Biology subjects

Clohessy, J.

Publications and source records attributed to Clohessy, J..

3 recordsLinked to original sources

bioRxiv2026

MAPK signaling links BRD2 chromatin occupancy to PI3K/AKT inhibitor sensitivity

Bromodomain and extra-terminal (BET) proteins, BRD2, BRD3, BRD4, and BRDT, couple histone acetylation to transcription by recruiting elongation and transcription factor complexes to chromatin. Although BET proteins are promising therapeutic targets, the functions of individual family members remain incompletely understood. We identify BRD2 as a co-targetable vulnerability with PI3K/AKT inhibition in breast cancer. Pan-BET inhibition and BRD2 knockout synergized with PI3K pathway inhibitors in breast cancer cell lines, patient-derived organoids, and in vivo models. BRD2 knockout impaired proliferation of triple-negative breast cancer cells and upregulated signaling and stress-response pathways, including the DNA damage response. Mechanistically, BRD2 is phosphorylated at Ser37 by the mitogen- and stress-activated kinases MSK and RSK, and Ser37 phosphorylation is required for chromatin binding and reader function. Finally, mechanistic digital twin modeling identified BETi-PI3Ki regimens that maintained efficacy while reducing drug exposure. Together, these findings identify BRD2 as a phosphorylation-dependent, co-targetable vulnerability in PI3K-inhibited breast cancer.

cancer biology↗

bioRxiv2020

Cabozantinib unlocks efficient in vivo targeted delivery of neutrophil-loaded nanoparticles into murine prostate tumors

A major barrier to the successful application of nanotechnology for cancer treatment is the efficient delivery of therapeutic payloads to metastatic tumor deposits. We have previously discovered that cabozantinib, a tyrosine kinase inhibitor, triggers neutrophil-mediated anti-cancer innate immunity, resulting in tumor regression in an aggressive PTEN/p53-deficient genetically engineered murine model of advanced prostate cancer. Here, we specifically investigated the potential of cabozantinib-induced neutrophil activation and recruitment to enhance delivery of bovine serum albumin (BSA)-coated polymeric nanoparticles (NPs) into murine PTEN/p53-deficient prostate tumors. Based on the observation that BSA-coating of NPs enhanced association and internalization by activated neutrophils in vitro, relative to uncoated NPs, we systemically injected BSA-coated, dye-loaded NPs into prostate-specific PTEN/p53-deficient mice that were pre-treated with cabozantinib. Flow cytometric analysis revealed a 4-fold increase of neutrophil-associated NPs within the tumor microenvironment (TME) of mice pre-treated with cabozantinib relative to untreated controls. At steady-state, following 3 days of cabozantinib/NP administration, 1% of systemically injected dye-loaded NPs selectively accumulated within the TME of mice that were pre-treated with cabozantinib, compared to 0.11% uptake for mice that did not receive cabozantinib pre-treatment. Strikingly, neutrophil depletion with Ly6G antibody abolished NP accumulation in tumors to baseline levels, demonstrating targeted neutrophil-mediated NP delivery to the prostate TME. In summary, we have discovered a novel nano-immunotherapeutic strategy for enhanced intratumoral delivery of injected NPs, which results in significantly higher NP accumulation than reported strategies in the nanotechnology literature to-date.

cancer biology↗

bioRxiv2019

Pancreatic tumor organoids for modeling in vivo drug response and discovering clinically-actionable biomarkers

Patient-derived models are transforming translational cancer research. It is not clear if the emergence of patient-derived organoid (PDO) models can extend the utility of the widely used patient-derived xenograft (PDX). In addition, the utility of PDO models for serum biomarker discovery is not known. Here, we demonstrate that PDO models recapitulate the genomics, cell biology, glycomics and drug responses observed in PDX models. Furthermore, we demonstrate the applicability of PDO models for identification of N-glycans that are enriched in the glycome of pancreatic ductal adenocarcinoma (PDAC). Surprisingly, among all the glycans observed in PDX and PDOs, a core set of 57 N-glycans represent 50-94% of the relative abundance of all N-glycans detected, suggesting that only a subset of glycans dominate the cell surface landscape in PDAC. In addition, we outline a tumor organoid-based pipeline to identify surface proteins in extracellular vesicles (EV) from media supernatant of PDO cultures. When combined with the affinity-based validation platform, the EV surface proteins discovered in PDOs are effective in differentiating patients with PDAC from those with benign pancreatitis in the clinic, identifying PDO as powerful discovery platform for serum biomarkers. Thus, PDOs extend the utility of the archival collections of PDX models for translational research and function as a powerful platform for identification of clinically-actionable biomarkers in patients blood. Significance statementTumor organoids extend the utility of PDX models as platforms for investigating drug response, glycosylation changes and function as new platforms for discovering blood-based biomarkers

cancer biology↗