Cellular proliferation and tumor suppression pathways as potential targets in clinically aggressive sarcomas.

Abstract

e23551 Background: Sarcomas are rare, heterogeneous, and aggressive malignancies with poor prognosis, driven by dysregulated proliferation pathways (e.g., CDK4/6, c-Myc) and impaired tumor suppression mechanisms (e.g., CDKN2A/p16INK4a-RB, p14ARF-MDM2-p53). These genetic alterations result in uncontrolled growth, metastasis, and therapy resistance. Emerging therapies targeting these pathways, such as CDK4/6 inhibitors and MDM2 antagonists, show promise. Furthermore, genomic testing can provide insights into mesenchymal stem cell-derived sarcomagenesis and oncogenic microenvironmental interactions providing new opportunities for precision-based treatments. This study investigates molecular pathways in aggressive sarcomas which could assist in expanding targeted treatment options beyond the current common genetic fusions. Methods: Retrospectively, we investigated the comprehensive genomic profiling of 10 sarcoma patients including subtypes leiomyosarcoma(n=2), ewing sarcoma(n=1), metastatic angiosarcoma(n=2), extraskeletal myxoid chondrosarcoma(n=1), pleomorphic liposarcoma(n=1), retroperitoneal leiomyosarcoma(n=1), soft tissue sarcoma(n=1) and differentiated spindle cell sarcoma(n=1) at different disease stages including progressive, metastatic, and recurrent disease types. Next Generation Sequencing (NGS) test was performed using OncoIndx Assay (Shafi et al., 2024). Results: The study cohort comprised 10 sarcoma patients, including males (n=6) and females (n=4). Disease stages included progressive (n=4), metastatic (n=3), and recurrent (n=3), as identified through PET scans and histopathological examination (HPE). Recent therapeutic regimen predominantly included chemotherapy (Eribulin, Palliative chemo, Trabectedin, Gem + Docetaxel), combined therapy (Paclitaxel + Pembro, Pazopanib + DCT), and surgery. Primary genomic findings highlighted the impairment of two critical pathways including cell proliferation (n=3/10) and tumor suppression (n=4/10). Further, no genomic alteration was detected in three patients despite aggressive disease as per PET/HPE findings. In addition, genomic findings from three patients also exhibited a high tumor mutation burden (TMB) thereby expanding their possibilities to immunotherapy. Conclusions: This study highlights the utility of comprehensive genomic profiling in broadening the scope of treatment by highlighting the exact drivers for and disease aggressiveness in sarcomas. The presence of genomic alterations in cell proliferation and tumor suppression pathways could also be early indicators of disease aggressiveness if closely monitored. With only a few selected fusions currently crucial in sarcomas, this study extends the molecular repertoire for practice. Also, additional analysis like RNA sequencing might be more beneficial in such scenarios.