Abstract 2469
Background
Soft-tissue sarcomas (STS) are life-threatening diseases, for which more efficient therapeutic options are necessary. Trabectedin (T) is an anti-tumor drug approved for the treatment of advanced STS. Synergistic drug combinations could improve T results in STS patients. Rapamycin (R) is an mTOR pathway inhibitor. Synergy with T has been described in ovary clear cell carcinoma. Of note, R suppresses DNA double-strand breaks repair, thus generating the perfect set-up for T activity. Altogether, we hypothesize that T+R combination (T+R) is synergistic in STS, and that mTOR inhibition enhances T activity.
Methods
Human STS cell lines (n = 9) were treated with increasing doses of T (1x10-7M to 1x10-11M) and/ or R (1x10-9 to 1x10-11) to determine IC50 and combination index (CI) values. Cells were initially exposed to R, 2 hours later T was added, under the assumption that R pre-treatment favors T cytotoxicity. Cell viability, at 72 h, was measured by MTS assay. Apoptosis was determined by Western Blot for PARP and Caspase 3 cleavage. In vivo experiments were performed in immunocompetent 3-methylcolanthrene fibrosarcoma mice: T was administrated via IV (0.15 mg/kg; q7dx1) and R via IP (0.50 mg/kg; q7dx2). Body weight and tumor volume were measured every 2 days for 15 days of treatment. Tumors were collected for analysis (snap frozen and paraffin embedding).
Results
T+R was synergistic in all STS cell lines: CP0024 primary leiomyosarcoma and 93T449 liposarcoma cell lines showed strong synergism with CI at the ED50 of 0.129 and 0.027, respectively. This synergy was followed by an increase of PARP and Caspase 3 cleavage. The synergism was confirmed in vivo: mice treated with R+T showed tumor growth delay in comparison to the drugs alone (p < 0.05). Stable disease was achieved in 7 out of 7 mice.
Conclusions
R+T is synergic in STS and deserves exploration in clinical setting. Further research will reveal the mechanisms underlying this synergy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Javier Martín Broto.
Funding
PharmaMar.
Disclosure
D.S. Moura: Research grant / Funding (institution): PharmaMar; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Novartis; Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Eisai. M. Lopez-Alvarez: Travel / Accommodation / Expenses: Eisai. N. Hindi: Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): PharmaMar; Honoraria (self): PharmaMar. J. Martin-Broto: Research grant / Funding (institution): PharmaMar; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Novartis; Honoraria (self): PharmaMar; Honoraria (self): Lilly; Honoraria (self): Novartis; Speaker Bureau / Expert testimony: PharmaMar. All other authors have declared no conflicts of interest.
Resources from the same session
2728 - MicroRNA expression and DNA methylation profiles do not distinguish between primary and recurrent well-differentiated liposarcoma
Presenter: Melissa Vos
Session: Poster Display session 1
Resources:
Abstract
3197 - Genomic Alterations, Tumor Mutation Burden and Prognosis of Chinese Cardiac Sarcoma Patients
Presenter: Na Zhu
Session: Poster Display session 1
Resources:
Abstract
4214 - Evaluation of a peptide-conjugated alkylator melflufen in osteosarcoma preclinical models
Presenter: Konstantin Byrgazov
Session: Poster Display session 1
Resources:
Abstract
2654 - Expression analysis of NHEJ and HR genes in Ewing sarcomas: indications of DSB repair dysfunction
Presenter: Anastasios Kyriazoglou
Session: Poster Display session 1
Resources:
Abstract
4383 - Epidemiology of Synovial Sarcoma in EU28 countries
Presenter: Nedra Joseph
Session: Poster Display session 1
Resources:
Abstract
1937 - Resection Of High-Grade Large Soft Tissue Sarcoma With Adequate Wide Margin Can Lead To Good Local Control Without Adjuvant Radiotherapy
Presenter: Toshiyuki Kunisada
Session: Poster Display session 1
Resources:
Abstract
3757 - Influence of eribulin on proliferation, migration and invasion properties of leiomyosarcoma cell line models
Presenter: Marta Mendiola
Session: Poster Display session 1
Resources:
Abstract
1040 - EREMISS: Efficacy of regorafenib (REG) as maintenance therapy in non-adipocytic soft tissue sarcomas (STS) having received 1st-line doxorubicin-based chemotherapy (Doxo-CT)
Presenter: Nicolas Penel
Session: Poster Display session 1
Resources:
Abstract
1048 - A Phase 2 biomarker-driven study evaluating the clinical efficacy of an MDM2 inhibitor, milademetan, in patients with intimal sarcoma, a disease with a high unmet need
Presenter: Kan Yonemori
Session: Poster Display session 1
Resources:
Abstract
1511 - A pilot study of oral paclitaxel (ORAXOL) in subjects with cutaneous angiosarcomas (KX-ORAX-010)
Presenter: Herbert Loong
Session: Poster Display session 1
Resources:
Abstract