Abstract 3443
Background
Breast cancer is the most common cancer in women. Most breast tumors are ER(+)/hormone-dependent, this makes it possible to treat them with tamoxifen and other SERM/SERD drugs. Combination treatment of tamoxifen with novel drugs provides an efficient way for reduction of the drug concentration. The aim of the work was to obtain novel less toxic oligomycin derivatives for combinatorial treatment with tamoxifen.
Methods
Oligomycin A was produced at BIOAN (Moscow, Russia) using Streptomyces avermitilis NIC B62. The oligomycin derivatives were synthesized from oligomycin A. MCF-7 breast cancer cell line and MCF-10A human mammary epithelial cell line were obtained from the ATCC collection. Hormone-resistant subline was developed by long-term treatment of MCF-7 line with tamoxifen. Antiproliferative activity was measured by MTT.
Results
A series of less toxic oligomycin A derivatives, selectively modified at the C-33 position of the side chain, was synthesized, and their activity against hormone-dependent breast cancer cells was tested. Lead compound, a (33S)-diastereomer of oligomycin A (epi-oligomycin A), was chosen, which showed high activity towards MCF-7 breast cancer cells and MCF-7/TR hormone-resistant cells. Low doses of tamoxifen and epi-oligomycin A, which had no significant effects on the growth of MCF-7 cells, were evaluated. In combination, low doses of tamoxifen and epi-oligomycin A caused a significant antiproliferative effects on MCF-7 cells. Moreover, it was possible to return the sensitivity of hormone-resistant subline to tamoxifen by epi-oligomycin A treatment. Non-malignant epithelial cells, MCF-10A, were less sensitive to epi-oligomycin A.
Conclusions
Novel epi-oligomycin A enhances response to tamoxifen, which allows for reduction of the effective drug concentration. Combinatorial strategy with epi-oligomycin A may hold promise in development of therapies against breast tumours, including those with acquired resistance to the hormonal treatment. The research is supported by Russian Science Foundation (chemistry, agreement 15-15-00141) and the Russian Foundation for Basic Research (biology, 18-015-00422).
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Russian Science Foundation (chemistry, agreement 15-15-00141) and the Russian Foundation for Basic Research (biology, 18-015-00422).
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
5103 - CANOPY phase 3 program: Three studies evaluating canakinumab in patients with non-small cell lung cancer (NSCLC)
Presenter: Luis Paz-Ares
Session: Poster Display session 1
Resources:
Abstract
3666 - The Elderly Patient Individualized Chemotherapy (EPIC) trial, a study for an aged population of non-small cell lung cancer.
Presenter: Francesco Passiglia
Session: Poster Display session 1
Resources:
Abstract
4799 - KEYNOTE-495/KeyImPaCT: A Randomized, Biomarker-Directed, Phase 2 Trial of Pembrolizumab-Based Therapy for Non–Small Cell Lung Cancer (NSCLC)
Presenter: Martin Gutierrez
Session: Poster Display session 1
Resources:
Abstract
6035 - Safety, tolerability and activity of autologous T cells with enhanced T-cell receptors specific to NY ESO 1/LAGE 1a (GSK3377794) alone, or in combination with pembrolizumab, in advanced non small cell lung cancer: A Phase 1b/2a randomised pilot study
Presenter: Karen Reckamp
Session: Poster Display session 1
Resources:
Abstract
2176 - IFCT-1701 DICIPLE: a randomized phase 3 trial comparing continuation Nivolumab-Ipilimumab doublet immunotherapy until progression versus observation in patients with PDL1-positive stage IV Non-Small Cell Lung Cancer (NSCLC) after Nivolumab-Ipilimumab induction treatment
Presenter: Gerard Zalcman
Session: Poster Display session 1
Resources:
Abstract
2352 - ATALANTE-1 randomized phase 3 trial, OSE-2101 versus standard treatment as second or third line in HLA-A2 positive advanced non-small cell lung cancer (NSCLC) patients
Presenter: Enriqueta Felip
Session: Poster Display session 1
Resources:
Abstract
2451 - Phase Ib dose-escalation/expansion study of BI 836880, a VEGF/Ang2-blocking nanobody®, in combination with BI 754091, an anti-PD-1 antibody, in patients with advanced solid tumours
Presenter: Nicolas Girard
Session: Poster Display session 1
Resources:
Abstract
4285 - Radiosurgery followed by Tumor Treating Fields (TTFields) for brain metastases (1-10) from NSCLC in the phase 3 METIS trial
Presenter: Minesh Mehta
Session: Poster Display session 1
Resources:
Abstract
4909 - Nivolumab plus ipilimumab (NI) versus chemotherapy plus nivolumab (CN) in squamous cell lung cancer (SqCLC): the SQUINT trial
Presenter: Lorenza Landi
Session: Poster Display session 1
Resources:
Abstract
4125 - DUBLIN-3, a Stage IIIb/IV NSCLC Phase (Ph)3 Trial Comparing the Plinabulin (P)/Docetaxel(D) Combination with D Alone
Presenter: Ramon Mohanlal
Session: Poster Display session 1
Resources:
Abstract