The fatty acid-binding protein 5 inhibitor SBFI-103 can potentially eliminate drug-resistant prostate cancer cells at a well-tolerated dose.
Prostate cancer (PCa) treatment faces challenges due to the lack of effective targets, as initial success with androgen receptor blockade gives way to drug resistance and lethal relapse of the disease. Research has shown that lethal recurrent disease often involves the loss of the tumor suppressor genes PTEN and TP53.
A study published in the journal Cancers assessed the efficacy of inhibiting fatty acid-binding protein 5 (FABP5) for targeting PTEN-deficient, therapy-resistant PCa. The study utilized a genetically engineered mouse model for advanced PCa called RapidCaP. A combined analysis of primary cancer cells from RapidCaP (RCaP) cells and large-scale patient datasets was performed.
FABP5 Emerges as the Key Driver in PCa From the FABP Gene Family
The FABP gene family encompasses 10 genetic paralogs involved in lipid signaling. The TCGA PCa dataset was analyzed to assess which FABP genes are most altered in human PCa. FABPs 4, 5, 9, and 12 genes were altered in one-third of the tumors, owing to co-amplification from genomic proximity and their location on the long arm of chromosome 8.
Increases in mRNA expression were evaluated to disentangle gene correlation from genomic location. FABP5 demonstrated the highest cancer-specific mRNA expression, which was also significantly correlated with MYC gene amplification (a driver gene of PCa). In contrast, other FABPs did not exhibit this correlation with MYC amplification. In the mouse model, only FABP5 mRNA demonstrated high expression in RCaP cells. This analysis highlights FABP5 as the PCa-relevant driver of the FABP gene family.
RCaP Cells Can be Used as a Murine-Derived Model for Incurable PCa
RapidCaP tumorigenesis begins by introducing Cre-recombinase into the prostates of PtenloxP/loxP; Trp53loxP/loxP mice, initiating disease in a few cells, which then expand into lesions within weeks. Cells isolated from these lesions (RCaP cells) displayed elevated FABP5 expression. They also expressed the androgen receptor (AR) but showed limited response to dihydrotestosterone (DHT), suggesting an uncoupling of AR function from their proliferation.
When exposed to two clinically relevant AR antagonists (darolutamide and enzalutamide), RCaP cells exhibited resistance, confirming that they had attained insensitivity to castration. Additionally, these cells displayed insensitivity to taxanes. Thus, it was established that RCaP cells can be utilized as a murine-derived proxy cell type for incurable PCa.
Finally, cell viability was tested against an increasing concentration of SBFI-103, a truxillic acid mono-ester (TAME)-based FABP5 inhibitor. The RCaP cells demonstrated sensitivity to TAME-based FABP5 inhibitors. A comparison of three SBFI analogs demonstrated that SBFI-103 most effectively reduced the viability of RCaP cells.
SBFI-103 Shows Remarkable Efficacy in Eliminating Drug-Resistant PCa Cells
A series of trials involving RCaP cell transplantation into mice were performed to assess the in vivo efficacy of the FABP5 inhibitor SBFI-103, as it had shown the highest in vitro efficacy against RCaP cells, along with a good in vivo toxicity profile. The drug was administered at two doses daily: 20 mg/kg (which has previously demonstrated human PC3 cancer cell suppression) and 40 mg/kg (to test for dose dependency). After 30 days, significant tumor volume reduction (50%) was observed with the lower dose, and the higher dose achieved even further tumor volume reduction (75%) compared to the average vehicle treatment.
Even more substantial anti-tumor effects of SBFI-103 were revealed in postmortem analysis. These included tumor volume reduction by 80% and lesion mass reduction by 95% at the higher dose. Histopathology revealed that the high-dose-treated samples showed only a few cancer cells and hyalinization of the lesion, indicating cancer suppression. By comparison, vehicle-treated lesions showed high-grade, poorly differentiated carcinoma with high mitotic figures.
Further analysis showed that the sparse tumor cells in the high-dose-treated samples were 98% negative for the proliferation marker Ki-67. These in vivo experiments demonstrate SBFI-103’s ability to eliminate most PCa cells resistant to conventional treatments at a well-tolerated 40 mg/kg dose.
Source:
Swamynathan, M. M., Mathew, G., Aziz, A. A., Gordon, C., Hillowe, A., Wang, H., Jhaveri, A., Kendall, J., Cox, H., Giarrizzo, M., Azabdaftari, G., Rizzo, R. C., Diermeier, S. D., Ojima, I., Bialkowska, A. B., Kaczocha, M., & Trotman, L. C. (2023). FABP5 Inhibition against PTEN-Mutant Therapy Resistant Prostate Cancer. Cancers, 16(1), 60. https://doi.org/10.3390/cancers16010060
