Back to Annual Report

EARLY 2000s

A lone scientist pursues his research in one of Fox Chase’s many labs.

 

LOOKING AHEAD: THE NEXT 10 YEARS IN RESEARCH

For Fox Chase Cancer Center, research and clinical application have long been processes that work best in tandem. For decades, Fox Chase has believed that scientific discovery leads the way by translating discovery into treatment that improves and saves lives.

From the creation of the world’s first anti-cancer vaccine, to pioneering insights into how cancers develop and spread, to the development of novel drugs that target cancer cell vulnerabilities, Fox Chase’s Nobel- and Lasker Award-winning investigators have consistently been at the helm of groundbreaking cancer science and care.

The next decade will be no different. Looking forward, Fox Chase researchers will focus on tools that have the capacity to transform the cancer treatment landscape. Areas such as immunotherapy, cancer risk and outcomes in populations, cancer epigenetics and genome integrity, aging and cancer, and novel targets have moved to the forefront of cancer research as critical subjects to be investigated.

Because of its enormous therapeutic potential, Fox Chase plans to focus on specific areas of immunotherapy, the use of the body’s immune system to fight cancer, in order to address some of the barriers to its effectiveness. Specifically, over the next few years, Fox Chase scientists will investigate immune cells and signaling pathways — that is, how the body knows its immune system has been breached. They will also focus on translational immuno-oncology, the discovery and use of medicines to augment the ability of the immune system to fight cancer.

Cancer epigenetics and genome integrity is another area Fox Chase plans to explore in the coming years. By acquiring advanced technologies and recruiting new faculty to work in epigenomics and cancer genetics, Fox Chase will continue to focus on combining individual tumor-oriented basic research with a translational approach.

Cancer and aging is yet another area of focus for the next 10 years. Aging plays a significant role in cancer, as it affects all bodily processes. Inflammation, epigenetics, and the effect of aging on therapeutic response are all being investigated by Fox Chase researchers. Advancing research in this area will make Fox Chase one of the few National Cancer Institute-designated cancer centers to have aging and cancer as a major research focus.

Lastly, Fox Chase will continue to aggressively research cancer risk and outcomes in various populations. This work will allow Fox Chase to serve as a national leader in cancer health equity by answering important questions about how behaviors, environment, and social determinants of health interact with genetics to influence cancer risk.

 

NEW STUDY EXPANDS UNDERSTANDING OF KEY GENE

Researchers at Fox Chase have made a new discovery about the transcription factor ThPOK, a gene that may be useful in the treatment of sepsis, other types of infection, and ultimately, cancer.

Discovered in 1997 by Dietmar J. Kappes, PhD, Director of the Transgenic Mouse Facility and a Professor in the Nuclear Dynamics and Cancer Research Program at Fox Chase, the ThPOK gene plays a key role in the generation of CD4 T-cells, white blood cells that play a critical role in immune function. The groundbreaking discovery laid the foundation for a generation of research into this master-regulator of CD4 T cell development and function.

Kappes and a team of researchers reported the new finding that ThPOK also limits the production of neutrophils — a type of white blood cell that act as the immune system’s first line of defense —and promotes a pro-inflammatory effect of neutrophils.

This discovery suggested that ThPOK was necessary for neutrophil development and served as a “brake” to maintain neutrophil equilibrium and that this brake is installed through regulation of a cellular process.

Prior and ongoing studies from the Kappes lab indicate that ThPOK can act as both a negative and positive regulator of cancer development, depending on the cellular context. Figuring all this out will occupy the Kappes lab and collaborators for many years to come.

 

NEW THERAPY HELPS BLOCK LUNG INJURIES CAUSED BY FLU

Fox Chase researchers have shown that a newly developed compound was able to block necroptosis, a type of cell death that leads to lung inflammation and damage, following infection with the influenza virus. The compound could be used to block this pathway in a number of diseases.

Necroptosis is triggered by the activation of the receptor interacting protein kinase 3 (RIPK3) pathway. This type of cell death produces strong immune responses by rupturing dead cells and releasing their contents throughout the body. When controlled, this form of cell death is effective at ridding the body of a virus. However, if unchecked, necroptosis can cause severe inflammation and lung damage and can even lead to death.

Siddharth Balachandran, PhD, a Professor in the Cancer Signaling and Microenvironment Research Program, and his colleagues used mice infected with the flu virus to show that a newly developed RIPK3 inhibitor called UH15-38 selectively blocked necroptosis and dampened inflammation, even when administered later in the course of an infection, a milestone in viral infection research.

“We have now shown the possibility that RIPK3 can be inhibited, which is significant because it is central to programmed necrotic death in human tissues,” said Balachandran. “Any disease involving chronic inflammation and necrotic death, such as colitis, lung fibrosis, liver disease, or psoriasis, could potentially benefit from blockade of this pathway.”

 

FINDINGS MAY BE KEY TO NEW LEUKEMIA TREATMENTS

Previous research has shown that blocking the ability of leukemia cells to repair self-inflicted genetic damage can cause them to die off on their own. But while this approach is effective in the short term, the cancer eventually comes back. However, recent research could lead to the development of new treatments.

A new study by scientists at the Fels Cancer Institute for Personalized Medicine at the Lewis Katz School of Medicine at Temple University and Fox Chase has shown that leukemia cells can be killed much more effectively by identifying leukemias with specific genetic mutations and using a combination of DNA repair inhibitors to attack them.

Researchers tested a combination of PARP1 and another inhibitor. In both cell-based and animal studies, they found that this approach significantly enhanced the ability to kill leukemia cells.

The finding brings researchers a step closer to developing new treatment options for acute myeloid leukemia, one of the deadliest and treatment-resistant forms of the disease, said senior author Tomasz Skorski, MD, PhD, DSc, Director of the Fels Institute and a Professor in the Nuclear Dynamics and Cancer Research Program at Fox Chase.

The research team’s next step is to move forward with a clinical trial to test the combined therapy, Skorski added.

 

POSSIBLE NEW DRUG CANDIDATE FOR PANCREATIC CANCER

A new study led by Igor Astsaturov, MD, PhD, Co-Director of the Marvin & Concetta Greenberg Pancreatic Cancer Institute at Fox Chase, demonstrated that two key components are necessary for a new drug candidate, LP-184, to effectively treat pancreatic adenocarcinoma.

The research is part of a two-year collaboration between his lab and Lantern Pharma, said Astsaturov, who is also the inaugural holder of the Paul F. Engstrom Professorship in Oncology at Fox Chase. Lantern is developing LP-184.

Researchers believe the molecule causes direct DNA damage, so they focused their efforts on studying the activity of the drug in models that carried mutations in commonly altered components in the DDR pathway. Additionally, researchers found that LP-184 is a pro-drug that needs to be activated inside the cancer cells by a specific enzyme called prostaglandin reductase (PTGR1) that is often elevated in solid tumors but not in normal tissues.

“The study showed that when cells lose PTGR1 they lose sensitivity to the drug,” said Astsaturov. “Based on our findings, we anticipate that LP-184 will expand therapy options to a large subset of patients with genetically defined pancreatic adenocarcinoma.”

 

GRANT TO STUDY RNA, TELOMERASE, AND DISEASE

Lu Chen, PhD, an Assistant Professor in the Nuclear Dynamics and Cancer Research Program and a member of the Cancer Epigenetics Institute, was awarded a $2.5 million grant from the National Institute of General Medical Sciences (NIGMS) to investigate RNA structure and stability. This work has implications for cancer, Alzheimer’s, and other degenerative diseases and continues the Fox Chase legacy of basic research.

Chen received an NIGMS Maximizing Investigators’ Research Award. Considered on par with an R01 — the oldest and more common “workhorse” biomedical research grant — the MIRA provides more funds and flexibility, giving investigators the freedom to explore new concepts.

Chen and his team are using the grant to explore the use of cutting-edge RNA mapping techniques. “We’re trying to find a way to understand how the RNA structure and location are in turn contributing to RNA’s function inside of a cell,” Chen said.

RNA is an essential component of the enzyme telomerase, which synthesizes the ends of the telomeres found at the tips of chromosomes. Telomerase helps enable 90% of cancer cells to replicate indefinitely. However, when stem cells don’t have enough telomerase due to aging or genetic mutations, they begin to shut down. This contributes to degenerative diseases like pulmonary fibrosis, liver cirrhosis, and Alzheimer’s.

 

 

GRANT FUNDS STUDY OF CERVICAL CANCER DISPARITIES

Researchers at Fox Chase received a $3 million grant from the National Institute on Minority Health and Health Disparities, part of the National Institutes of Health, to evaluate the effectiveness of the Health Enhancement Resource System (HERS) intervention.

The system, which uses text message reminders and interactions, was created to increase the rate of follow-up visits for individuals who receive abnormal cervical screening results.

The HERS program was initiated last year with another grant that allowed researchers to test the HERS intervention’s feasibility. Now, with the NIH funding and in collaboration with investigators at Rutgers University and Thomas Jefferson University, researchers can evaluate its effectiveness.

The research was conducted by Suzanne Miller, PhD, a Professor, and Erin K. Tagai, PhD, MPH, an Assistant Professor, in the Cancer Prevention and Control Research Program at Fox Chase.

With this program, Miller and Tagai hope to significantly increase attendance at the first recommended follow-up after an abnormal Pap test and thereby improve patient outcomes in terms of early prevention and quality of life.

 

RESEARCH COULD LEAD TO NEW TARGETED MEDICINES FOR LEUKEMIA

Researchers at Fox Chase demonstrated how amplification and rearrangement of a gene associated with leukemia is directly controlled by epigenetic factors. The findings indicate that these epigenetic regulators can be used as possible drug targets, paving the way for improved personalized, targeted medicines.

The research was conducted by Johnathan Whetstine, PhD, director of the Cancer Epigenetics Institute at Fox Chase. Whetstine and his colleagues focused on the factors surrounding the recurrence of leukemia following chemotherapy, specifically how the MLL gene breaks apart, repairs, and amplifies.

Through multiple studies, Whetstine and colleagues showed for the first time that loss of a commonly deleted enzyme in leukemia, KDM3B, directly increases copies and rearrangement of MLL. KDM3B is an enzyme that erases methylation.

“To find out how this occurs, we did a screen and discovered that a very specific methyl transferase called G9a was important in driving methylation, and in turn, this process. When we inhibited G9a, we prevented the amplifications and rearrangements,” said Whetstine.

This study sheds light on how epigenetics directly controls the emergence of amplifications and rearrangements as well as on how to therapeutically control the emergence of treatment induced MLL amplifications and rearrangements driving therapy-induced leukemia.

 

NEW STRATEGY COULD IMPROVE LEUKEMIA TREATMENT

Scientists at the Fels Cancer Institute for Personalized Medicine and the Lewis Katz School of Medicine at Temple University and Fox Chase have developed a new strategy that can be used to attack and destroy leukemia clones. It could prevent patients from relapsing after treatment and be applied to other cancers.

Senior author Tomasz Skorski, MD, PhD, DSc, and his research team had previously reported that acute myeloid leukemia cells accumulate high levels of DNA damage. To survive and grow, malignant cells must repair these DNA lesions, which make them vulnerable to DNA damage repair inhibitors (DDRi).

In a new study, the researchers identified a combination of two DDR inhibitors that was effective against all cancer clones, making the effects of treatment last longer. The findings are significant because the approach could be applied not just to leukemia, but to other types of cancer.

“We evaporated human leukemia in mice,” Skorski said. “We’re really hoping that this will be the first step for the field to shift from personalized medicine into clonal medicine. We think if we combine our approach with standard cytotoxic drugs, we will be able to lower the doses of these drugs, reducing toxicity for patients and achieving an even better effect.”

 

GRANT RENEWAL WILL ADDRESS CANCER HEALTH DISPARITIES

Lewis Katz School of Medicine/Fox Chase Cancer Center and Hunter College of the City University of New York received a five-year, $13.3 million competitive grant renewal from the National Cancer Institute (NCI), part of the National Institutes of Health, to address cancer health disparities.

“In the next five years, our partnership aims to break systemic structural barriers and promote inclusiveness across disciplines in order to advance cancer health equity,” said Grace X. Ma, PhD, Contact Principal Investigator on the grant and Associate Dean of Health Disparities at Temple University’s Lewis Katz School of Medicine.

The grant enables NCI-designated cancer centers and institutions serving underserved health disparity populations and underrepresented students to better support underserved populations. It will continue to support groundbreaking work in reducing cancer health disparities that adversely affect African American, Asian-Pacific American, and Hispanic American communities across the Philadelphia and New York City metropolitan areas, as well as New Jersey.

“The support from this grant allows us to foster new and innovative approaches to health challenges that have been affecting these populations for many years,” said Camille Ragin, PhD, MPH, Co-Principal Investigator on the grant and Associate Director of Diversity, Equity, Inclusion, and Accessibility at Fox Chase.

 

EDNA ‘ETI’ CUKIERMAN AWARDED PROFESSORSHIP IN PANCREATIC CANCER

Edna “Eti” Cukierman, PhD, Co-Director of the Marvin & Concetta Greenberg Pancreatic Cancer Institute and the Marvin & Concetta Greenberg Chair in Pancreatic Cancer Research at Fox Chase, was awarded the American Cancer Society’s (ACS) Wilmott Family Professorship in Pancreatic Cancer.

ACS professorships recognize individuals who have made pivotal contributions that have changed cancer research and oncology care, as well as those who have a proven track record of mentorship and leadership in the cancer research community. They are considered the most prestigious ACS research awards. Cukierman, who is also the Co-Leader of the Cancer Signaling and Microenvironment Research Program, is the first Fox Chase faculty member to receive an ACS professorship, which bestows $400,000 in funding to one researcher every five years.

With this support, Cukierman will work to address unmet medical needs of pancreatic cancer patients through research while also closing educational gaps for under-represented trainees and supporting individuals who would otherwise not have the opportunity to conduct high-level research.

 

 

 

MAKING LUNG CANCER VULNERABLE TO THE IMMUNE SYSTEM

Researchers at Fox Chase Cancer Center have identified a genetic mechanism that can make small cell lung cancer tumors vulnerable to attack by the immune system. The discovery could be used to develop drugs that would make immunotherapy effective in small cell lung cancer for the first time.

Small cell lung cancer causes so-called “cold” tumors that can’t be detected by the immune system. In this study, researchers looked at using a strategy called viral mimicry to turn these cold tumors “hot,” making it possible for immune cells to detect and target them. Viral mimicry involves inducing a reaction in cancer cells that appears similar to a viral infection, which attracts the attention of the immune system.

When researchers genetically depleted the gene DHX9 in cancer cells in the lab, levels of dsRNA significantly increased and immune signaling was activated.

A follow-up study looked at combining DHX9 depletion with immunotherapy in mice. “The tumors almost disappeared and survival dramatically increased in the mice,” said Israel Cañadas, PhD, an Assistant Professor in the Nuclear Dynamics and Cancer Research Program at Fox Chase and the study’s lead author.

Researchers are now partnering with a pharmaceutical company on the development of a DHX9 inhibitor.

 

 

FUNDING SUPPORTS COLLABORATIVE RESEARCH

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

Several projects were funded by $50,000 pilot grants from the Department of Cancer and Cellular Biology at the Katz School of Medicine. They include:

Sara Small, MD, PhD, and Nathaniel Snyder, PhD, MPH, DABT, of the Katz School of Medicine, received funding for their project, “Targeting SLFN11-Low Acute Myeloid Leukemia.”

Michael Hall, MD, MS, FASCO, and Erin Tagai, PhD, MPH, of Fox Chase, and Slobodan Vucetic, PhD, MS, of Temple University, received funding for their project, “Development of a Gen-Chat, a Natural Language Processing-Based System to Improve Patient-Reported Outcomes Among Patients Receiving Genetic Testing Results.”

Mitchell Fane, PhD, of Fox Chase, and Lucia Borriello, PhD, of the Katz School of Medicine, received funding for their project, “The Role of Age Mediated NK-Cell Decrease in Promoting Reactivation From Metastatic Breast Cancer Dormancy.”