Third-generation taxanes SB-T-121605 and SB-T-121606 are effective in pancreatic ductal adenocarcinoma

Tomas Sychra; Alzbeta Spalenkova; Stepan Balatka; Radka Vaclavikova; Karolina Seborova; Marie Ehrlichova; Jaroslav Truksa; Cristian Sandoval-Acuña; Vlasta Nemcova; Arpad Szabo; Kamila Koci; Tereza Tesarova; Lei Chen; Iwao Ojima; Martin Oliverius; Pavel Soucek

doi:10.1016/j.isci.2024.109044

Third-generation taxanes SB-T-121605 and SB-T-121606 are effective in pancreatic ductal adenocarcinoma

iScience. 2024 Jan 26;27(2):109044. doi: 10.1016/j.isci.2024.109044. eCollection 2024 Feb 16.

Authors

Tomas Sychra^{1

2}, Alzbeta Spalenkova^{3

4}, Stepan Balatka^{3

4}, Radka Vaclavikova^{3

4}, Karolina Seborova^{3

4}, Marie Ehrlichova^{3

4}, Jaroslav Truksa⁵, Cristian Sandoval-Acuña⁵, Vlasta Nemcova⁶, Arpad Szabo^{2

7}, Kamila Koci², Tereza Tesarova^{3

4}, Lei Chen⁸, Iwao Ojima⁸, Martin Oliverius^{1

2}, Pavel Soucek^{3

4}

Affiliations

¹ Department of Surgery, University Hospital Kralovske Vinohrady, 100 00 Prague, Czech Republic.
² Third Faculty of Medicine, Charles University, 100 00 Prague, Czech Republic.
³ Toxicogenomics Unit, National Institute of Public Health, 100 00 Prague, Czech Republic.
⁴ Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, 323 00 Pilsen, Czech Republic.
⁵ Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV Research Center, 252 50 Vestec, Czech Republic.
⁶ Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, 100 00 Prague, Czech Republic.
⁷ Department of Pathology University Hospital Kralovske Vinohrady, 100 00 Prague, Czech Republic.
⁸ Institute of Chemical Biology & Drug Discovery, State University of New York at Stony Brook, Stony Brook, NY 11794-3400, USA.

Abstract

Pancreatic cancer is a severe malignancy with increasing incidence and high mortality due to late diagnosis and low sensitivity to treatments. Search for the most appropriate drugs and therapeutic regimens is the most promising way to improve the treatment outcomes of the patients. This study aimed to compare (1) in vitro efficacy and (2) in vivo antitumor effects of conventional paclitaxel and the newly synthesized second (SB-T-1216) and third (SB-T-121605 and SB-T-121606) generation taxanes in KRAS wild type BxPC-3 and more aggressive KRAS G12V mutated Paca-44 pancreatic cancer cell line models. In vitro, paclitaxel efficacy was 27.6 ± 1.7 nM, while SB-Ts showed 1.7-7.4 times higher efficacy. Incorporation of SB-T-121605 and SB-T-121606 into in vivo therapeutic regimens containing paclitaxel was effective in suppressing tumor growth in Paca-44 tumor-bearing mice at small doses (≤3 mg/kg). SB-T-121605 and SB-T-121606 in combination with paclitaxel are promising candidates for the next phase of preclinical testing.

Keywords: Cancer; Cell biology; Pharmacology.