Project description:We aimed to determine carbazole blue's (CB) targets by gene expression microarray. Our results show that CB inhibits the expression of pro-tumorigenic genes that promote unchecked replication and aberrant DNA repair that cancer cells get addicted to survive.
Project description:The major limitations of DNA-targeting chemotherapy drugs include life-threatening toxicity, acquired resistance and occurrence of secondary cancers. Here, we report a small molecule, Carbazole Blue (CB), that binds to DNA and inhibits cancer growth and metastasis by targeting DNA-related processes that tumor cells use but not the normal cells. We show that CB inhibits the expression of pro-tumorigenic genes that promote unchecked replication and aberrant DNA repair that cancer cells get addicted to survive. In contrast to chemotherapy drugs, systemic delivery of CB suppressed breast cancer growth and metastasis with no toxicity in pre-clinical mouse models. Using PDX and ex vivo explants from estrogen receptor (ER) positive, ER mutant and TNBC patients, we further demonstrated that CB effectively blocks therapy-sensitive and therapy-resistant breast cancer growth without affecting normal breast tissue. Our data provide a strong rationale to develop CB as a viable therapeutic for treating breast cancers.
Project description:PARP1 is an abundant nuclear protein that is involved in a number of biological processes linked to cellular stress responses. PARP1 inhibitors (PARPi) are known to kill tumor cells via two mechanisms (PARP1 catalytic inhibition and PARP1 trapping). In this work we discovered a PROTAC degrader of PARP1 -180055, which uncoupled PARP1 trapping and inhibition. Moreover, 180055 has great potential for treating cancers.
Project description:Inflammation has long been recognized to contribute to cancer development, particularly across the gastrointestinal tract. Patients with inflammatory bowel disease have an increased risk for bowel cancers, and it has been posited that a field of genetic changes may underlie this risk. Wnt pathway alterations are infrequent, and our data suggest transcriptional rewiring away from Wnt. These findings suggest neoplastic bowel lesions developing in a background of inflammation experience lineage plasticity away from Wnt activation early during tumorigenesis and largely occur as genetically independent events.
Project description:Inflammation has long been recognized to contribute to cancer development, particularly across the gastrointestinal tract. Patients with inflammatory bowel disease have an increased risk for bowel cancers, and it has been posited that a field of genetic changes may underlie this risk. Wnt pathway alterations are infrequent, and our data suggest transcriptional rewiring away from Wnt. These findings suggest neoplastic bowel lesions developing in a background of inflammation experience lineage plasticity away from Wnt activation early during tumorigenesis and largely occur as genetically independent events.