Combining Snail-mediated EMT targeting with chemotherapy as a potential treatment strategy for prostate and breast cancer

Goal

To identify a biomolecule at the intersection of epithelial-to-mesenchymal transition (EMT), metastasis, and chemoresistance, and develop a therapeutic strategy by targeting the biomolecule using a small molecule drug in combination with chemotherapy.

Contribution

I conceived and designed the project, identifying Snail as a biomolecule implicated in EMT, metastasis, and chemoresistance through an extensive literature review and database analysis. Despite Snail being considered undruggable due to its unfavorable surface topology as a transcription factor, I leveraged insights from a seminal study to validate a small molecule fragment targeting Snail via computational solvent mapping. Using this fragment, I screened FDA-approved drugs and identified Remdesivir as a potential inhibitor. I evaluated the cytotoxicity of Remdesivir in combination with Docetaxel or Doxorubicin in sequential therapy against cancer cells. Further investigations included assessing the impact of Remdesivir on metastatic prostate (PC3) and triple-negative breast cancer (4T1 and MDA-MB-231) cells at the protein and RNA levels. I also evaluated morphological changes, invasive and migratory potential, and explored the synergistic action of the drug combination through apoptosis and ROS-mediated apoptosis analysis. Additionally, I conducted in vivo studies to investigate the therapeutic efficacy of the combination therapy.

Results

The combination treatment demonstrated synergistic cytotoxicity. Targeting Snail with Remdesivir led to reduced Snail protein expression, accompanied by decreased EMT, metastasis, and chemoresistance markers. Cancer cells exhibited diminished migratory and invasive potential. In vivo studies showed significant tumor regression in the combination treatment group compared to control and single-treatment groups. Further investigations are ongoing.

Impacts

Metastasis accounts for approximately 90% of cancer-related deaths, with EMT playing a pivotal role in this process. Chemoresistance further exacerbates metastatic potential, making these areas critical targets in cancer therapy. Snail, as a key player in these processes, presents unique challenges due to its undruggable nature. This study addresses these challenges by repurposing Remdesivir, an FDA-approved drug, which saves time and resources compared to developing new molecules. The findings demonstrate that Remdesivir effectively targets Snail and enhances the efficacy of chemotherapeutic drugs, offering a promising therapeutic strategy to improve cancer treatment outcomes.

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