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Evaluation of the SSTR2-targeted radiopharmaceutical 177Lu-DOTATATE and SSTR2-specific 68Ga-DOTATATE PET as imaging biomarker in patients with intracranial meningioma

Kurz, Sylvia C; Zan, Elcin; Cordova, Christine; Troxel, Andrea B; Barbaro, Marissa; Silverman, Joshua S; Snuderl, Matija; Zagzag, David; Kondziolka, Douglas; Golfinos, John G; Chi, Andrew S; Sulman, Erik P
BACKGROUND:There are no effective medical therapies for patients with meningioma who progress beyond surgical and radiotherapeutic interventions. Somatostatin receptor Type 2 (SSTR2) represents a promising treatment target in meningiomas. In this multicenter, single-arm phase II clinical study (NCT03971461), the SSTR2-targeting radiopharmaceutical 177Lu-DOTATATE is evaluated for its feasibility, safety, and therapeutic efficacy in these patients. PATIENTS AND METHODS/METHODS:Adult patients with progressive intracranial meningiomas received 177Lu-DOTATATE at a dose of 7.4 GBq (200 mCi) every eight weeks for four cycles. 68Ga-DOTATATE PET-MRI was performed before and six months after begin of treatment. The primary endpoint was progression-free survival (PFS) at 6 months (PFS-6). Secondary endpoints were safety and tolerability, overall survival (OS) at 12 months (OS-12), median PFS, and median OS. RESULTS:Fourteen patients (F=11, M=3) with progressive meningiomas (WHO 1=3, 2=10, 3=1) were enrolled. Median age was 63.1 (range 49.7-78) years. All patients previously underwent tumor resection and at least one course of radiation. Treatment with 177Lu-DOTATATE was well tolerated. Seven patients (50%) achieved PFS-6. Best radiographic response by modified Macdonald criteria was stable disease (SD) in all seven patients. A >25% reduction in 68Ga-DOTATATE (PET) was observed in five meningiomas and two patients. In one lesion, this corresponded to >50% reduction in bidirectional tumor measurements (MRI). CONCLUSIONS:Treatment with 177Lu-DOTATATE was well tolerated. The predefined PFS-6 threshold was met in this interim analysis, thereby allowing this multicenter clinical trial to continue enrollment. 68Ga-DOTATATE PET may be a useful imaging biomarker to assess therapeutic outcome in patients with meningioma.
PMID: 38048045
ISSN: 1557-3265
CID: 5595302

Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways

Venneti, Sriram; Kawakibi, Abed Rahman; Ji, Sunjong; Waszak, Sebastian M; Sweha, Stefan R; Mota, Mateus; Pun, Matthew; Deogharkar, Akash; Chung, Chan; Tarapore, Rohinton S; Ramage, Samuel; Chi, Andrew; Wen, Patrick Y; Arrillaga-Romany, Isabel; Batchelor, Tracy T; Butowski, Nicholas A; Sumrall, Ashley; Shonka, Nicole; Harrison, Rebecca A; de Groot, John; Mehta, Minesh; Hall, Matthew D; Daghistani, Doured; Cloughesy, Timothy F; Ellingson, Benjamin M; Beccaria, Kevin; Varlet, Pascale; Kim, Michelle M; Umemura, Yoshie; Garton, Hugh; Franson, Andrea; Schwartz, Jonathan; Jain, Rajan; Kachman, Maureen; Baum, Heidi; Burant, Charles F; Mottl, Sophie L; Cartaxo, Rodrigo T; John, Vishal; Messinger, Dana; Qin, Tingting; Peterson, Erik; Sajjakulnukit, Peter; Ravi, Karthik; Waugh, Alyssa; Walling, Dustin; Ding, Yujie; Xia, Ziyun; Schwendeman, Anna; Hawes, Debra; Yang, Fusheng; Judkins, Alexander R; Wahl, Daniel; Lyssiotis, Costas A; de la Nava, Daniel; Alonso, Marta M; Eze, Augustine; Spitzer, Jasper; Schmidt, Susanne V; Duchatel, Ryan J; Dun, Matthew D; Cain, Jason E; Jiang, Li; Stopka, Sylwia A; Baquer, Gerard; Regan, Michael S; Filbin, Mariella G; Agar, Nathalie Y R; Zhao, Lili; Kumar-Sinha, Chandan; Mody, Rajen; Chinnaiyan, Arul; Kurokawa, Ryo; Pratt, Drew; Yadav, Viveka N; Grill, Jacques; Kline, Cassie; Mueller, Sabine; Resnick, Adam; Nazarian, Javad; Allen, Joshua E; Odia, Yazmin; Gardner, Sharon L; Koschmann, Carl
UNLABELLED:Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. SIGNIFICANCE:The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293.
PMCID:10618742
PMID: 37584601
ISSN: 2159-8290
CID: 5626362

CLINICAL EFFICACY AND PREDICTIVE BIOMARKERS OF ONC201 IN H3K27M-MUTANT DIFFUSE MIDLINE GLIOMA [Meeting Abstract]

Kawakibi, A R; Tarapore, R; Gardner, S; Chi, A; Kurz, S; Wen, P Y; Arrillaga-Romany, I; Batchelor, T; Butowski, N; Sumrall, A; Shonka, N; Harrison, R; DeGroot, J; Mehta, M; Odia, Y; Hall, M; Daghistani, D; Cloughesy, T; Ellingson, B; Kim, M; Umemura, Y; Garton, H; Franson, A; Schwartz, J; Li, S; Cartaxo, R; Ravi, K; Cantor, E; Cummings, J; Paul, A; Walling, D; Dun, M; Cain, J; Li, J; Filbin, M; Zhao, L; Kumar-Sinha, C; Mody, R; Chinnaiyan, A; Kurokawa, R; Pratt, D; Venneti, S; Grill, J; Kline, C; Mueller, S; Resnick, A C; Nazarian, J; Waszak, S; Allen, J E; Koschmann, C
Patients with H3K27M-mutated diffuse midline glioma (DMG) have no proven effective therapies beyond radiation. ONC201, a DRD2 antagonist and mitochondrial ClpP agonist, has shown promise in this population. Clinical and genetic variables associated with ONC201 response in H3K27M-mutant DMG continue to be investigated. A combined clinical and genetic study evaluated patients with H3K27M-DMG treated with single-agent ONC201 at the established phase 2 dose. Clinical outcomes of patients treated on two recently completed multi-site clinical studies (NCT03416530 and NCT03134131, n = 75) were compared with historical control data from patients with confirmed H3K27M-DMG (n = 391 total, n = 119 recurrent). Patients treated with ONC201 monotherapy following initial radiation, but prior to recurrence, demonstrated a median overall survival (OS) of 25.6 months from diagnosis and recurrent patients demonstrated a median OS of 16.2 months from recurrence, both of these more than doubling historical outcomes. Using a Cox model to correct for age, gender and tumor location, OS of ONC201-treated patients with H3K27M-mutant tumors remained significantly better than non-ONC201-treated historical controls (p = 0.0001). A survival and radiographic analysis based on tumor location, revealed stronger responses in thalamic patients. In patients with thalamic tumors treated after initial radiation (n = 16), median OS was not reached with median follow up of 22.1 months (historical control median OS of 12.5 months, n = 83, p = 0.0001). Significant correlations were found between baseline cerebral blood flow (CBF) on perfusion imaging and OS (Pearson's r = 0.75, p = 0.003) and between nrCBF and PFS (r = 0.77, p = 0.002). Baseline tumor sequencing from treated patients (n = 20) demonstrates EGFR mutation (n = 3) and high EGFR expression as a marker of resistance and improved response in tumors with MAPK-pathway alterations (n = 5). In conclusion, ONC201 demonstrates unprecedented clinical and radiographic efficacy in H3K27M-mutant DMG with outcomes enriched in patients with thalamic tumors, treatment prior to recurrence, MAPKpathway alterations, and patients with relatively high CBF
EMBASE:639939966
ISSN: 1523-5866
CID: 5513292

Radiogenomics identifying important biological pathways in gliomas [Comment]

Jain, Rajan; Chi, Andrew S
PMID: 33630091
ISSN: 1523-5866
CID: 4835732

Dissecting the immunosuppressive tumor microenvironments in Glioblastoma-on-a-Chip for optimized PD-1 immunotherapy

Cui, Xin; Ma, Chao; Vasudevaraja, Varshini; Serrano, Jonathan; Tong, Jie; Peng, Yansong; Delorenzo, Michael; Shen, Guomiao; Frenster, Joshua; Morales, Renee-Tyler Tan; Qian, Weiyi; Tsirigos, Aristotelis; Chi, Andrew S; Jain, Rajan; Kurz, Sylvia C; Sulman, Erik P; Placantonakis, Dimitris G; Snuderl, Matija; Chen, Weiqiang
Programmed cell death protein-1 (PD-1) checkpoint immunotherapy efficacy remains unpredictable in glioblastoma (GBM) patients due to the genetic heterogeneity and immunosuppressive tumor microenvironments. Here, we report a microfluidics-based, patient-specific 'GBM-on-a-Chip' microphysiological system to dissect the heterogeneity of immunosuppressive tumor microenvironments and optimize anti-PD-1 immunotherapy for different GBM subtypes. Our clinical and experimental analyses demonstrated that molecularly distinct GBM subtypes have distinct epigenetic and immune signatures that may lead to different immunosuppressive mechanisms. The real-time analysis in GBM-on-a-Chip showed that mesenchymal GBM niche attracted low number of allogeneic CD154+CD8+ T-cells but abundant CD163+ tumor-associated macrophages (TAMs), and expressed elevated PD-1/PD-L1 immune checkpoints and TGF-β1, IL-10, and CSF-1 cytokines compared to proneural GBM. To enhance PD-1 inhibitor nivolumab efficacy, we co-administered a CSF-1R inhibitor BLZ945 to ablate CD163+ M2-TAMs and strengthened CD154+CD8+ T-cell functionality and GBM apoptosis on-chip. Our ex vivo patient-specific GBM-on-a-Chip provides an avenue for a personalized screening of immunotherapies for GBM patients.
PMID: 32909947
ISSN: 2050-084x
CID: 4589392

'Real world' use of a highly reliable imaging sign: 'T2-FLAIR mismatch' for identification of IDH mutant astrocytomas

Jain, Rajan; Johnson, Derek R; Patel, Sohil H; Castillo, Mauricio; Smits, Marion; Bent, Martin J van den; Chi, Andrew S; Cahill, Daniel P
The T2-FLAIR mismatch sign is an easily detectable imaging sign on routine clinical MRI studies that suggests diagnosis of IDH-mutant 1p/19q non-codeleted gliomas. Multiple independent studies show that the T2-FLAIR mismatch sign has near-perfect specificity, but low sensitivity, for diagnosing IDH-mutant astrocytomas. Thus, the T2-FLAIR mismatch sign represents a non-invasive radiogenomic diagnostic finding with potential clinical impact. Recently, false positive cases have been reported, many related to variable application of the sign's imaging criteria, differences in image acquisition as well as to differences in the included patient populations. Here we summarize the imaging criteria for the T2-FLAIR mismatch sign, review similarities and differences between the multiple validation studies, outline strategies to optimize its clinical use, and discuss potential opportunities to refine imaging criteria in order to maximize its impact in glioma diagnostics.
PMID: 32064507
ISSN: 1523-5866
CID: 4313062

Expression profiling of the adhesion G protein-coupled receptor GPR133 (ADGRD1) in glioma subtypes

Frenster, Joshua D; Kader, Michael; Kamen, Scott; Sun, James; Chiriboga, Luis; Serrano, Jonathan; Bready, Devin; Golub, Danielle; Ravn-Boess, Niklas; Stephan, Gabriele; Chi, Andrew S; Kurz, Sylvia C; Jain, Rajan; Park, Christopher Y; Fenyo, David; Liebscher, Ines; Schöneberg, Torsten; Wiggin, Giselle; Newman, Robert; Barnes, Matt; Dickson, John K; MacNeil, Douglas J; Huang, Xinyan; Shohdy, Nadim; Snuderl, Matija; Zagzag, David; Placantonakis, Dimitris G
Background/UNASSIGNED:Glioma is a family of primary brain malignancies with limited treatment options and in need of novel therapies. We previously demonstrated that the adhesion G protein-coupled receptor GPR133 (ADGRD1) is necessary for tumor growth in adult glioblastoma, the most advanced malignancy within the glioma family. However, the expression pattern of GPR133 in other types of adult glioma is unknown. Methods/UNASSIGNED:We used immunohistochemistry in tumor specimens and non-neoplastic cadaveric brain tissue to profile GPR133 expression in adult gliomas. Results/UNASSIGNED:We show that GPR133 expression increases as a function of WHO grade and peaks in glioblastoma, where all tumors ubiquitously express it. Importantly, GPR133 is expressed within the tumor bulk, as well as in the brain-infiltrating tumor margin. Furthermore, GPR133 is expressed in both isocitrate dehydrogenase (IDH) wild-type and mutant gliomas, albeit at higher levels in IDH wild-type tumors. Conclusion/UNASSIGNED:The fact that GPR133 is absent from non-neoplastic brain tissue but de novo expressed in glioma suggests that it may be exploited therapeutically.
PMCID:7262742
PMID: 32642706
ISSN: 2632-2498
CID: 4517542

Exploring Predictors of Response to Dacomitinib in EGFR-Amplified Recurrent Glioblastoma

Chi, Andrew S; Cahill, Daniel P; Reardon, David A; Wen, Patrick Y; Mikkelsen, Tom; Peereboom, David M; Wong, Eric T; Gerstner, Elizabeth R; Dietrich, Jorg; Plotkin, Scott R; Norden, Andrew D; Lee, Eudocia Q; Nayak, Lakshmi; Tanaka, Shota; Wakimoto, Hiroaki; Lelic, Nina; Koerner, Mara V; Klofas, Lindsay K; Bertalan, Mia S; Arrillaga-Romany, Isabel C; Betensky, Rebecca A; Curry, William T; Borger, Darrel R; Balaj, Leonora; Kitchen, Robert R; Chakrabortty, Sudipto K; Valentino, Michael D; Skog, Johan; Breakefield, Xandra O; Iafrate, A John; Batchelor, Tracy T
PURPOSE/OBJECTIVE:gene amplification, which occurs in approximately half of GBM, with dacomitinib, a second-generation, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that penetrates the blood-brain barrier, in a multicenter phase II trial. PATIENTS AND METHODS/METHODS:gene amplification could predict response to dacomitinib, and in a predefined subset of patients, we measured post-treatment intratumoral dacomitinib levels to verify tumor penetration. RESULTS:ECD missense mutation was not associated with clinical benefit. We evaluated the pretreatment transcriptome in circulating extracellular vesicles (EVs) by RNA sequencing in a subset of patients and identified a signature that distinguished patients who had durable benefit versus those with rapid progression. CONCLUSION/CONCLUSIONS:ECD mutation status in archival tumors did not predict clinical benefit. RNA signatures in circulating EVs may warrant investigation as biomarkers of dacomitinib efficacy in GBM.
PMCID:7446412
PMID: 32923886
ISSN: 2473-4284
CID: 4592502

CLINICAL EFFICACY AND PREDICTIVE BIOMARKERS OF ONC201 IN H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMA [Meeting Abstract]

Kawakibi, Abed Rahman; Tarapore, Rohinton S.; Gardner, Sharon; Thomas, Chase; Cartaxo, Rodrigo; Yadav, Viveka Nand; Chi, Andrew; Kurz, Sylvia; Wen, Patrick; Arrillaga-Romany, Isabel; Batchelor, Tracy; Butowski, Nicholas; Sumrall, Ashley; Shonka, Nicole; Harrison, Rebecca; de Groot, John; Mehta, Minesh; Odia, Yazmin; Hall, Matthew; Daghistani, Doured; Cloughesy, Timothy; Ellingson, Benjamin; Umemura, Yoshie; Garton, Hugh; Franson, Andrea; Robertson, Patricia; Schwartz, Jonathan; Cantor, Evan; Miklja, Zachary; Mullan, Brendan; Bruzek, Amy; Siada, Ruby; Cummings, Jessica; Paul, Alyssa; Wolfe, Ian; Jiang, Li; Filbin, Mariella; Vats, Pankaj; Kumar-Sinha, Chandan; Mody, Rajen; Chinnaiyan, Arul; Venneti, Sriram; Lu, Guangrong; Mueller, Sabine; Martinez, Daniel; Resnick, Adam; Nazarian, Javad; Waszak, Sebastian; Allen, Joshua; Koschmann, Carl
ISI:000590061300185
ISSN: 1522-8517
CID: 4688082

EFFICACY OF ONC201 IN PATIENTS WITH ONC201 FOR RECURRENT H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMA [Meeting Abstract]

Arrillaga-Romany, Isabel; Kurz, Sylvia; Tarapore, Rohinton S.; Sumrall, Ashley; Butowski, Nicholas; Harrison, Rebecca; de Groot, John; Chi, Andrew; Shonka, Nicole; Umemura, Yoshie; Odia, Yazmin; Mehta, Minesh; Nghiemphu, Phioanh; Cloughesy, Timothy; Taylor, Lynne; Graber, Jerome; Kilburn, Lindsay; Dixit, Karan; Lu, Guangrong; Allen, Joshua; Batchelor, Tracy; Lassman, Andrew; Wen, Patrick
ISI:000590061300205
ISSN: 1522-8517
CID: 4688092