Palbociclib in combination with sunitinib exerts a synergistic anti-cancer effect in patient-derived xenograft models of various human cancers types. (28th June 2022)

• Record Type: Journal Article
• Authors: Moskovits, Neta; Peretz, Idit; Chausky, Eva; Itzhaki, Ella; Shmuel, Nofar; Meerson, Raisa; Tarasenko, Nataly; Kaufman, Aleksandr; Stemmer, Amos; Yaffe, Ranny; Bareket-Samish, Avital; Edison, Natalia; Goldman, Tal; Stemmer, Salomon M.
• Is Part Of: Cancer letters. Volume 536(2022)
• Publication Date: 2022-06-28
• Subjects: Efficacy -- Palbociclib -- PDX models -- Sunitinib -- Synergy; CSF-1R colony stimulating factor receptor Type 1 -- FBS fetal bovine serum -- FDA Food and Drug Administration -- HCC hepatocellular carcinoma -- HER2 human epidermal growth factor receptor 2 -- HR hormone receptor -- IACUC institutional Animal Care and Use Committee -- IP intraperitoneal -- IRB institutional review board -- mtRTKI multi-targeted receptor tyrosine kinase inhibitor -- PDX patient-derived xenograft -- RCC renal cell carcinoma -- RMC Rabin Medical Center -- SC subcutaneously -- SOC standard-of-care -- TGI tumor growth inhibition -- TNBC triple negative breast cancer -- VEGFR vascular endothelial growth factor receptor; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2022.215665
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: The efficacy/safety of combining palbociclib (a CDK4/6 inhibitor) and sunitinib (a multi-targeted receptor tyrosine kinase inhibitor) was evaluated, using patient-derived xenograft (PDX) models. Twenty-three PDX mice models were developed from patients with various solid tumors. The mice were randomized to 4 groups (5–6 mice in each): control/palbociclib (100 mg/kg)/sunitinib (50 mg/kg)/combination. Drugs were administered orally, 5 days/week. In 17/23 PDX models (74%), the combination demonstrated a synergistic inhibitory effect vs the monotherapies ("responder" models) with no unexpected toxicities. In 13/17 responder models, where standard-of-care (SOC) was an additional comparator, the combination was more effective than SOC in 7 models, as effective in 4, and less effective in 2. The mean ± SEM experiment duration in 15/17 responder models (2/17 were excluded due to technical issues) was 86 ± 12 and 31 ± 5 days for the combination and control groups, respectively (p = 0.0002). The effect of the combination was dose-dependent. Cell-viability experiments in A549/MDA-MB-231/HT-29 cell lines and experiments using tumor-derived primary cell spheroids supported the PDX findings. In conclusion, combination of palbociclib and sunitinib exerts a synergistic anti-tumor effect without adding unexpected toxicity. A clinical trial assessing this combination is underway. Highlights: Patient-derived xenografts (PDX) are effective translational pre-clinical models. 23 PDX models were developed from patients with various solid tumors. In these models, a synergistic anti-tumor effect was seen for palbociclib + sunitinib. In certain PDX models, the combination was more effective than standard-of-care. In-vitro experiments also showed a synergistic effect for this combination.