally, these grants often accord researchers the opportunity to investigate unique, broader areas of science that may be outside the immediate purview of cancer. Groups like the W.M. Keck Foundation, which supports outstanding science, engineering, and medical research, have accorded researchers like John Karanicolas, PhD, Co-Leader of the Cancer Signaling and Microenvironment Research Program at Fox Chase, the opportunity to develop new tools that can have a far-reaching impact on cancer and other diseases.

His research will focus on the development of machine learning tools for identifying compounds that stabilize select protein interactions. With this funding, Karanicolas and his team will be able to focus more holistically on the creation of these tools before determining their optimal applications.

Outside grants provide researchers with expanded opportunities in the lab, but their effects can also have a significant impact on the surrounding community. With grants like one from Stand Up To Cancer, researchers will be able to make great strides in areas that directly impact community members, specifically clinical trial access.

With this grant, which was awarded to Martin Edelman, MD, Associate Director for Clinical Research Integration at Fox Chase, and Linda Fleisher, PhD, MPH, Research Professor in the Cancer Prevention and Control Research Program at Fox Chase, multidisciplinary teams will work to remove barriers to phase 1 and phase 2 cancer clinical trial participation for underserved populations.

The grant will also aid in building additional services such as palliative and adjuvant supportive care, as well as utilizing bicultural patient navigators for addressing individual patient barriers to care. Funding from the grant will also help enhance community outreach and education with the goal of increasing understanding of clinical trials.

Grants such as these and the many others frequently awarded to researchers at Temple Health and Fox Chase are not only an acknowledgement of the talented scientists that work at these institutions, but a reflection of their passion and collaborative instincts.

New Tool for Drug Development

John Karanicolas, PhD, Co-Leader of the Cancer Signaling and Microenvironment Research Program at Fox Chase Cancer Center, was awarded a $1 million grant from the W.M. Keck Foundation to develop a platform that could assist in the development of new drugs.

“Scientifically, the goal of this project is to design new compounds known as molecular glues,” said Karanicolas. Molecular glues are small molecules that bind to the surface of a target protein and change its shape, allowing it to engage with a different set of protein partners than its usual repertoire.

“This is important because in many cases proteins act on their signaling partners through proximity, so simply bringing two proteins close to one another can, in some special cases, be enough to activate the signaling pathway,” said Karanicolas.

“This idea of molecular glues can be used to enhance existing signaling pathways or to rewire cellular signaling pathways in a way that may allow us to reach what were previously ‘undruggable’ targets,” meaning ones that do not respond to existing drugs.

Furthering Understanding of Proteins

Roland L. Dunbrack Jr., PhD, Director of the Molecular Modeling Facility at Fox Chase, released a new database that contains clusters of homologous protein assembly structures observed in independent structure experiments found in the Protein Data Bank.

ProtCAD, the Protein Common Assembly Database, is a searchable database designed to help with one of the unsolved problems in structural biology: How to determine the correct assembly for proteins in crystallographic structures. Using this type of structural information can help researchers understand the behavior of proteins involved in cancer development, prevention, and treatment.

ProtCAD is the natural evolution of a previously released database called ProtCID (Protein Common Interface Database), which included data on the individual domain level of proteins. “ProtCAD takes that a step further. Instead of just a single interface, we are looking at whole assemblies, including structures of three, four, or more proteins coming together,” Dunbrack said.

Boosting Effectiveness of Cancer Drugs

Researchers at Fox Chase discovered that the drug efflux pump MDR1 promotes resistance to a promising new class of drugs called PROTACS — proteolysis-targeting chimeras.

However, the researchers also found that in cultured cancer cells and mouse models, this resistance was prevented by combining PROTAC treatment with the drug lapatinib, which blocks MDR1 efflux pumps and also inhibits the epidermal growth factor receptor, a frequent oncogene and cause of resistance to cancer drugs.

“The hope is to have a double-pronged effect,” said James S. Duncan, PhD, Associate Professor in the Cancer Signaling and Microenvironment Research Program. “By combining lapatinib with a PROTAC drug we would have the ability to block MDR1-mediated resistance and the epidermal growth factor receptor with a single agent and allow patients to more fully benefit from treatment with PROTAC drugs.”

Insight Into DNA Damage Mechanisms

It’s long been known that DNA damage caused by environmental triggers, as well as other sources of oxidative stress, contribute to the development and progression of a wide variety of cancers. Now a study by a Fox Chase scientist provides new insight into how an enzyme called apurinic/apyrimidinic 1 (APE1) repairs this damage.

The study showed, for the first time, how APE1 binds to a common oxidative DNA lesion and sculpts the DNA to hold it in place for repair. It identified the key regions of the enzyme that are involved in the repair process, findings that could help lay the groundwork for future therapeutic treatments targeting this process.

“The more we understand how this enzyme works, the better we are able to design a drug or manipulate that mechanism to modulate its activity to enhance or decrease the effects of DNA damage,” said Amy Whitaker, PhD, an Assistant Professor in the Nuclear Dynamics and Cancer Research Program at Fox Chase and the study’s author.

Exploring Pancreatic Cancer Cell Survival

Researchers at Fox Chase demonstrated how cancer cells can survive in the body even when faced with a lack of sufficient nutrition, a finding that could be used as a potential indicator of disease status in the organs of pancreatic cancer patients.

The work was first conceptualized by Kristopher Raghavan, PhD, lead author of the study, who at the time was a graduate student in the lab of Edna “Eti” Cukierman, PhD, Co-Director of the Marvin and Concetta Greenberg Pancreatic Cancer Institute at Fox Chase.

Raghavan sought to determine the characteristics of extracellular vesicles, which are generated by tumor-supporting cells, and the role they play in providing nutrition to pancreatic cancer cells. Extracellular vesicles are small structures released by all cells that deliver selected sets of molecules to recipient cells, thus altering the recipient cells’ functions.

They found that even when pancreatic cancer cells are surrounded by an environment that provides them with poor nutrition, they can survive through the support of the material contained within extracellular vesicles generated by the cancer-associated fibroblast units. 

Fighting Mesothelioma With Broccoli

Researchers at Fox Chase Cancer Center and Temple Health received a three year, $1.2 million contract to study sulforaphane, a promising cancer preventive agent derived from broccoli and other cruciferous vegetables, for the prevention of malignant mesothelioma.

“Because advanced cancers such as malignant mesothelioma develop resistance to therapy, there is an urgent need for preventive measures,” said Joseph R. Testa, PhD, FACMG, a Professor in the Cancer Prevention and Control Research Program and Chief of Genomic Medicine at Fox Chase, the project’s principal investigator.

Joseph Friedberg, MD, FACS, Thoracic Surgeon-in-Chief at Temple Health and Co-Director of the Temple Health Mesothelioma and Pleural Disease Program, conceived the idea for the research. “I routinely see patients who had the same exposure to asbestos as their family member, who I am treating for mesothelioma. Right now we have nothing to offer them but surveillance,” Friedberg said.

“The ability to offer these individuals, as well as millions of others at risk, a nontoxic supplement that could prevent this cancer would be an immense contribution. I am ecstatic to have the opportunity to work on this project at Fox Chase with Dr. Testa, one of the foremost mesothelioma researchers in the world.”

Sulforaphane is characterized by a substance that is highly reactive and thought to be responsible for some of its cancer-preventive properties, Testa said. Yuwaraj Kadariya, MD, PhD, an Assistant Research Professor in Testa’s lab, will serve as co-investigator on the sulforaphane project.

The grant is funded through the National Cancer Institute’s PREVENT Cancer Preclinical Drug Development Program. Margie Clapper, PhD, Co-Leader of the Cancer Prevention and Control Research Program, serves as principal investigator of Fox Chase’s role as a prime contractor of the PREVENT program.

Funding Supports Collaborative Research

Researchers at Fox Chase, the Lewis Katz School of Medicine at Temple University, and the Temple University Kornberg School of Dentistry have received pilot grants and other funding to support research into a number of areas and encourage further collaboration between faculty at the institutions.

Pedro Torres-Ayuso, PhD, of the Katz School of Medicine, received two $50,000 Career Enhancement Program awards under the Specialized Program of Research Excellence (SPORE) at Fox Chase for his project, “Testing Understudied Kinase TNIK as a Target in Head and Neck Squamous Cell Carcinoma.” His project involves key collaborations with John Karanicolas, PhD, and James Duncan, PhD, of Fox Chase.

Several projects were funded by pilot grants from the Department of Cancer and Cellular Biology at the Katz School of Medicine. They include:

Torres-Ayuso and Hossein Borghaei, DO, MS, of Fox Chase, received $50,000 for their project, “Targeting Amplified TNIK for Novel Targeted and Combination Therapies in Lung Squamous Cell Carcinomas.”

Nezar Al-Hebshi, PhD, of the Kornberg School of Dentistry, Kelly Whelan, PhD, of the Katz School of Medicine, and Kerry Campbell, PhD, of Fox Chase, received $50,000 for their project, “Anticancer Properties of Oral Commensal Bacteria in OSCC.”

Lucia Borriello, PhD, and Beata Kosmider, PhD, of the Katz School of Medicine, and Borghaei received $50,000 for their project, “Effect of Smoking and Aged Microenvironment on Lung Cancer Recurrence.”