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Joseph M. Amann
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FP05 - Mesothelioma, Thymoma and Other Thoracic Malignancies (ID 135)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Mesothelioma, Thymoma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP05.02 - An Early Detection and Prognostic Blood Biomarkers Signature for Malignant Pleural Mesothelioma Based on Targeted Proteomics (ID 3473)
00:00 - 00:00 | Author(s): Joseph M. Amann
- Abstract
- Presentation
Introduction
We have investigated an academically developed targeted proteomics signature for the early detection and for prognostication of malignant pleural mesothelioma (MPM) from the blood.
Methods
We have studied a multicenter cohort of more than 400 MPM patients and asbestos exposed donors. Serum samples were processed on 96-well plates for enrichment of N-linked glycoproteins before analysis by liquid-chromatography mass spectrometry (LC-MS) based targeted proteomics for a multiplexed peptide biomarkers signature.
Results
We have verified the use of a multiplexed MPM proteomics signature identified in our previous work in cell lines and blood (the original signature was composed of seven peptides, the current signature is a reduced version of six peptides). The multiplexing approach offered by LC-MS proteomics in serum allowed to increase the discriminatory capacity of the signature over the single biomarkers. The proteomics signature presented an AUC of 0.738 and for early stage MPM (stage I/II) AUC was 0.765. This performance was comparable to what we observed using well established and commercially optimized MPM blood biomarkers, underlying the potential of our academic developed strategy once optimized for routine clinical use. The signature presented a negative-likelihood ratio of 0.11 for early stage MPM, highlighting the sensitivity of the approach and its potential utility for MPM early detection strategies, once integrated with complementary MPM biomarkers with high specificity. In addition, the proteomics signature was able to significantly separate high and low risk groups of MPM patients based on their survival (HR of 1.659), supporting in this way treatment decisions based on patients prognosis.
Conclusion
The targeted proteomics signature in blood represents an additional diagnostic approach for MPM early detection and treatment decisions.
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P47 - Small Cell Lung Cancer/NET - Biology / Translational (ID 234)
- Event: WCLC 2020
- Type: Posters
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P47.10 - Predicting ROR1/BCL2 Combination Targeted Therapy of Small Cell Carcinoma of the Lung (ID 1895)
00:00 - 00:00 | Author(s): Joseph M. Amann
- Abstract
Introduction
Small cell lung cancer (SCLC) remains a deadly form of cancer, with a 5-year survival rate of less than 10 percent, necessitating novel therapies. Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1) is an oncofetal protein that is emerging as a therapeutic target and is co-expressed with BCL2 in multiple tumor types due to microRNA coregulation. We hypothesize that ROR1-targeted therapy is effective in small cell lung cancer and synergizes with therapeutic BCL2 inhibition.
Methods
Tissue microarrays (TMAs) and formalin-fixed paraffin-embedded (FFPE) SCLC patient samples were utilized to determine the prevalence of ROR1 and BCL2 expression in SCLC. Eight SCLC-derived cell lines were used to determine the antitumor activity of a small molecule ROR1 inhibitor (KAN0441571C) alone and in combination with the BCL2 inhibitor venetoclax. The Chou-Talalay method was utilized to determine synergy with the drug combination.
Results
ROR1 and BCL2 protein expression was identified in 93% (52/56) and 86% (48/56) of SCLC patient samples, respectively. Similarly, ROR1 and BCL2 were shown by qRT-PCR to have elevated expression in 79% (22/28) and 100% (28/28) of SCLC patient samples, respectively. KAN0441571C demonstrated efficacy in 8 SCLC cell lines, with an IC50 of 500 nM or less. Synergy as defined by a combination index of <1 via the Chou-Talalay method between KAN0441571C and venetoclax was demonstrated in all 8 SCLC cell lines.
Conclusion
We have demonstrated that ROR1 inhibition is synergistic with BCL2 inhibition in SCLC models and shows promise as a novel therapeutic target in SCLC.
