(P 186) PRECLINICAL STUDY OF DOXORUBICIN IN COMBINATION WITH PANOBINOSTAT IN XENOGRAFT MICE MODELS OF SOFT TISSUE SARCOMAS

Objective: Soft tissue sarcomas (STS) are rare diseases typically arising from connective tissues. Doxorubicin, the primary first line chemo drug of this disease, has shown cardiotoxicity and muti-drug chemo-resistance in many cases. Our project focused on the combination therapy of chemotherapy and histone deacetylate inhibitors (HDACi). We have previously shown synergism of doxorubicin when combined with Panobinostat (LBH589) in a group of STS cell lines. The efficiency of this combinatorial strategy has not been validated in vivo.

Methods: Based on our previous findings in vitro (Table 1), an epithelial sarcoma (ES) xenograft was selected to validate the synergism of LBH589 plus doxorubicin and a uterine leiomyosarcoma (U-LMS) xenograft was set as a negative comparison group. All the nude mice were injected with the same cell number of each cell line and they were randomly divided into treatment groups of vehicle control, LBH589, doxorubicin and LBH589 + doxorubicin group when tumors reached the size of 3x3mm2. Drug efficacy was evaluated every two or three days by monitoring the change in tumor size with a caliper. After getting the positive results in this step, we tried to reduce the dose of doxorubicin to 1/2 and 1/8 and repeated the same procedure in ES mice models to find if the synergism can still be validated. Immunohistochemical staining (IHC) assays on mice tissues of each sample were tried to determine the proliferation stages as well.

Results: In consistence with results in vitro, the drug combination LBH589 plus doxorubicin can strongly inhibit tumor growth in ES mice models. Tumor measurement showed that mice were affected mildly by single drug treatment but inhibited significantly by co-treatment. Statistical analysis showed both tumor size and tumor weight in the co-treatment group are much lower than vehicle and two single drug treatment groups (p < 0.001) (Figure 1). LBH589 plus doxorubicin group did not show any remarkable inhibition in U-LMS xenograft mice models (Table 2). For the further exploration in reducing dose of doxorubicin, analysis at the end point of the treatment showed that cutting dose of doxorubicin to 1/2 and 1/8 can still exert effects on tumor volume (p = 0.036 and 0.017 respectively), but has weakly effects in tumor weight in both groups. IHC assays on ki-67 showed the proliferation level of each mice group is same with observations of tumor volume.

Conclusion: Through animal studies, we have validated the drug efficiency of doxorubicin in combination with LBH589 in two STS xenografts, which provides supportive information for further clinical trials on STS subtypes. We also found that cutting the dose of doxorubicin in this combination can still inhibit tumor volume, indicating using a low dose of doxorubicin in combination with LBH589 can be a potential direction for those patients with large tumor size and severe toxicity side effects.

CTOS2022_Table1.docx

CTOS 2022_Table2.docx

CTOS2022_Figure1.docx