Study of a new therapeutic compound for the treatment of aggressive leiomyosarcoma

Despite advancements in treatments, cancer cure remains difficult due to the biological complexity of tumors and the development of resistance to therapies. This emphasises the urgent need for innovative drugs and therapeutic strategies. For advanced stages of cancer, treatments are predominantly palliative, aimed at symptom management and improving the quality of life. Such a challenge is leiomyosarcoma (LMS), a rare but highly aggressive tumor that accounts for 10-20% of all soft tissue sarcomas. Although surgical resection is the standard treatment for localized LMS, the high rate of recurrences and metastases presents generally poor prognoses. Combinations of drugs have been studied in clinical trials, but the efficacy resulted modest, further highlighting the need for new treatments. The rapid increase in cancer diagnoses has also resulted in an increased usage of chemotherapeutic agents over the last two decades. These drugs prevent cellular proliferation by disrupting DNA synthesis and thereby present a significant ecological risk. In the context of growing concerns about environmental impact, the development of eco-friendly therapies is crucial to mitigate adverse effects on ecological health while addressing the pressing need for effective cancer treatments. In our work we identified XMH95 as a potential new therapeutic agent against aggressive LMS. We demonstrated its selective cytotoxicity towards aggressive LMS cell lines, causing caspase-dependent apoptosis, while having cytostatic effects on less aggressive LMS cells and immortalized HUtSMC. To better understand its mechanism of action RNA-seq experiments were performed. The results showed that XMH95 upregulates inflammatory and antiviral genes, together with stress response pathways that induce apoptosis. While, the repressed genes are associated with ATP synthesis and mitochondrial respiration, indicating a disruption in energy metabolism and mitochondrial integrity, evidenced later by mitochondrial fragmentation. The mechanism of action includes upregulation of CDK inhibitors, which arrest the cell cycle. Additionally, it upregulates pro-apoptotic BH3-only genes such as PUMA, BIK, and NOXA, which trigger intrinsic apoptotic pathway and caspase activation. We also found that XMH95 exhibits fluorescence after UV light exposure and a nuclear localization similar to Hoechst. In silico predictions confirmed that XMH95 can bind the DNA minor groove. Despite sharing DNA-binding capabilities with Hoechst, XMH95 demonstrated superior cytotoxicity. Comparative gene expression analysis showed overlap in early responses, but XMH95 uniquely interferes with mitochondrial functions. Indeed, almost all mitochondrial genes were specifically repressed by the compound. Despite this, repression of mitochondrial functions alone is not enough to induce cell death, suggesting that additional factors are likely involved. Beyond LMS cells, XMH95 exerts its cytotoxicity also in colorectal cancer cells, establishing the possibility of a broad-spectrum application as an anti-neoplastic agent. In conclusion, our data seem promising for a new treatment against aggressive LMS, and likely against more diffused type of cancers.