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
3317 - Circulating tumor DNA (ctDNA) analysis in patients (pts) with non-small cell lung cancer (NSCLC) treated with telisotuzumab vedotin (teliso-v), an antibody-drug conjugate targeting c-Met
Presenter: Rebecca Heist
Session: Poster Display session 1
Resources:
Abstract
3887 - First Real Life Data on Durvalumab after definitive concomitant ChemoRadiotherapy (cCRT) in unresectable Stage (St) III Non-Small Cell Lung Cancer (NSCLC) in France: Analysis of 591 patients (pts) enrolled in the French cohort (c) Temporary Authorization of Use (ATU)
Presenter: Virginie Avrillon
Session: Poster Display session 1
Resources:
Abstract
682 - EGFR Inhibitor Versus Chemotherapy as Adjuvant Treatment for Locally-advanced EGFR-mutant Non-Small Cell Lung Cancer
Presenter: Peng Xie
Session: Poster Display session 1
Resources:
Abstract
2509 - Afatinib in EGFR TKI-naïve patients with EGFR mutation-positive (EGFRm+) NSCLC: interim analysis of a Phase IIIb, multi-national, open-label study
Presenter: Filippo de Marinis
Session: Poster Display session 1
Resources:
Abstract
3300 - First-line ceritinib versus chemotherapy in patients (pts) with advanced ALK rearranged (ALK+) non-small cell lung cancer (NSCLC): ASCEND-4 Asian subgroup analysis
Presenter: Daniel SW Tan
Session: Poster Display session 1
Resources:
Abstract
2653 - A combined analysis of two Phase IIIb studies of afatinib in EGFR TKI-naïve patients (pts) with EGFR mutation-positive (EGFRm+) NSCLC
Presenter: Filippo de Marinis
Session: Poster Display session 1
Resources:
Abstract
3663 - Impact of plasma EGFR mutation fractions on response to first generation tyrosine-kinase inhibitor in treatment of naïve non-small cell lung cancer patients
Presenter: Xiaohong Wang
Session: Poster Display session 1
Resources:
Abstract
5921 - Definition of an afatinib trough concentration threshold in the treatment of NSCLC
Presenter: Stephane Bouchet
Session: Poster Display session 1
Resources:
Abstract
2852 - A Phase Ib Trial of Neoadjuvant Chemoradiotherapy and Durvalumab(MEDI4736) for Potentially Resectable stage III Non-Small Cell Lung Cancer (NSCLC)
Presenter: Beung chul AHN
Session: Poster Display session 1
Resources:
Abstract
3273 - Low expression of Notch1 and combined Notch1/HES1 are associated with adverse survival factor for limited stage small cell lung cancer
Presenter: Jinsoo Lee
Session: Poster Display session 1
Resources:
Abstract