Abstract
Background:
Gene expression profiling of HGSOC revealed four molecularly distinct subtypes (C1, C2, C4 and C5) 1. MYCN over-expression, which can drive a mesenchymal or epithelial-mesenchymal transitional prone phenotype, is a key feature in the C5 subtype of HGSOC 2. Targeting MYCN and MYC over-expression with the BRD4 inhibitor (I-BET-762) has efficacy in ovarian cancer pre-clinical models 3. We aim to explore the mechanism of activity and resistance of I-BET-762 in C5 HGSOC, with a focus on the pro-survival pathway, using BH3-mimetic therapy (ABT-199).
Methods:
Six well-characterised C5 HGSOC patient derived xenograft (PDX) models were tested for in vivo response to single agent I-BET-762 (25mg/kg on alternate days for 21 days) or combination I-BET-762/ABT-199 (100mg/kg Mon to Fri for 21 days) regimens. RNA and DNA samples were prepared.
Results:
Surprisingly, only one of six C5 PDX responded to single agent I-BET-762. Two of five non-I-BET-762 responders showed evidence of tumour regression with I-BET-762 and ABT-199 combination, albeit short-lived responses. Short term harvest experiments were performed with the one I-BET-762 responder and one PDX that responded to combination I-BET-762 and ABT-199 treatment. RNASeq, ATACSeq and ChIPSeq were performed and analysis is currently underway to elucidate the underlying mechanisms of activity.
Conclusions:
BRD4 inhibition with I-BET-762 is only an effective treatment in a specific subset of HGSOC. The escape from the apoptotic pathway may be one of the mechanisms of drug resistance to I-BET-762. Understanding this mechanism may be crucial in establishing a more effective combination regimen.
Gene expression profiling of HGSOC revealed four molecularly distinct subtypes (C1, C2, C4 and C5) 1. MYCN over-expression, which can drive a mesenchymal or epithelial-mesenchymal transitional prone phenotype, is a key feature in the C5 subtype of HGSOC 2. Targeting MYCN and MYC over-expression with the BRD4 inhibitor (I-BET-762) has efficacy in ovarian cancer pre-clinical models 3. We aim to explore the mechanism of activity and resistance of I-BET-762 in C5 HGSOC, with a focus on the pro-survival pathway, using BH3-mimetic therapy (ABT-199).
Methods:
Six well-characterised C5 HGSOC patient derived xenograft (PDX) models were tested for in vivo response to single agent I-BET-762 (25mg/kg on alternate days for 21 days) or combination I-BET-762/ABT-199 (100mg/kg Mon to Fri for 21 days) regimens. RNA and DNA samples were prepared.
Results:
Surprisingly, only one of six C5 PDX responded to single agent I-BET-762. Two of five non-I-BET-762 responders showed evidence of tumour regression with I-BET-762 and ABT-199 combination, albeit short-lived responses. Short term harvest experiments were performed with the one I-BET-762 responder and one PDX that responded to combination I-BET-762 and ABT-199 treatment. RNASeq, ATACSeq and ChIPSeq were performed and analysis is currently underway to elucidate the underlying mechanisms of activity.
Conclusions:
BRD4 inhibition with I-BET-762 is only an effective treatment in a specific subset of HGSOC. The escape from the apoptotic pathway may be one of the mechanisms of drug resistance to I-BET-762. Understanding this mechanism may be crucial in establishing a more effective combination regimen.
| Original language | English |
|---|---|
| Publication status | Published - Nov 2018 |
| Event | Biennial Meeting of the International Gynecologic Cancer Society - Kyoto, Japan Duration: 14 Sept 2018 → 16 Sept 2018 https://igcs2018.com |
Conference
| Conference | Biennial Meeting of the International Gynecologic Cancer Society |
|---|---|
| Abbreviated title | IGCS |
| Country/Territory | Japan |
| City | Kyoto |
| Period | 14/09/18 → 16/09/18 |
| Internet address |
Keywords
- HGSOC
- IBET
- BRD4
- ATAC-sequencing
