In a recent study, researchers at Fox Chase Cancer Center 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.

“These vesicles serve as package-like delivery of cellular materials systems that not only include numerous molecules inside them but also have exposed receptors on their surface. In some ways, these vesicles are much more effective than single traveling molecules because they encompass a full code of intended delivery signals. It is a much more sophisticated way for cells to communicate, locally and systemically, with other cells in the human body,” said Cukierman.

One of the unique aspects of pancreatic cancer is its stroma—its supporting tissue. The presence of stroma, including a characteristic fibrous protein network, causes the collapse of local vessels, making the environment surrounding the tumor a poor source of sustained nutrition.

However, this stroma is filled with cancer-associated fibroblasts, the type of cell present in pancreatic cancer that generates the fibrous network and secretes multiple substances, including small extracellular vesicles.

Through this study, Raghavan, Cukierman, and their colleagues were able to take cancer-associated fibroblasts from patient samples and grow them as functional units by culturing them in their self-generated fibrous networks. They then isolated the secreted vesicles before comparing them with those from non-pathogenic fibroblast units.

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.

Cukierman said an additional finding of the study was that in order for the extracellular vesicles to effectively help cancer cells survive, the cancer-associated fibroblasts must express the protein Netrin G1, a stroma target discovered by the Cukierman lab in 2021. Interestingly, this and another receptor protein were uniquely detected in the vesicles isolated by the tumor supportive cancer-associated fibroblasts.

“We also compared blood samples from cancer patients and from healthy donors, isolated vesicles from these samples, and looked for the same receptor protein biomarkers. To our surprise, we observed that these two unique receptor proteins were much higher in vesicles from patients with cancer,” Cukierman said. The results were significant enough for the research team to look for these biomarkers in ongoing clinical trials.

“This is exciting because it will help us see if we’re changing the tumor stroma so it no longer supports the cancer based on the types of systemic vesicles we find circulating in patients’ blood,” Cukierman said.

NetrinG1+ Cancer-Associated Fibroblasts Generate Unique Extracellular Vesicles That Support the Survival of Pancreatic Cancer Cells Under Nutritional Stress

Fox Chase Cancer Center (Fox Chase), which includes the Institute for Cancer Research and the American Oncologic Hospital and is a part of Temple Health, is one of the leading comprehensive cancer centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase is also one of just 10 members of the Alliance of Dedicated Cancer Centers. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence five consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach. It is the policy of Fox Chase Cancer Center that there shall be no exclusion from, or participation in, and no one denied the benefits of, the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.

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Fox Chase Researchers Discover How Pancreatic Cancer Cells Manage to Survive in Poor Nutritional Environments

Researchers at Fox Chase Cancer Center have 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 

 research program at Fox Chase. “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.”

PROTACS are a promising new class of drugs known as protein degraders because they destroy target proteins in cells using the proteasome degradation pathway. PROTACs have two functional ends. One end engages an E3 ubiquitin ligase and the other a disease-causing protein called a protein of interest or oncogene. By connecting to the ubiquitin ligase, the PROTAC marks the protein for destruction.

“You highjack the cancer cell’s own proteasome machinery to degrade the oncogene,” Duncan said. “This is important because there are a lot of protein targets that are considered to be beyond treatment with traditional inhibitors.”

Cancer cells have an ability to eventually evade the effects of drugs, so targeted cancer therapies, no matter how effective they are initially, will likely encounter resistance. To discover what might drive PROTAC resistance, Duncan and colleagues systematically exposed cancer cells to PROTACs.

Using proteomics, the global analysis of proteins in cells, they identified a specific protein called MDR1 that was increased dramatically in the cells that acquired resistance to PROTACS. “Cancer cells upregulated MDR1 and this protein pumped PROTACS out of the cell, limiting the amount of drug within the cancer cell,” Duncan said.

Interestingly, upregulation of MDR1 has been linked to resistance to other anticancer drugs as well, including chemotherapy. In addition, there are several cancer types that naturally have cells that overexpress—produce high levels—of MDR1 that would likely have intrinsic resistance to PROTACs.

Duncan said that although there are existing small molecule inhibitors for drug efflux pumps like MDR1, they have not shown great success in clinical trials. There are some protein kinase inhibitors like lapatinib that are currently used to treat cancers and have a dual function that allows them to inhibit a kinase and the activity of the drug efflux pump.

Using cell lines from colorectal cancer that overexpress MDR1, Duncan and colleagues found that PROTACs targeting either the protein kinase MEK1/2 or the GTPase KRAS only worked when combined with lapatinib. In mouse models, the combination of MEK1/2 PROTACs with lapatinib improved inhibition of KRAS-mutant colorectal cancer samples that overexpressed MDR1 compared with either agent alone, and also prevented PROTAC resistance.

“This is important because there are a number of cancers that are driven by KRAS and/or MEK1/2 and have high levels of the MDR1 efflux pump,” Duncan said.

Based on these results, concurrent blockade of MDR1 will likely be needed to achieve a durable benefit from PROTACs. Future clinical trials should explore PROTACs in combination with lapatinib, particularly in those cancers that rely on epidermal growth factor receptor, Duncan said.

The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells

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


Lapatinib May Boost Effectiveness of Drugs That Destroy Cancer Proteins by Blocking Resistance

, chief of the Division of Genitourinary Medical Oncology and professor in the 

 at Fox Chase Cancer Center, has been appointed Deputy Director.

“Conducting world-class cancer science is an integral part of our Fox Chase mission and identity as a National Cancer Institute (NCI)-designated Comprehensive Cancer Center. Strong leadership in this area is critical to supporting our research enterprise and to promoting progress and success. That’s why I am so pleased to announce the appointment of Dr. Plimack to this key position,” said 

“Dr. Plimack’s work ethic, dedication to excellence, and clinical expertise will serve us all well as she assumes her vital new role.”

Plimack will oversee the Clinical and Translational Research Plan as she takes on this newly created role. Her primary areas of focus will include:

Programmatic scientific strategy, in which she will lead the growth of interdisciplinary translational science by building alliances across clinical disciplines and among clinical and basic science research faculty both at Fox Chase and throughout Temple Health.

Further development of the Fox Chase Bladder Cancer Program towards an integrated and collaborative research program by addressing NCI requirements for collaborative project funding and promoting the establishment of a Genitourinary Center of Excellence.

Development of institutional diversity, equity, and inclusion (DEI) initiatives by addressing DEI as an integral part of our Cancer Center Support Grant renewal and by improving the Fox Chase culture to aid retention and recruitment of women and Underrepresented in Medicine faculty and staff.

A national leader in genitourinary oncology, Plimack is director of Genitourinary Clinical Research at Fox Chase. She joined Fox Chase in 2008 after completing her medical oncology fellowship at the MD Anderson Cancer Center in Houston.

Internationally recognized for her expertise in bladder and kidney cancers, Plimack is a leader in clinical trial design and implementation. Her research has formed the basis of a biomarker-directed bladder preservation platform led by Fox Chase investigators.

She leads a Stand Up To Cancer-funded multicenter clinical trial in metastatic bladder cancer, and has been active in drug development on steering committees and data safety boards of trials that have led to the approval of multiple new agents used to treat patients with genitourinary malignancies.

Plimack earned her medical degree with honors in Pathology from New York University School of Medicine and a Master of Science in Patient-Based Biologic Research from the University of Texas Graduate School of Biomedical Sciences. She completed both her internship and internal medicine residency at New York University Medical Center/Bellevue Hospital.

Among her many professional activities and leadership roles, Plimack is an elected member of the American Society of Clinical Oncology Board of Directors, chair of the Scientific Advisory Board for the Bladder Cancer Advocacy Network, and member of the National Comprehensive Cancer Network (NCCN) Board of Directors.

In addition, she is a member of the NCCN guidelines panels for kidney and bladder/penile cancers. Last year, she was appointed medical oncology editor of 

—the official journal of the European Association of Urology. She also serves on the editorial boards of 

 magazine Top Doctor, Plimack also appears regularly in Castle Connolly’s Top Doctors. She has also achieved status as a five-star provider—the highest possible rating for clinical care based on patient satisfaction data compiled by Press Ganey.


The Hospital of Fox Chase Cancer Center and its affiliates (collectively “Fox Chase Cancer Center”), a member of the Temple University Health System, is one of the leading cancer research and treatment centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence five consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship and community outreach. It is the policy of Fox Chase Cancer Center, that no one shall be excluded from or denied the benefits of or participation in the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.

Elizabeth Plimack, MD, MS, chief of the Division of Genitourinary Medical Oncology and professor in the Department of Hematology/Oncology at Fox Chase Cancer Center, has been appointed Deputy Director.

Fox Chase Cancer Center

Articles

Fox Chase Researchers Discover How Pancreatic Cancer Cells Manage to Survive in Poor Nutritional Environments

Lapatinib May Boost Effectiveness of Drugs That Destroy Cancer Proteins by Blocking Resistance

Elizabeth Plimack, MD, MS, Appointed Deputy Director at Fox Chase Cancer Center