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3 results on '"Gilad Vainer"'

1. Treatment of ErbB2 breast cancer by mitochondrial targeting

Author

Sophia Eldad, Rachel Hertz, Gilad Vainer, Ann Saada, and Jacob Bar-Tana

Subjects
Breast cancer, ErbB2, mTORC1, Lipid rafts, Mitochondria, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background ErbB2 breast cancer still remains an unmet need due to primary and/or acquired resistance to current treatment strategies. MEDICA compounds consist of synthetic long-chain α,ω-dicarboxylic acids previously reported to suppress breast cancer in PyMT transgenic mice. Methods MEDICA efficacy and mode of action in the ErbB2 context was studied in ErbB2 transgenic mice and human breast cancer cells. Results MEDICA treatment is shown here to suppress ErbB2 breast tumors and lung metastasis in ErbB2/neu MMTV transgenic mice, to suppress ErbB2/neu xenografts in nod/scid mice, and to suppress survival of AU565 and BT474 human ErbB2 breast cancer cells. Suppression of ErbB2 breast tumors by MEDICA is due to lipid raft disruption with loss of ErbB family members, including EGFR, ErbB2, and ErbB3. In addition, MEDICA inhibits mTORC1 activity, independently of abrogating the ErbB receptors and their signaling cascades. The double hit of MEDICA in abrogating ErbB and mTORC1 is partly accounted for by targeting mitochondria complex I. Conclusions Mitochondrial targeting by MEDICA suppresses ErbB2 breast tumors and metastasis due to lipid raft disruption and inhibition of mTORC1 activity. Inhibition of mTORC1 activity by MEDICA avoids the resistance acquired by canonical mTORC1 inhibitors like rapalogs or mTOR kinase inhibitors.

Published
2020
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3. 7 Analytical comparison of a PD-L1 22C3 antibody laboratory-developed test protocol on the Benchmark XT and PD-L1 IHC 22C3 pharmDx: pan-tumor and triple-negative breast cancer samples

Author

Gilad Vainer, Ghadeer Zatara, Lingkang Huang, Shanthy Nuti, and Kenneth Emancipator

Subjects
Pharmacology, Cervical cancer, Oncology, Cancer Research, medicine.medical_specialty, Intraclass correlation, business.industry, Concordance, Immunology, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Pembrolizumab, medicine.disease, Head and neck squamous-cell carcinoma, Breast cancer, Internal medicine, medicine, Molecular Medicine, Immunology and Allergy, Immunohistochemistry, business, RC254-282, Triple-negative breast cancer
Abstract

BackgroundPD-L1 IHC 22C3 pharmDx is an FDA-approved companion diagnostic for pembrolizumab across multiple tumor types designed for use on the Autostainer Link 48 (AL48). Many pathology laboratories do not have access to the AL48 and therefore do not use PD-L1 IHC 22C3 pharmDx but instead assess PD-L1 using laboratory-developed tests (LDTs) on the Ventana BenchMark platform. We compared our PD-L1 22C3 antibody-based LDT on the BenchMark XT platform with PD-L1 IHC 22C3 pharmDx using cervical cancer (CC), head and neck squamous cell carcinoma (HNSCC), urothelial carcinoma (UC), esophageal SCC (ESCC), and triple-negative breast cancer (TNBC) samples.MethodsTumor specimens from patients with CC, HNSCC, UC, ESCC, and TNBC were stained with the 22C3 antibody, scored using the LDT on the BenchMark XT as previously described,1 and compared with PD-L1 IHC 22C3 pharmDx scored by a trained pathologist, who measured PD-L1 with the use of combined positive score (CPS) and standard cutoffs (HNSCC and CC, ≥1; UC, ESCC, and TNBC, ≥10). Agreement in PD-L1 CPS as determined using the LDT and the PD-L1 IHC 22C3 pharmDx was evaluated.Results423 samples with CC (n = 77), HNSCC (n = 126), UC (n = 121), ESCC (n = 80), and TNBC (n = 19) were evaluated in this study. The pan-tumor (CC, HNSCC, UC, and ESCC) intraclass correlation coefficient (ICC) of PD-L1 CPS as a continuous variable was 0.95 (95% CI, 0.94%–0.96%); Spearman correlations were 0.95. ICC (95% CI) was 0.92 (0.88–0.95) for CC, 0.97 (0.96–0.98) for HNSCC, 0.95 (0.92–0.97) for UC, and 0.92 (0.88–0.95) for ESCC; Spearman correlation was 0.93, 0.96, 0.92, and 0.89, respectively. The overall percentage agreement at the respective CPS cutoff was 96% (CC), 96% (HNSCC), 96% (UC), and 90% (ESCC). Staining patterns by 22C3 LDT and PD-L1 IHC 22C3 pharmDx were also very similar in our TNBC pilot study; however, correlation was not calculated because of the small sample numbers.ConclusionsThe PD-L1 22C3 antibody-based LDT on the BenchMark XT demonstrated high concordance with PD-L1 IHC 22C3 pharmDx. These findings suggest the comparability of PD-L1 IHC 22C3 pharmDx with an LDT based on the 22C3 antibody across several tumor types. Further validation for TNBC is ongoing to confirm the data from the pilot run.ReferenceNeuman T, et al. J Thorac Oncol. 2016;11:1863–1868.

Published
2021
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