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Conditional Dependency of LP-184 on Prostaglandin Reductase 1 is Synthetic Lethal in Pancreatic Cancers with DNA
Diana Restifo1, Joseph R McDermott2, Dusica Cvetkovic3
1The Marvin & Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Abstract:
The greater efficacy of DNA-damaging drugs for pancreatic adenocarcinoma (PDAC) relies on targeting cancer-specific vulnerabilities while sparing normal organs and tissues due to their inherent toxicities. We tested LP-184, a novel acylfulvene analog, for its activity in preclinical models of PDAC carrying mutations in the DNA damage repair (DDR) pathways. Cytotoxicity of LP-184 is solely dependent on prostaglandin reductase 1 (PTGR1), so that PTGR1 expression robustly correlates with LP-184 cytotoxicity in vitro and in vivo. Low-passage patient-derived PDAC xenografts with DDR deficiencies treated ex vivo are more sensitive to LP-184 compared with DDR-proficient tumors. Additional in vivo testing of PDAC xenografts for their sensitivity to LP-184 demonstrates marked tumor growth inhibition in models harboring pathogenic mutations in ATR, BRCA1, and BRCA2. Depletion of PTGR1, however, completely abrogates the antitumor effect of LP-184. Testing combinatorial strategies for LP-184 aimed at deregulation of nucleotide excision repair proteins ERCC3 and ERCC4 established synergy. Our results provide valuable biomarkers for clinical testing of LP-184 in a large subset of genetically defined characterized refractory carcinomas. High PTGR1 expression and deleterious DDR mutations are present in approximately one third of PDAC making these patients ideal candidates for clinical trials of LP-184.
Insights
A novel drug, LP-184, shows promise against pancreatic cancer (PDAC) by targeting DNA damage repair (DDR) defects. Its efficacy is linked to PTGR1 expression, suggesting potential for targeted patient selection in clinical trials.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) often exhibits resistance to conventional therapies.
- Targeting cancer-specific vulnerabilities is crucial for effective treatment with DNA-damaging agents.
- Understanding DNA damage repair (DDR) pathway mutations can inform therapeutic strategies.
Purpose of the Study:
- To evaluate the efficacy of LP-184, a novel acylfulvene analog, in preclinical models of PDAC.
- To identify biomarkers predictive of LP-184 response, specifically PTGR1 expression and DDR mutations.
- To explore combinatorial strategies with LP-184 for enhanced therapeutic effects.
Main Methods:
- In vitro and in vivo testing of LP-184 in patient-derived PDAC xenografts.
- Assessment of LP-184 cytotoxicity correlation with PTGR1 expression.
- Evaluation of LP-184 sensitivity in PDAC models with specific DDR mutations (ATR, BRCA1, BRCA2).
- Investigating the role of PTGR1 depletion on LP-184 efficacy.
- Testing combinatorial therapy involving LP-184 and nucleotide excision repair protein modulators (ERCC3, ERCC4).
Main Results:
- LP-184 demonstrated significant cytotoxicity dependent on PTGR1 expression in PDAC models.
- PDAC xenografts with DDR deficiencies were more sensitive to LP-184.
- Tumor growth inhibition was observed in models with ATR, BRCA1, and BRCA2 mutations.
- PTGR1 depletion abolished the antitumor effect of LP-184.
- Synergistic effects were observed when combining LP-184 with agents targeting ERCC3 and ERCC4.
Conclusions:
- LP-184 exhibits potent antitumor activity in preclinical PDAC models, particularly those with DDR deficiencies.
- PTGR1 expression serves as a predictive biomarker for LP-184 efficacy.
- Combinations targeting nucleotide excision repair may enhance LP-184's therapeutic potential.
- Approximately one-third of PDAC patients with high PTGR1 and DDR mutations are suitable candidates for LP-184 clinical trials.
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