ESTRO 2023 - Abstract Book

S916

Digital Posters

ESTRO 2023

to identify novel SMIs of Transgelin-2 and demonstrate the potential of these inhibitors in overcoming treatment resistance in GBM. Materials and Methods RNAi-mediated TAGLN2 knockdown (KD) approach was employed to assess the functions of Transgelin-2 in PDX GBM cell lines. Computational screening of NCI libraries was employed to identify SMIs that were able to bind to Transgelin-2. SMIs were screened for their ability to permeate BBB, using SwissADME webtool. A series of in vitro binding/functional assays were performed to measure their potential to bind and inhibit Transgelin-2-dependent functions in GBM 08-387 and -3359 PDX cell lines. Further, the potential of these inhibitors to sensitize GBM cells towards standard TMZ and/or RT was evaluated. Results TAGLN2 KD significantly inhibited proliferation, survival, clonal expansion, and invasion of GBM cell lines in vitro. We also found that Transgelin-2 KD significantly increased the sensitivity of these cells to both RT and TMZ in vitro. In-silico virtual screenings identified potential SMIs of Transgelin-2. In-silico analysis predicted SMIs that permeated BBB. In vitro binding studies confirmed that select SMIs were able to bind to Transgelin-2 with high affinity and inhibit the Transgelin-2 dependent actin-polymerization. Further, these SMIs significantly inhibited the proliferation, survival, migration/invasion and clonal expansion of GBM cells. Importantly, they did not exhibit toxicity to normal human cells (Normal Human Astrocytes, Human Lung Fibroblasts) in vitro. In addition, select SMIs reduced the level of Transgelin-2 protein in a dose- and time- dependent fashion in GBM cells. Our in vitro data also suggest that these inhibitors significantly sensitized GBM cell lines towards TMZ and/or RT in a dose- and time-dependent fashion. Conclusion Our data suggest that Transgelin-2 contributes to the proliferation, invasion and resistance to chemo-radiation treatment of PDX cells with wt-IDH1/2 in vitro. We identified novel SMIs of Transgelin-2 and validated their potential to bind and inhibit Transgelin-2 mediated functions in PDX cell lines without detectable toxicity in normal human cells, thereby serving as potential candidates for preclinical trials. S.L. Villa 1,2 , A. Fodor 1 , L. Ruffino 3 , C. Gigliotti 4 , F. Zerbetto 1 , I. Dell'Oca 1 , P. Mangili 4 , P.A. Passoni 1 , A. Del Vecchio 4 , L.R. Barzaghi 3 , P. Mortini 3,5 , S. Arcangeli 2 , N.G. Di Muzio 1,6 1 IRCCS San Raffaele Scientific Institute, Radiation Oncology, Milan, Italy; 2 University of Milano-Bicocca, Radiation Oncology, Milan, Italy; 3 IRCCS San Raffaele Scientific Institute, Neurosurgery, Milan, Italy; 4 IRCCS San Raffaele Scientific Institute, Medical Physic, Milan, Italy; 5 "Vita-Salute" San Raffaele University, Neurosurgery, Milan, Italy; 6 "Vita-Salute" San Raffaele University, Radiation Oncology, Milan, Italy Purpose or Objective To compare fractionated stereotactic radiotherapy with Gamma Knife (fGK) for complex meningiomas to helical IMRT/VMAT in terms of outcomes, prognostic factor and toxicity in a consecutive cohort of patients treated in single institution. Materials and Methods All patients treated in our institution for large or skull base meningiomas between 2015 and 2017 (radiologically or histologically diagnosed) with fGK in 3 fractions or conventionally fractionated helical IMRT/VMAT were retrospectively analyzed. Ten out of 110 patients identified, lost to follow-up, were excluded. The others were divided in two groups. Group 1 included 49 patients treated with fGK (Gamma Knife Perfexion™ ,Elekta, Stockholm, Sweden) in 3 fraction for a median total dose of 7Gy (5.5-9 Gy) prescribed at the 50% isodose of, to GTV (with no margins). Group 2 included 51 patients who underwent helical IMRT/VMAT with TomoTherapy® (Accuray, Maddison, WI, USA) or RapidArc™ (Varian, Palo Alto, CA, USA) in 27 (25-30) fractions with a median prescription dose of 50.4 Gy (46.8-60 Gy). Biologically equivalent dose (BED3) prescribed, considering α / β = 3 for meningioma, was 70 Gy (IQR 70)in group 1 and 80.64 (IQR: 77.76-90) in group 2. CTV was obtained with an isotropic expansion of 3-5mm of - GTV, then other 4-5 mm were added to obtain . Median GTV was 4.14 cc (IQR: 1.79-10.55), while median PTV 11.69 cc (IQR 65.5-147.66). Results All patients treated in our institution between 2015 and 2017 for large or skull base meningiomas (radiologically or histologically diagnosed) with fGK in 3 fractions or conventionally fractionated helical IMRT/VMAT were retrospectively analyzed. Ten out of 110 patients identified, lost to follow-up, were excluded. The others were divided in two groups. Group 1 included 49 patients treated with fGK (Gamma Knife Perfexion™ ,Elekta, Stockholm, Sweden) in 3 fraction for a median total dose of 7Gy (5.5-9 Gy) prescribed at the 50% isodose of, to GTV (with no margins). Group 2 included 51 patients who underwent helical IMRT/VMAT with TomoTherapy® (Accuray, Maddison, WI, USA) or RapidArc™ (Varian, Palo Alto, CA, USA) in 27 (25-30) fractions with a median prescription dose of 50.4 Gy (46.8-60 Gy). Biologically equivalent dose (BED3) prescribed, considering α / β = 3 for meningioma, was 70 Gy (IQR 70)in group 1 and 80.64 (IQR: 77.76-90) in group 2. CTV was obtained with an isotropic expansion of 3-5mm of - GTV, then other 4-5 mm were added to obtain . Median GTV was 4.14 cc (IQR: 1.79-10.55), while median PTV 11.69 cc (IQR 65.5-147.66). PO-1146 Fractionated Gamma Knife versus helical IMRT/VMAT in large or skull base meningioma