Abstract 2800: Transforming growth factor-beta 2 (TGF-β2) antisense oligonucleotide (ASO) OT-101 synergizes with chemotherapy in preclinical tumor models
Authors: D'Cruz Osmond , Lee Cynthia , Trieu Vuong , Hwang Larn 
Published: July 2017

Background: Overexpression of TGF-β2 has been implicated in the malignant progression of tumors by inducing immunosuppression, proliferation, angiogenesis and metastasis. Clinical failures of TGF-β inhibitors in targeting the tumor promoting arm of TGF-β signaling is attributed to multiple isoforms and receptor functions. OT-101 (Trabedersen) is a phosphorothioate ASO designed to specifically target human TGF-β2 mRNA with superior clinical activity in patients with TGF-β2-overexpressing tumors. Herein, we report the synergizing effect of OT-101 with chemotherapy in multiple human tumor xenograft models for further exploration of clinical combinations.

Methods: The in vivo efficacy studies of intraperitoneal (IP, 16 or 50 mg/kg) or subcutanous (SC, 1-64 mg/kg) repeated administration (qdx3/wk or qdx21) of OT-101 as single agent and in combination with Gemcitabine (15 mg/kg, qdx2/wk, IP), Dacarbazine (1-10 mg/kg, qdx4/wk, IP) or Paclitaxel (10 mg/kg, qdx5, IV) were evaluated in nude mice (10/subgroup) bearing either (i) orthotopic human L3.6pl pancreatic cancer (PAC), (ii) human metastatic C8161 melanoma, (iii) subcutaneous glioblastoma (U87-MG) or (iv) subcutaneous ovarian (SK-OV-3) tumors. Mice were monitored thrice a week for adverse effects, body weight loss, tumor size and survival outcome. The incidence of 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-5-bromo-2'-deoxy-uridine antibody to determine tumor cell proliferation and with anti-CD31/PECAM-1 antibody to determine vascularization.

Results: OT-101 significantly reduced tumor growth (p = 0.0084), lymph node metastasis (p = 0.023), and tumor angiogenesis (p &lt;0.0001) in the orthotopic PAC model. Mean tumor vessel density was significantly reduced (p &lt;0.0001) in all groups in comparison to untreated control. OT-101 demonstrated synergy in tumor growth inhibition and increased survival in human malignant melanoma (C8161, p = 0.038, vs. Dacarbazine alone), glioblastoma (U87-MG, p = 0.001 vs. Paclitaxel) and ovarian (SKOV-3, p &lt;0.05 vs. Paclitaxel) cancer models when combined with either Dacarbazine (C8161) or Paclitaxel (U87-MG and SK-OV-3). No syngergy was observed with Gemcitabine (PAC). The combination regimen tested was effective and tolerable. Significant antitumor activity was achieved at human dose equivalent of 80 mg/m2/day which is well below the optimized clinical dose used for IV infusion of patients at 140 mg/m2/day.

Conclusions: The preclinical data lay the groundwork for further exploration of combination therapy in the clinic as well as demonstrating that TGF-β2 is a druggable target. Of interest is the preferential synergy between OT-101 and Paclitaxel or Dacarbazine, but not with Gemcitabine.

Citation Format: Osmond D'Cruz, Cynthia Lee, Vuong Trieu, Larn Hwang. Transforming growth factor-beta 2 (TGF-β2) antisense oligonucleotide (ASO) OT-101 synergizes with chemotherapy in preclinical tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2800. doi:10.1158/1538-7445.AM2017-2800