Biology subjects

Carstens, J. L.

Publications and source records attributed to Carstens, J. L..

3 recordsLinked to original sources

bioRxiv2026

Matched pancreatic cancer liver metastatic model system reveals cancer cell-dependent organotropism and site-specific tumor microenvironment reflective of human disease

Background: Pancreatic ductal adenocarcinoma (PDAC) mortality is driven largely by liver metastatic disease; however, the malignant cell states and tumor microenvironmental features of PDAC liver metastases remain obscure. Methods: We developed a transplant model system of matched pancreatic and liver tumors to study PDAC metastatic progression. Using this model, we identified murine PDAC cell lines with distinct liver metastatic capacities and performed multiomic profiling of matched primary pancreatic and metastatic liver tumors. Transcriptional programs associated with high and low liver tropism were defined and evaluated across tumor models and independent human PDAC datasets. Spatial and tumor-immune interaction analyses were used to characterize microenvironmental niches, immune composition, and cellular relationships within primary and metastatic tumors. Results: A high-liver-tropic transcriptional program was enriched in high liver-tropic cell lines and malignant cells within liver metastases, conserved across human PDAC datasets, and associated with inferior patient survival. High- and low-liver-tropic tumor states occupied distinct liver microenvironmental niches and exhibited different tumor-immune communication networks, accompanied by local and systemic changes in immune composition. Liver metastases also displayed features of enhanced immunosuppression, including increased proximity of CD4+ and CD8+ T cells to tumor cells and greater spatial association between regulatory T cells and exhausted CD8+ T cells. Conclusions: These findings identify conserved PDAC cell states associated with differential liver metastatic capacity and demonstrate that liver metastasis is accompanied by spatial and immunologic remodeling of the tumor microenvironment. Together, the study provides a framework for understanding how tumor-intrinsic metastatic programs interact with site-specific immune ecosystems in PDAC.

cancer biology↗

bioRxiv2024

ADT-1004: A First-in-Class, Orally Bioavailable Selective pan-RAS Inhibitor for Pancreatic Ductal Adenocarcinoma

Here, we evaluated in vivo antitumor activity, target engagement, selectivity, and tumor specificity of ADT-1004, an orally bioavailable prodrug of ADT-007 having highly potent and selective pan-RAS inhibitory activity. ADT-1004 strongly blocked tumor growth and RAS activation in mouse PDAC models without discernable toxicity. As evidence of target engagement and tumor specificity, ADT-1004 inhibited activated RAS and ERK phosphorylation in PDAC tumors at dosages approximately 10-fold below the maximum tolerated dose and without discernable toxicity. ADT-1004 inhibited ERK phosphorylation in PDAC tumors. In addition, ADT-1004 blocked tumor growth and ERK phosphorylation in PDX PDAC models with KRASG12D, KRASG12V, KRASG12C, or KRASG13Q mutations. ADT-1004 treatment increased CD4+ and CD8+ T cells in the TME consistent with exhaustion and increased MHCII+ M1 macrophage and dendritic cells. ADT-1004 demonstrated superior efficacy over sotorasib and adagrasib in tumor models involving human PDAC cells resistant to these KRASG12C inhibitors. As evidence of selectivity for tumors from PDAC cells with mutant KRAS, ADT-1004 did not impact the growth of tumors from RASWT PDAC cells. Displaying broad antitumor activity in multiple mouse models of PDAC, along with target engagement and selectivity at dosages that were well tolerated, ADT-1004 warrants further development. SignificanceADT-1004 displayed robust antitumor activity in aggressive and clinically relevant PDAC models with unique tumor specificity to block RAS activation and MAPK signaling in RAS mutant cells. As a pan-RAS inhibitor, ADT-1004 has broad activity and potential efficacy advantages over allele-specific KRAS inhibitors by averting resistance. These findings support clinical trials of ADT-1004 for KRAS mutant PDAC.

cancer biology↗

bioRxiv2023

Novel Pan-RAS Inhibitor ADT-007 Induces Tumor Regression in Mouse Models of GI Cancer

Here, we describe a novel pan-RAS inhibitor, ADT-007, that potently inhibited the growth of RAS mutant cancer cells irrespective of the RAS mutation or isozyme. RASWT cancer cells with GTP-activated RAS from upstream mutations were equally sensitive. Conversely, RASWT cancer cells harboring downstream BRAF mutations and normal cells were essentially insensitive to ADT-007. Sensitivity of cancer cells to ADT-007 required activated RAS and dependence on RAS for proliferation, while insensitivity was attributed to metabolic deactivation by UDP-glucuronosyltransferases expressed in RASWT and normal cells but repressed in RAS mutant cancer cells. ADT-007 binds nucleotide-free RAS to block GTP activation of effector interactions and MAPK/AKT signaling, resulting in mitotic arrest and apoptosis. ADT-007 displayed unique advantages over mutant-specific KRAS and pan-KRAS inhibitors, as well as other pan-RAS inhibitors that could impact in vivo antitumor efficacy by escaping compensatory mechanisms leading to resistance. Local administration of ADT-007 showed robust antitumor activity in syngeneic immune-competent and xenogeneic immune-deficient mouse models of colorectal and pancreatic cancer. The antitumor activity of ADT-007 was associated with the suppression of MAPK signaling and activation of innate and adaptive immunity in the tumor immune microenvironment. Oral administration of ADT-007 prodrug also inhibited tumor growth, supporting further development of this novel class of pan-RAS inhibitors for RAS-driven cancers. SIGNIFICANCEADT-007 has unique pharmacological properties with distinct advantages over other RAS inhibitors by circumventing resistance and activating antitumor immunity. ADT-007 prodrugs and analogs with oral bioavailability warrant further development for RAS-driven cancers.

cancer biology↗