CU Anschutz Team Awarded $200,000 ASPIRE Grant to Target NPEPPS Enzyme and Overcome Dual Resistance to Chemotherapy and Immunotherapy
核心洞察
A multidisciplinary team led by James Costello, PhD, at CU Anschutz has received a two-year, $200,000 CU ASPIRE grant to study how the NPEPPS (搜索) enzyme drives cancer resistance to both platinum-based chemotherapy and immunotherapy.
NPEPPS (搜索) blocks drug entry via volume-regulated anion channels (VRAC) and reduces antigen presentation, enabling cancer cells to evade cisplatin and immune-system T cells, respectively.
The team aims to develop NPEPPS (搜索)-blocking drugs for combination with existing therapies and identify biomarkers to select patients most likely to benefit, initially focusing on bladder and ovarian cancers.
A research team at the University of Colorado Anschutz (搜索) Medical Campus has secured a two-year, $200,000 grant to investigate a key enzyme that enables cancer cells to resist two of oncology's cornerstone treatment modalities — platinum-based chemotherapy and immunotherapy. The project, led by James Costello, PhD, associate professor in the Department of Pharmacology and co-director of the Cancer Center's Biostatistics and Bioinformatics Shared Resource, is funded through CU ASPIRE, the CU Anschutz School of Medicine Programmatic Incubator for Research, with joint support from the cancer center and the school of medicine.
The initiative brings together a multi-institution team with expertise spanning structural biology, cancer biology, immunology, and drug design. Costello's own focus is computational systems biology, integrating computer science, mathematics, and data science to model complex biological systems. "They support big-project ideas that require a team, bringing knowledge in various fields together to do what any individual lab would not be able to do alone," Costello said of the ASPIRE program.
NPEPPS (搜索): A Dual Mechanism of Resistance
At the center of the investigation is NPEPPS (搜索), an enzyme that Costello and longtime collaborator Dan Theodorescu, MD, PhD, of the University of Arizona — a former CU Anschutz Cancer Center director — established as a driver of cisplatin resistance in research published in 2024.
NPEPPS (搜索) undermines cancer treatment through two distinct mechanisms. First, it acts as a cellular gatekeeper, blocking volume-regulated anion channels (VRAC) that platinum-based chemotherapy drugs such as cisplatin use to enter cancer cells and exert their cytotoxic effects. Second, NPEPPS is directly involved in processing small protein fragments that become antigens — the biological identifiers on the surface of cancer cells that allow the immune system's T cells to recognize and attack malignancies. By reducing antigen presentation, NPEPPS helps cancer cells evade immunotherapy.
Toward a Synergistic Treatment Strategy
The central hypothesis driving the project is that pharmacologically blocking NPEPPS (搜索) could render cancer cells more vulnerable to both chemotherapy and immunotherapy simultaneously. "In his 2024 study, we showed that, by targeting NPEPPS, we could make resistant cancer cells more sensitive to chemotherapy," Costello said.
The team now aims to deepen understanding of NPEPPS (搜索) function at the molecular level, characterize the consequences of its inhibition, and ultimately develop NPEPPS-blocking drugs to pair with existing chemotherapeutic and immunotherapeutic agents. A parallel goal is the identification of biomarkers to guide patient selection.
"We have two angles — the chemotherapy angle and the immunotherapy angle," Costello explained. "If we could manipulate NPEPPS (搜索) in both settings at the same time, we potentially could have a synergistic effect in getting more platinum into the cells, and also increasing the response to immunotherapy by making the cells more recognizable to the immune system."
Clinical Scope and Initial Focus
The potential reach of the research is substantial. Costello noted that approximately 20% of all cancer patients receive a platinum-based drug at some point during their treatment course. Platinum-based chemotherapy is particularly prevalent in bladder cancer (搜索) and ovarian cancer (搜索), and the project will initially concentrate on these tumor types.
Costello's team includes CU Anschutz Cancer Center member Benjamin Bitler, PhD, associate professor in the Department of Obstetrics and Gynecology and holder of the Kay and Thomas Dunton Endowed Chair in Ovarian Cancer (搜索) Research, and John Bankston, PhD, associate professor in the Department of Physiology and Biophysics, along with Theodorescu and additional faculty from the University of Arizona and Johns Hopkins University School of Medicine.
Building Toward a P01 Grant
The ASPIRE mechanism is designed to support research teams in generating preliminary data that can underpin competitive applications for major funding. Costello indicated that the team hopes the work funded by this grant will produce sufficient evidence to apply for a large NIH Program Project Grant (P01) in fall 2027, enabling a sustained, long-term research effort.
"When you bring a whole team like this together, we can think about approaches, develop experiments, and not miss things, so we can have a really competitive grant application," Costello said. "Especially in today's age of AI and machine learning, we're able to leverage those tools and resources to help with the fundamental questions that we're interested in. We're able to go where the science leads."