Advancing Cancer Therapeutics: Synergizing mTOR Inhibitors with STL001's Enhanced Modes of Action and Tetrandrine Potential

Written by Axel Martinelli in collaboration with Lexogen
⏱ 6 min read

Lab desk with Omics Playground on the screen

FOXM1, a transcription factor commonly overexpressed in various cancers, plays a critical role in tumor progression, therapy resistance, and poor patient outcomes. In their study, Raghuwanshi et al. introduce STL001, a novel small molecule inhibitor targeting FOXM1, and demonstrate its potential to improve the efficacy of a broad range of cancer treatments. 

The research highlights STL001’s ability to suppress FOXM1 activity, reduce cancer cell proliferation, and sensitize tumors to chemotherapy, targeted therapies, and immunotherapies. These results highlight the therapeutic potential of FOXM1 inhibition as a strategy to improve treatment outcomes in various cancer types.

While the main article highlights STL001’s ability to sensitize cancer cells to a broad range of chemotherapies [1], this post leverages BigOmics Analytics’ Omics Playground platform to gain additional insights. We’ll look into the:

  • Correlation Between STL001 and mTOR Inhibitors
  • Modes of Action Enhanced by STL001
  • Synergy Between STL001 and Tetrandrine

The analyses reveal intriguing correlations between STL001, mTOR inhibitors, and other mechanisms of action, as well as its potential synergy with tetrandrine.

The insights also point to potential follow-up experiments, which are outlined in Lexogen‘s blog post “Scientific Insight: Overcoming Chemoresistance with Combination Strategies for Multimodal Cancer Therapies”.

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Correlation Between STL001 and mTOR Inhibitors

A striking similarity in the expression profiles of STL001 and mTOR/PI3K inhibitors (which are interconnected signaling pathways) was observed (Figure 1). This is particularly interesting because both FOXM1 and mTOR signaling pathways play a central role in regulating cell growth, proliferation and survival. Here’s how this correlation is possible:

  • Common pathway interactions: FOXM1 and mTOR signaling pathways intersect in critical cellular processes such as cell cycle regulation, DNA repair and metabolism. For example, FOXM1 has been linked to the activation of AMPK/mTOR signaling in certain cancers [1,2].
  • Common downstream targets: RNA sequencing data showed that STL001 suppresses FOXM1-dependent signaling pathways, including those involved in mitotic checkpoints (e.g. PLK1, AURKB) and DNA repair (e.g. FANCONI pathway), which also overlap with mTOR-regulated processes [1-3].
  • Enhanced apoptosis: Both mTOR inhibition and FOXM1 suppression lead to enhanced apoptosis by impairing survival signals [2]. Their combined use could enhance these effects and make cancer cells more susceptible to treatments [1,2,4].

This correlation opens the door to exploring combination therapies with STL001 and mTOR inhibitors to achieve synergistic anticancer effects.

Mode of actions plot produced with Omics Playground
Figure 1. Correlation in expression profiles between STL001 and mTOR/PI3K inhibitors, as highlighted using the L1000 Drug connectivity map [5] meta-analysis implemented in Omics Playground.

Modes of Action Enhanced by STL001

Omics Playground highlighted several modes of action enhanced by STL001, including cell cycle inhibitors, apoptosis enhancers, and DNA damage repair inhibitors (Figure 2). These mechanisms closely align with the drugs tested as partners in the main article:

  • Cell cycle inhibitors: STL001 suppresses key regulators such as PLK1 and AURKB that are critical for mitotic progression [1]. This is consistent with drugs such as paclitaxel (a microtubule stabilizer) used in the study [6]. By further disrupting mitosis, STL001 enhances the cytotoxicity of paclitaxel.
  • Apoptosis enhancers: STL001 promotes apoptosis through caspase activation [1]. This complements drugs such as doxorubicin and cisplatin that cause DNA damage but rely on apoptotic pathways for cell death [7].
  • Inhibitors of DNA repair: FOXM1 regulates genes involved in DNA repair (e.g. ATR, FANCONI) [1]. By suppressing these signaling pathways, STL001 sensitizes cancer cells to DNA-damaging agents such as irinotecan and 5-FU [8,9].

These results confirm that the mechanisms of action of STL001 are highly synergistic with the chemotherapeutic agents tested in the main study.

Using the CTRP (v2) database developed by the Broad institute [10] Omics Playground performed a meta-analysis based on the mechanisms of actions of the tested small molecules to identify mechanisms enhanced by exposure to STL001.
Figure 2. Using the CTRP (v2) database developed by the Broad institute [10] Omics Playground performed a meta-analysis based on the mechanisms of actions of the tested small molecules to identify mechanisms enhanced by exposure to STL001.

Synergy Between STL001 and Tetrandrine

The platform identified tetrandrine as having a similar expression profile to STL001 (Figure 3). Tetrandrine is a plant alkaloid with anti-cancer properties, but its potential synergy with STL001 relies on their complementary mechanisms:

  • Apoptosis induction: Both compounds enhance apoptosis, but through different pathways. Tetrandrine activates mitochondrial apoptotic pathways [11], while STL001 suppresses FOXM1-mediated survival signals.
  • Drug resistance reversal: Tetrandrine is known to reverse multidrug resistance (MDR) [11], which complements STL001’s ability to overcome FOXM1-driven resistance mechanisms.
  • Cell cycle regulation: Both compounds are known to induce suppression of cell cycle regulators [1,11], suggesting that they target similar oncogenic networks.

Given these shared properties, combining tetrandrine with STL001 could further increase therapeutic efficacy by targeting cancer cells at multiple vulnerabilities.

Gene set enrichment analysis against the Drug database contained in the Omics Playground platform indicates a strong correlation in gene expression profiles between STL001 and Tetrandrine.
Figure 3. Gene set enrichment analysis against the Drug database contained in the Omics Playground platform indicates a strong correlation in gene expression profiles between STL001 and Tetrandrine.

Conclusion

The Omics Playground platform has provided valuable insights into the broader implications of STL001’s activity. Its similarity to mTOR inhibitors highlights the potential for combination therapies targeting convergent signaling pathways. Furthermore, its ability to enhance cell cycle inhibition, apoptosis induction and DNA damage sensitivity fits perfectly with the chemotherapeutics tested in the study. Finally, its correlation with tetrandrine suggests a novel combination strategy worth exploring.

These findings highlight the versatility of STL001 as part of multimodal cancer therapies aimed at overcoming resistance and improving patient outcomes.

What next?

Insights from analyses on the Omics Playground platform provide new opportunities for subsequent investigations. Further exploration of additional therapeutic combinations may enable refinement of treatment strategies. For example, combining FOXM1 inhibition with mTOR inhibitors could effectively target overlapping signaling pathways, while combining with tetrandrine could increase STL001 activity and potentially reduce toxicity.

These insights pave the way for follow-up experiments to test these novel drug combinations in cell-based assays using RNA-seq, helping to validate their therapeutic potential.

Read more about follow-up experiment opportunities in Lexogen’s recent post about Overcoming Chemoresistance with Combination Strategies for Multimodal Cancer Therapies.

Key Takeaways

  • STL001 & mTOR Inhibitors: Omics Playground analysis shows STL001 shares expression profiles with mTOR/PI3K inhibitors, suggesting synergy in targeting cell growth and survival.
  • Enhanced Mechanisms: STL001 boosts cell cycle inhibition, apoptosis, and DNA damage sensitivity, complementing chemotherapeutic agents.
  • STL001 & Tetrandrine: Tetrandrine, an anti-cancer alkaloid, mirrors STL001’s profile, hinting at a promising combination strategy.
  • Follow-up Experiments: Omics Playground highlighted STL001’s potential in combination therapies which suggests how follow-up experiments can be designed to test novel drug combinations in cell-based assays using RNA-seq to validate their therapeutic potential. Read more about this in Lexogen’s latest article.

About BigOmics

BigOmics Analytics is a Swiss-based company that expedites tertiary RNA-Seq and proteomics data analysis, by providing a data discovery platform for scientists to efficiently scale their data analysis and obtain reproducible results. Through its collaborative analysis platform, Omics Playground, researchers can interactively analyze and share data and insights, fostering efficient collaboration. 

Curious about the insights Omics Playground can bring to your drug discovery project? Request a pilot here.

About Lexogen

Lexogen – Driving RNA Research in Drug Discovery. We develop innovative solutions for RNA sequencing that empower scientists to gain deeper insights into gene regulation and advance research in areas such as cancer, immunology, and neuroscience. Lexogen is a leading provider of kits, reagents and NGS services.

Our end-to-end solutions include whole transcriptome RNA-seq, (high-throughput) expression profiling, single-cell sequencing and DNA-seq – from sample preparation to data analysis. Lexogen’s expertise in RNA biology and commitment to quality and efficiency ensure accurate and reliable results to successfully advance your research.

Lexogen NGS Services has a proven track record in drug discovery and precision medicine, supporting projects across key stages including: target identification, pathway analysis, mode-of-action elucidation, biomarker discovery, immune profiling, and drug repurposing. We leverage advanced technologies like SLAMseq and LUTHOR to provide our clients with comprehensive and insightful data. 

Consult with us to discuss your specific research needs and explore how our innovative solutions can advance your drug discovery program.

About the Author

Axel Martinelli

Axel Martinelli’s academic background is in molecular biology and parasitology. He earned a Ph.D. on the genetics of strain-specific immunity against malaria infections and a master’s degree in bioinformatics with specialization in the analysis of omics data. During his postdoctoral career, he worked on genomics and transcriptomics studies and is currently the head of biology at Bigomics Analytics.

References

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  3. Xie J., Wang X. Proud C.G. mTOR inhibitors in cancer therapy. F1000Res. 2016 Aug 25;5:F1000 Faculty Rev-2078.
  4. Faivre, S., Kroemer, G., Raymond, E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 5, 671–688 (2006).
  5. Subramanian A., Narayan R., Corsello S.M. et al. A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles. Cell. 2017 Nov 30;171(6):1437-1452.e17.
  6. Jordan M.A. Mechanism of action of antitumour drugs that interact with microtubules and tubulin. Curr Med Chem Anti-Cancer Agents. 2002;2:1–17.
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  8. Rothenberg M.L. Irinotecan (CPT-11): recent developments and future directions–colorectal cancer and beyond. Oncologist. 2001;6(1):66-80.
  9. Adamsen B.L., Kravik K.L., De Angelis P.M. DNA damage signaling in response to 5-fluorouracil in three colorectal cancer cell lines with different mismatch repair and TP53 status. Int J Oncol. 2011 Sep;39(3):673-82.
  10. Seashore-Ludlow B., Rees M.G., Cheah J.H. et al. Harnessing Connectivity in a Large-Scale Small-Molecule Sensitivity Dataset. Cancer Discov. 2015 Nov;5(11):1210-23
  11. Liu T., Liu X, Li W. Tetrandrine, a Chinese plant-derived alkaloid, is a potential candidate for cancer chemotherapy. Oncotarget. 2016 Jun 28;7(26):40800-40815.