(M1530-03-18) A Novel Therapeutic Approach for Treatment of Taxane-Resistant Prostate Cancer

Purpose: Prostate cancer is one of the most diagnosed malignancies in men and a leading cause of cancer-related deaths. While localized cases respond well to treatment, progression to metastatic disease remains a challenge due to resistance to therapies(1). Studies have shown that RNA-Binding Motif (RBM) proteins play key roles in post-transcriptional regulation, and RBM3, in particular, is upregulated in primary prostate cancer but downregulated in metastases. This suggests RBM3 may influence disease progression by attenuating cancer cell stemness(2–4). Our lab has discovered lead compounds that upregulate RBM3 in metastatic taxane-resistant prostate cancer cells. The purpose of this study is to determine their toxicity profile, efficacy, and generate mechanism of action hypothesis for further analysis.

Methods: Our lab identified novel compounds that induce the expression of RBM3 and inhibit the viability of taxane-resistant PC3 cells by screening of several small molecule libraries (FDA-approved drugs, NCI Developmental Therapeutics Program diversity set), and some proprietary compound libraries. Viability assays were performed for all the compounds to determine their inhibitory concentration (figure 1). In vivo toxicity studies were done using immunocompetent Balb/C mice. Blood samples and organs were collected for analysis. Blood smears were prepared from whole blood and analyzed for the morphological changes of blood cells and chemistry (Table 1). For RNA sequencing, PC3 TxR were treated with the compound at 8, 24,36 and 48hr time points. RNA was extracted and sequenced.

Results: Viability assay resulted in IC₅₀ values range of 1-6µM.  For toxicity studies, at a dose of 50mg/kg, there was no organ toxicity detected. For blood chemistry, several parameters were out of reference range, however, when individual organs were examined, no compound-attributed irregularities were observed (Table 1). RNA sequencing showed that the primary mechanism of cell death was apoptosis and there was upregulation in inflammatory and immune pathways (Figure 1).

Conclusion: Our results suggest that upregulation of RBM3 in metastatic taxane-resistant prostate cancer cells can lead to the apoptotic cell death and immune signaling. This potentially opens a new approach of rendering “immunologically cold” prostate cancer visible to the immune system which can be used to potentiate existing immunotherapies. Additionally, the lack of compound-attributed organ toxicity suggests the safety of this approach.

References: 1. Seruga B, Ocana A, Tannock IF. Drug resistance in metastatic castration-resistant prostate cancer. Nature Reviews Clinical Oncology 2011 8:1 [Internet]. 2010 Sep 21 [cited 2025 Apr 3];8(1):12–23. Available from: https://www.nature.com/articles/nrclinonc.2010.136
2. Jonsson L, Gaber A, Ulmert D, Uhlén M, Bjartell A, Jirström K. High RBM3 expression in prostate cancer independently predicts a reduced risk of biochemical recurrence and disease progression. Diagn Pathol [Internet]. 2011 Sep 28 [cited 2025 Apr 3];6(1):1–7. Available from: https://link.springer.com/articles/10.1186/1746-1596-6-91
3. Zeng Y, Wodzenski D, Gao D, Shiraishi T, Terada N, Li Y, et al. Stress-response protein RBM3 attenuates the stem-like properties of prostate cancer cells by interfering with CD44 variant splicing. Cancer Res [Internet]. 2013 Jul 1 [cited 2025 Apr 3];73(13):4123–33. Available from: /cancerres/article/73/13/4123/584209/Stress-Response-Protein-RBM3-Attenuates-the-Stem
4. Zhang S, Lv C, Niu Y, Li C, Li X, Shang Y, et al. RBM3 suppresses stemness remodeling of prostate cancer in bone microenvironment by modulating N6-methyladenosine on CTNNB1 mRNA. Cell Death & Disease 2023 14:2 [Internet]. 2023 Feb 7 [cited 2025 Apr 3];14(2):1–14. Available from: https://www.nature.com/articles/s41419-023-05627-0

Acknowledgements: FDOH (Florida Department of Health) grant 24B09 (PI – Minond).


RNAseq of PC3 TxR cells treated with compound 2 after 24hrs


Results for blood chemistry and CBC