NIH grant: A Novel Cell Stress Response Mechanism in Pancreatic Cancer (1R01CA308198-01A1)

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NIH grant 1R01CA308198-01A1: A Novel Cell Stress Response Mechanism in Pancreatic Cancer
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Wantong  Yao. Award: $633089.
Start: 2026-08-01T00:00:00.
Pancreatic ductal adenocarcinoma (PDAC) is notoriously treatment resistant. Immunotherapy has revolutionized
the treatment of many cancer types, yet its success in PDAC remains profoundly limited. PDAC exists within an
unusually hostile tumor microenvironment featured by severe nutrient deprivation, hypoxia, oxidative stress, and
intense metabolic demands, all of which foster cancer progression and immune evasion. Emerging evidence
indicates that intrinsic characteristics of cancer cells actively shape this harsh tumor microenvironment to
suppress immune surveillance and promote tumor persistence. These stress-driven adaptations not only sustain
tumor aggressiveness but also expose actionable vulnerabilities for therapeutic intervention. In this study, we
leverage an innovative large-scale discovery platform to systematically identify immunotherapeutic targets by
interrogating the intricate interplay between tumor cells and the immune system within the unique PDAC
microenvironment. Through this approach, we have identified critical targets that enable PDAC cells to adapt to
stress, resist cell death, and escape immune surveillance. This application focuses on a previously unrecognized
stress-response regulator that is integral to both cancer cell survival and immune resistance and therefore
represents a promising candidate for new therapy development. Although little is known about this target in
human cancers, our research aims to uncover its role and mechanisms in modulating stress responses and
immune evasion, thereby providing foundational insights into its therapeutic potential. The major objectives of
this study are: i) to elucidate the novel molecular pathways that enable PDAC cells to adapt to adverse conditions
and evade immune surveillance; ii) to determine how these pathways contribute to tumor survival and immune
suppression; and iii) to evaluate the potential of targeting these pathways as a therapeutic strategy. By
addressing these knowledge gaps, our work will substantially advance our understanding of how pancreatic
cancer cells survive in a hostile microenvironment and escape immune detection, providing critical insights into
the mechanisms underlying PDAC resistance to conventional therapies and immunotherapy. The proposed
research represents an essential step toward our long-term goal of developing transformative therapeutic
strategies against this newly defined stress-response regulator and may ultimately inform new treatment
approaches for other cancers that are refractory to immune-based therapies, with the overarching aim of
improving outcomes for patients with this devastating disease. Animal models are essential for this project
because the dynamic interactions among pancreatic cancer cells, stromal components, and the immune system
occur within a complex in vivo environment that cannot be faithfully reproduced in vitro. Syngeneic allograft
models and a novel genetically engineered mouse model of PDAC will allow us to investigate tumor development,
immune evasion, and therapeutic responses in immunocompetent hosts, providing critical biological insights that
are not achievable using cell culture or other non-animal approaches.

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