Effect on tumor growth by TGF-β1/COX-2 siRNA combination product (STP705) in a human cholangiocarcinoma (HuCCT-1) xenograft tumor model in nude mice.

Abstract

e14652 Background: Cholangiocarcinoma (CCA) is a hepatobiliary cancer and although there have been advances recently there is a need for additional treatment methods for patients. Over expressions of TGF-β1 and COX-2 have been reported to play key roles in tumorigenesis of CCA. We studied the effect of STP705 on the growth of HuCCT-1 xenograft tumors in nude mice. STP705 is a TGF-β1/COX-2 specific siRNA combination product formulated in Histidine-Lysine co-Polymer nanoparticle delivery system. Methods: HuCCT-1 xenograft tumors were implanted subcutaneously into 24 BALB/c nude female mice (n = 8/group). Group 1 received vehicle control, group 2 (low-dose) received 8µg of STP705, and group 3 (high-dose) received 16µg of STP705. Intratumoral test article administration and tumor volume measurements were conducted twice a week for 3-weeks. Qualitative analysis was performed on H&E, Picrosirius red (PSR) and immunohistochemistry (IHC) stained sections of tumor tissues. Results: High- and low- dose groups of STP705 reported significantly lower mean tumor volume at day 21 (p = 0.005 & p = 0.036, respectively) as compared to control group. High-dose group reported significantly lower tumor volume at days 11 (p = 0.042), 15 (p = 0.003), and 18 (p = 0.007) as compared to the control group. IHC assessment demonstrated that STP705-treated animals had significantly lower (H-score ± SEM) TGF-β1, COX-2, HSP70, Bcl-xL and MMP-9 staining (52±9, 39±4, 178±8, 25±7 & 7±1, respectively) as compared to control animals (94±11, 66±8, 213±7, 59±8 & 11±2, respectively – with p < 0.05). Assessment of Caspase-3 and H&E (necrosis and inflammation) slides reported higher mean score for STP705-treated animals, while PSR staining reported lower fibroplasia for STP705-treated animals as compared to the control animals. Conclusions: The data suggests that STP705-treatment suppresses TGF-β1 and COX-2 expression resulting in inhibition of (i) tumor cell survival, (ii) fibrosis, (iii) promotes apoptosis, and (iv)decreased invasiveness of tumor cells. Overall, STP705 is an innovative siRNA-based treatment that results in significant suppression of tumor growth in a HuCCT-1 xenograft mouse tumor model.

Non-Coding RNAs: Foes or Friends for Targeting Tumor Microenvironment

“…Silencing expression of TGF-β1 and COX-2 to inhibit cell survival and induce tumor cell apoptosis Cutaneous squamous cell carcinoma skin cancer [196,197]…”

Antitumoral RNA‐targeted oligonucleotide therapeutics: The third pillar after small molecule inhibitors and antibodies

“…48 STP705 is composed of siRNA oligonucleotides targeting TGFB1 and COX-2 mRNAs formulated with nanoparticles containing a unique histidine-lysine copolymer peptide. 49,50 Clinical trials for STP705 with intravenous or intralesional administration in patients with advanced/metastatic solid tumors in phase 1 or cutaneous squamous cell carcinoma (in situ) in phase 2 are currently underway.…”

Nano‐Oncologicals: A Tortoise Trail Reaching New Avenues

“…[246] Similarly, Sirnaomics uses their branched histidine-lysine polypeptide-siRNA NPs, of 150 nm, for the codelivery of siRNAs targeting transforming growth factor-beta (TGF-β) and cyclooxygenase-2 (COX-2) genes for the treatment of cutaneous squamous cell carcinoma in a phase I clinical trial. [248][249][250] These NPs will be delivered locally into the tumor. Preclinical studies have shown that the combined inhibition of TGF-β and COX-2 results in increased apoptosis, reduced tumor growth and rate of invasion in hepatobiliary cancer models.…”

“…Preclinical studies have shown that the combined inhibition of TGF-β and COX-2 results in increased apoptosis, reduced tumor growth and rate of invasion in hepatobiliary cancer models. [248] The use of CPPs has also been harnessed for an improved RNA delivery to the tumor cells. For example, an octa-arginine (R8) peptide linked to a targeting ligand (RGDS) at one end and two C18 lipid tails at the other were used to condense siRNA.…”