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
3909 - Spectrum of pathogenic germline mutations in Chinese lung cancer patients through next-generation sequencing
Presenter: Ying Huang
Session: Poster Display session 1
Resources:
Abstract
3061 - Poor prognostic impact of NTRK2 gene variation in Esophageal Squamous Cell Carcinoma
Presenter: Ye Chen
Session: Poster Display session 1
Resources:
Abstract
4735 - Mutation profile of Tibetan lung cancer revealed by Whole Exome Sequencing
Presenter: Xin Wang
Session: Poster Display session 1
Resources:
Abstract
5236 - Synergistic activity between niraparib and chemotherapy in colorectal cancer: molecular determinants from a preclinical model
Presenter: Pietro Paolo Vitiello
Session: Poster Display session 1
Resources:
Abstract
4051 - cRGDfK (cRGD) conjugated Pyropheophor¬bide-a (Pyro), a new tumor photodynamic agent, is highly accumulated and specific in tumor cell killing
Presenter: Fengwei Wang
Session: Poster Display session 1
Resources:
Abstract
859 - The expression of MMR, CD133 and the presence of p53 wt predict the response to Cabazitaxel in malignant neural tumors cell lines.
Presenter: Kevin Doello
Session: Poster Display session 1
Resources:
Abstract
2497 - IKS01, a next generation antibody drug conjugate (ADC) designed to be efficacious in tumors with low and moderate levels of folate receptor expression
Presenter: Jenny Thirlway
Session: Poster Display session 1
Resources:
Abstract
1636 - Novel Non-Camptothecin Compounds with Antiproliferative Activities against Breast Cancer Cells
Presenter: Wen-shan Li
Session: Poster Display session 1
Resources:
Abstract
3443 - Sensitization of estrogen receptor-positive breast cancer cells to tamoxifen by novel epi-oligomycin A
Presenter: Margarita Yastrebova
Session: Poster Display session 1
Resources:
Abstract
840 - Autophagy inhibition enhances leflunomide-induced cytotoxicity in human bladder cancer cells
Presenter: Li Cheng
Session: Poster Display session 1
Resources:
Abstract