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MR Molecular Imaging of Prostate Cancer with a Small Molecular CLT1 Peptide Targeted Contrast Agent
Published on: September 3, 2013
Elucidating molecularly stratified single agent, and combination, therapeutic strategies targeting MCL1 for lethal
Juan M Jiménez-Vacas1, Daniel Westaby1,2, Ines Figueiredo1
1The Institute of Cancer Research, London, UK.
Abstract:
Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease requiring additional therapeutic strategies. MCL1, an anti-apoptotic BCL2 family member, promotes cancer-cell survival, but its role in mCRPC remains poorly understood. Here, we characterise MCL1 in multiple mCRPC biopsy cohorts and patient-derived models, assessing responses to MCL1 inhibition. MCL1 copy number gain (14%-34%) correlates with increased MCL1 expression and worse outcomes. MCL1 inhibition exhibits anti-tumour effects in MCL1-gained mCRPC models. Co-inhibition of MCL1 and AKT induces cancer-specific cell death in PTEN-loss/PI3K-activated models in vitro and in vivo, modulating BAD-BCLXL and BIM-MCL1 interactions, with durable anti-tumour activity in models with AKT inhibitor acquired resistance. Finally, CDK9-mediated MCL1 downregulation combined with AKT inhibition recapitulates these findings, providing further opportunities for clinical translation. These data support early phase clinical trials targeting MCL1, both as monotherapy for MCL1-gained mCRPC, and in combination with AKT inhibition for PTEN-loss/PI3K-activated mCRPC.
Insights
Targeting MCL1, an anti-apoptotic protein, shows promise for metastatic castration-resistant prostate cancer (mCRPC). MCL1 inhibition or combination therapy with AKT inhibitors offers new therapeutic strategies for mCRPC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) necessitates novel therapeutic approaches.
- MCL1, an anti-apoptotic protein, is implicated in cancer cell survival but its role in mCRPC is not well-defined.
Purpose of the Study:
- To characterize MCL1 in mCRPC and evaluate the efficacy of MCL1 inhibition.
- To explore combination therapies involving MCL1 and AKT inhibition for specific mCRPC subtypes.
Main Methods:
- Analysis of MCL1 in mCRPC biopsy cohorts and patient-derived models.
- Assessment of anti-tumour effects of MCL1 inhibition and combined MCL1/AKT inhibition.
- Investigation of molecular interactions (BAD-BCLXL, BIM-MCL1) and resistance mechanisms.
Main Results:
- MCL1 copy number gain (14%-34%) is associated with increased MCL1 expression and poorer outcomes in mCRPC.
- MCL1 inhibition demonstrated anti-tumour activity in MCL1-gained mCRPC models.
- Co-inhibition of MCL1 and AKT induced cancer-specific cell death in PTEN-loss/PI3K-activated models, overcoming acquired resistance to AKT inhibitors.
Conclusions:
- MCL1 is a viable therapeutic target in mCRPC, particularly in cases with MCL1 gain.
- Combination therapy with MCL1 and AKT inhibitors shows potential for PTEN-loss/PI3K-activated mCRPC.
- Findings support the clinical translation of MCL1-targeted therapies in mCRPC.
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