16 research outputs found
Abstract 1832: Ligand-dependent Wnt signaling directs metabolic adaptations to promote pancreatic tumorigenesis
No full textAbstract 1832: Ligand-dependent Wnt signaling directs metabolic adaptations to promote pancreatic tumorigenesis
No full text
Lysosome inhibition sensitizes pancreatic cancer to replication stress by aspartate depletion
No full textEvaluation of Potent Isoquinoline-Based Thiosemicarbazone Antiproliferatives Against Solid Tumor Models
No full textThe lead compound, an ⍺-N-heterocyclic
carboxaldehyde thiosemicarbazone HCT-13,
was highly potent against a panel of pancreatic, small cell lung carcinoma, and
prostate cancer models, with IC90 values in the low-to-mid nanomolar
range. We show that the cytotoxicity of HCT-13 is copper-dependent, that it acts as a copper ionophore,
induces production of reactive oxygen species (ROS), and promotes mitochondrial
dysfunction and S-phase arrest. Lastly, DNA damage response/replication stress
response (DDR/RSR) pathways, specifically Ataxia-Telangiectasia Mutated (ATM)
and Rad3-related protein kinase (ATR), were identified as actionable adaptive
resistance mechanisms following HCT-13 treatment. Taken together, HCT-13
is potent against solid tumor models and warrants in vivo evaluation
against aggressive tumor models, either as a single agent or as part of a
combination therapy
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Lysosome inhibition sensitizes pancreatic cancer to replication stress by aspartate depletion
No full textFunctional lysosomes mediate autophagy and macropinocytosis for nutrient acquisition. Pancreatic ductal adenocarcinoma (PDAC) tumors exhibit high basal lysosomal activity, and inhibition of lysosome function suppresses PDAC cell proliferation and tumor growth. However, the codependencies induced by lysosomal inhibition in PDAC have not been systematically explored. We performed a comprehensive pharmacological inhibition screen of the protein kinome and found that replication stress response (RSR) inhibitors were synthetically lethal with chloroquine (CQ) in PDAC cells. CQ treatment reduced de novo nucleotide biosynthesis and induced replication stress. We found that CQ treatment caused mitochondrial dysfunction and depletion of aspartate, an essential precursor for de novo nucleotide synthesis, as an underlying mechanism. Supplementation with aspartate partially rescued the phenotypes induced by CQ. The synergy of CQ and the RSR inhibitor VE-822 was comprehensively validated in both 2D and 3D cultures of PDAC cell lines, a heterotypic spheroid culture with cancer-associated fibroblasts, and in vivo xenograft and syngeneic PDAC mouse models. These results indicate a codependency on functional lysosomes and RSR in PDAC and support the translational potential of the combination of CQ and RSR inhibitors
Evaluation of Potent Isoquinoline-Based Thiosemicarbazone Antiproliferatives Against Solid Tumor Models
No full textAbstract 4264: Lysosome inhibition sensitizes pancreatic cancer to replication stress by aspartate depletion
No full textAbstract 4264: Lysosome inhibition sensitizes pancreatic cancer to replication stress by aspartate depletion
No full text[18F]CFA as a clinically translatable probe for PET imaging of deoxycytidine kinase activity
No full textDeoxycytidine kinase (dCK), a rate-limiting enzyme in the cytosolic deoxyribonucleoside (dN) salvage pathway, is an important therapeutic and positron emission tomography (PET) imaging target in cancer. PET probes for dCK have been developed and are effective in mice but have suboptimal specificity and sensitivity in humans. To identify a more suitable probe for clinical dCK PET imaging, we compared the selectivity of two candidate compounds-[(18)F]Clofarabine; 2-chloro-2'-deoxy-2'-[(18)F]fluoro-9-β-d-arabinofuranosyl-adenine ([(18)F]CFA) and 2'-deoxy-2'-[(18)F]fluoro-9-β-d-arabinofuranosyl-guanine ([(18)F]F-AraG)-for dCK and deoxyguanosine kinase (dGK), a dCK-related mitochondrial enzyme. We demonstrate that, in the tracer concentration range used for PET imaging, [(18)F]CFA is primarily a substrate for dCK, with minimal cross-reactivity. In contrast, [(18)F]F-AraG is a better substrate for dGK than for dCK. [(18)F]CFA accumulation in leukemia cells correlated with dCK expression and was abrogated by treatment with a dCK inhibitor. Although [(18)F]CFA uptake was reduced by deoxycytidine (dC) competition, this inhibition required high dC concentrations present in murine, but not human, plasma. Expression of cytidine deaminase, a dC-catabolizing enzyme, in leukemia cells both in cell culture and in mice reduced the competition between dC and [(18)F]CFA, leading to increased dCK-dependent probe accumulation. First-in-human, to our knowledge, [(18)F]CFA PET/CT studies showed probe accumulation in tissues with high dCK expression: e.g., hematopoietic bone marrow and secondary lymphoid organs. The selectivity of [(18)F]CFA for dCK and its favorable biodistribution in humans justify further studies to validate [(18)F]CFA PET as a new cancer biomarker for treatment stratification and monitoring
