Abstract 5465
Background
Overexpression of TGF-β2 has been implicated in the malignant progression of tumors by inducing immunosuppression, proliferation, angiogenesis and metastasis. OT-101 (Trabedersen) is a phosphorothioate ASO designed to specifically target human TGF-β2 mRNA. Herein, we report the synergizing effect of OT-101 with chemotherapy in multiple human tumor xenograft models for further exploration of clinical combination strategies.
Methods
OT-101 was administered as single agent (1-64 mg/kg, qdx3/wk or qdx21) and in combination with Gemcitabine (GEM, 15 mg/kg, qdx2/wk), Dacarbazine (DTIC, 1-10 mg/kg, qdx4/wk) or Paclitaxel (PTX, 10 mg/kg, qdx5) to nude mice (10/subgroup) bearing either (i) orthotopic human L3.6pl pancreatic cancer (PAC), (ii) human metastatic C8161 melanoma, (iii) SC glioblastoma (U87) or (iv) SC ovarian (SKOV-3) tumors. Mice were monitored for adverse effects, body weight loss, tumor size and survival outcome. Lymph node and liver surface and micro-metastases as well as size and weight of the pancreatic tumors were determined. Tumor sections were stained with anti-BrdUrd and CD31 antibodies to determine tumor cell proliferation and vascularization, respectively.
Results
OT-101 significantly reduced tumor growth (p = 0.0084), lymph node metastasis (p = 0.023), and tumor angiogenesis (p
Conclusions
The preclinical data laid the groundwork for establishing combination therapies in the clinic. Of interest is the preferential synergy between OT-101 and PTX or DTIC, but not with GEM.
Clinical trial identification
Legal entity responsible for the study
Autotelic Inc
Funding
None
Disclosure
All authors have declared no conflicts of interest.