Integrative multi-Omic analysis of PEComa: biomarkers and novel therapeutic targets

Andrea Napolitano, MD, PhD,  Royal Marsden NHS Foundation Trust
Recipient of the: $50,000 Sarcoma Foundation of America Research Award

Perivascular Epithelioid Cell tumours (PEComas) are a group of ultra-rare mesenchymal tumours most commonly occurring in the 4th and 5th decade with a strong female predominance. Most PEComas have specific driver mutations in one of two genes called TSC1 and TSC2, making them potentially responsive to a class of drugs known as mTOR inhibitors. Other therapeutic options have very limited efficacy, and the median overall survival of patients with PEComa in the advanced setting is less than 3 years. Due to the rarity of this disease, large-scale “omic” analyses of specimens from PEComa patients with localized or metastatic disease have never been conducted before. There is therefore a significant gap in our knowledge of the molecular biology of PEComas, which translates into a lack of effective treatments and prognostic biomarkers. In particular, the molecular features of PEComas with various driver mutations are largely unknown, as well as those associated to disease relapse or metastatic dissemination. This proposal seeks to harness the power of comprehensive proteomic profiling by mass spectrometry as well as transcriptomic analysis by RNA sequencing to characterise, in unprecedented detail, the compendium of proteins and transcripts present in specimens from a cohort of PEComa patients. In particular, we will undertake a comparative analysis of primary surgical specimens (n=29) with different driver mutations (TSC1, TSC2, other) to identify functional pathways, potential biomarkers and new drug targets encoded within the PEComa proteome and transcriptome. In addition, we will investigate the role of tumour evolution in PEComa by evaluating a cohort of relapsed/metastatic specimens (n=17), which will also include a subset of samples with paired primary-relapsed/metastatic specimens (n=6) to discover if these lesions are molecularly different, with unique biology and targets. We will also perform a comparative analysis between our PEComa datasets and those from patients with other sarcoma subtypes, with the aim of identifying the specific signature that might predict responsiveness to mTOR inhibitors in other sarcoma patients. By providing the first-ever proteomic and transcriptomic portraits detailing the molecular pathways in PEComas, this project will address an existing knowledge gap in our understanding of the biology and clinical course of this disease. We anticipate that this study will deliver direct impact on improving outcomes of patient with PEComas by providing new candidate treatment options and prognostic biomarkers for patient stratification. The impact of our proposal will also extend to patients affected by other sarcoma subtypes, providing biomarkers of sensitivity to mTOR inhibitors.