Abstract 4156: Molecular profiling of ovarian cancer by targeted proteomics to inform personalized therapy
Authors: Sheeno P. Thyparambil, Wei-Li Liao, Eunkyung An, Anuja Bhalkikar, Thomas Guiel, Robert Heaton
Journal: Cancer Research (2020)

Abstract Chemotherapy is the mainstay for the treatment of ovarian cancer. Taxanes, platinum salts, 5-FU, anthracyclines, gemcitabine are used extensively in ovarian cancer, however, there is no biomarker of chemotherapy that is routinely used. We examined 169 ovarian cancer samples using targeted proteomics for biomarkers of response or resistance to chemotherapy agents. Biomarkers of resistance include ERCC1 (Platinum), TUBB3 (taxanes), ALDH1A1 (cyclophosphamide) while response biomarkers include TOPO1 (irinotecan, topotecan), TOPO2A (doxorubicin, epirubicin), hENT1 (Gemcitabine).We also measure markers for several antibody-drug conjugates (FR-alpha, Her2, Trop2, gPNMB, MSLN). Methods: Tumor areas from Formalin-fixed, paraffin-embedded (FFPE) tumor tissues from clinical samples of ovarian cancer that were received at our CLIA certified laboratory were microdissected and a selected reaction monitoring mass spectrometry (SRM-MS) quantitative proteomic analysis of 72 biomarkers were conducted. Discussion: The majority of ovarian cancer samples expressed a range of resistance markers for cyclophosphamide (ALDH1A1: 87% positive ranging from 227-10766 amol/µg), platinum agents (70% positive) and taxanes (71%positive). However, they also expressed a range of response biomarkers for chemotherapies that are conventionally used to treat ovarian cancer. These include irinotecan/topotecan (TOPO1: 97% positive ranging from 459 -3299), doxorubicin (TOPO2A: 50% positive ranging from 402-3825 amol/µg), gemcitabine (hENT1/RRM1: 42% positive). Novel chemotherapy agents that could potentially be used include temozolomide (40% of patients did not express MGMT, resistance marker for temozolomide). The vast majority (78%) of ovarian cancer samples did not express any drug efflux pump proteins MRP and MDR1. Examination of potential ADC markers revealed 74% positivity for the antibody target FR-alpha with a 42 fold range of expression (585 -25000 amol/µg) and 71% positivity for the payload resistance marker TUBB3. Similarly, Trop2 (56% positivity) exhibited a wide dynamic range (222-12778 amol/µg). Another ADC target mesothelin was expressed in 66% of the cases with a 35x range of expression (302 - 10,700 amol/µg). While 56% of ovarian cancer expressed Her2 (262 -5011 amol/µg), only 4% expressed high levels of Her2 (&amp;gt;750 amol/µg), making them suitable for current anti-Her2 therapy. Others could potentially benefit from clinical trials targeting low Her2 expression. The ability to multiplex 72 protein biomarkers from 2-3 FFPE sections provides immense actionable information on clinical treatment or for patient stratification for clinical trials. Citation Format: Sheeno P. Thyparambil, Wei-Li Liao, Eunkyung An, Anuja Bhalkikar, Thomas Guiel, Robert Heaton. Molecular profiling of ovarian cancer by targeted proteomics to inform personalized therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4156.