Impact of RB activation on the pancreatic cancer epigenome and tumor microenvironment
Document text
Principal Investigator: Erik Knudsen Organization: ROSWELL PARK CANCER INSTITUTE CORP Fiscal Year: 2024 Award: $479,955 Funding agency: National Cancer Institute Pancreatic ductal adenocarcinoma (PDAC) represents a therapy recalcitrant disease with 5-year survival rate of approximately 10%. Multiple failed clinical trials reinforce the need for new approaches to treatment that employ rationally developed therapies targeting key genetic features of PDAC tumors as well as the tumor microenvironment. Fundamentally PDAC is a KRAS-driven tumor; however, approaches to target KRAS either genetically or pharmaceutically have led to the realization that tumors can evolve mechanisms to continue cell division in the presence of such interventions. Using a combination of unbiased analyses and patient derived models we find that most tumors have evolved mechanisms to deregulate the retinoblastoma tumors suppressor (RB) pathway that limits the effectiveness of targeting RAS or effector pathways (e.g. MEK inhibition). Consequently, the activation of RB is sufficient to limit the proliferation and tumorigenic growth of PDAC models. In addition to effects on the proliferation, we have found that RB activation is sufficient to coordinate changes in gene expression that impact on genes related to classical vs. basal subtypes of PDAC and immunological gene expression programs (e.g. antigen presentation and interferon response). Unlike cell cycle responses, these changes in gene expression are more heterogeneous and the underlying mechanisms and key regulatory elements remain poorly understood. In Aim 1 we will delineate the RB regulation and mechanisms of gene expression regulation in PDAC models. While RB status clearly has effects on tumor cell division, an important element of RB-pathway activation are effects related to the tumor microenvironment. Preliminary and published data indicate that RB activation has broad effects on the tumor stroma and immunological milieu. Much of these studies have employed systemic strategies that impact on both the tumor and the host. In preliminary data, we have found that activation of RB selectively within the tumor is sufficient to change the fibroblastic and immunological cell subtypes with the tumor, albeit not at the same level of systemic treatments. Here we will interrogate the intersection between the tumor and the microenvironment and how these impact tumor-static response and can be exploited by immunotherapy approaches. Together, Aim 2 will define the impact of RB- activation on the tumor microenvironment using a combination of immune competent models and clinical specimens. Terms: <Antigen Presentation><Automobile Driving><Biochemical><Body Tissues><C-K-RAS><CDK4><CDK4 gene><Cancer Cause><Cancer Etiology><Cancers><Cell Body><Cell Cycle><Cell Division Cycle><Cell Division Kinase 4><Cell division><Cells><Cessation of life><Clinical><Clinical Trials><Collection><Combined Modality Therapy><Complement><Complement Proteins><Complex><Correlative Study><Coupled><Cyclin-Dependent Kinase 4><Cytostatic Agents><Cytostatic Drugs><Cytostatics><Data><Death><Disease><Disorder><Effectiveness><Elements><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Gene Action Regulation><Gene Expression><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Generalized Growth><Genes><Genetic><Growth><IFN><Immune mediated therapy><Immune response><Immune system><Immunochemical Immunologic><Immunocompetent><Immunologic><Immunological><Immunological response><Immunologically><Immunologically Directed Therapy><Immunologics><Immunotherapy><Interferons><Intervention><Intervention Strategies><K-RAS2A><K-RAS2B><K-Ras><K-Ras 2A><K-Ras-2 Oncogene><KRAS><KRAS2><KRAS2 gene><Ki-RAS><MEK inhibition><MEKs><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Mediating><Modeling><Multimodal Therapy><Multimodal Treatment><Oncogene K-Ras><Oncogenesis><PDA model><PDAC Model><PSK-J3><Pancreas Cancer><Pancreas Ductal Adenocarcinoma><Pancreatic Cancer><Pancreatic Ductal Adenocarcinoma><Pathway interactions><Patients><Population><Pre-Clinical Model><Preclinical Models><Prognosis><Proliferating><Publishing><RASK2><Regulation><Regulatory Element><Research Specimen><Resistance><Specimen><Survival Rate><Therapeutic><Tissue Growth><Tissues><Tumor Biology><Tumor Cell><United States><Work><cancer microenvironment><combination therapy><combined modality treatment><combined treatment><complementation><develop therapy><driving><engineered immune system><epigenetically><epigenome><host response><immune competent><immune engineering><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunoengineering><immunoresponse><improved outcome><inhibitor><intervention development><interventional strategy><malignancy><multi-modal therapy><multi-modal treatment><neoplasm/cancer><neoplastic cell><new approaches><novel approaches><novel strategies><novel strategy><ontogeny><pancreatic ductal adenocarcinoma model><pancreatic malignancy><pathway><programs><resistance to therapy><resistant><resistant to therapy><response><response to therapy><response to treatment><retinoblastoma tumor suppressor><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic resistance><therapeutic response><therapy development><therapy resistant><therapy response><treatment development><treatment resistance><treatment response><treatment responsiveness><tumor><tumor microenvironment><tumorigenesis><tumorigenic><v-Ki-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog>