tbuckley/cabot-search huggingface dataset:
Mechanistic definition of the cardiovascular mPGES-1/COX-2/ADMA axis
Authors: Nicholas S Kirkby, Joan Raouf, Blerina Ahmetaj-Shala, Bin Liu, Sarah I Mazi, Matthew L Edin, Mark Geoffrey Chambers, Marina Korotkova, Xiaomeng Wang, Walter Wahli, Darryl C Zeldin, Rolf Nüsing, Yingbi Zhou, Per-Johan Jakobsson, Jane A Mitchell
Journal: Cardiovascular Research (2019)

Abstract Aims Cardiovascular side effects caused by non-steroidal anti-inflammatory drugs (NSAIDs), which all inhibit cyclooxygenase (COX)-2, have prevented development of new drugs that target prostaglandins to treat inflammation and cancer. Microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors have efficacy in the NSAID arena but their cardiovascular safety is not known. Our previous work identified asymmetric dimethylarginine (ADMA), an inhibitor of endothelial nitric oxide synthase, as a potential biomarker of cardiovascular toxicity associated with blockade of COX-2. Here, we have used pharmacological tools and genetically modified mice to delineate mPGES-1 and COX-2 in the regulation of ADMA. Methods and results Inhibition of COX-2 but not mPGES-1 deletion resulted in increased plasma ADMA levels. mPGES-1 deletion but not COX-2 inhibition resulted in increased plasma prostacyclin levels. These differences were explained by distinct compartmentalization of COX-2 and mPGES-1 in the kidney. Data from prostanoid synthase/receptor knockout mice showed that the COX-2/ADMA axis is controlled by prostacyclin receptors (IP and PPARβ/δ) and the inhibitory PGE2 receptor EP4, but not other PGE2 receptors. Conclusion These data demonstrate that inhibition of mPGES-1 spares the renal COX-2/ADMA pathway and define mechanistically how COX-2 regulates ADMA.
GENE-17. ATRX LOSS IN GLIOMA RESULTS IN EPIGENETIC DYSREGULATION OF THE G2/M CHECKPOINT AND SENSITIVITY TO ATM INHIBITION
Authors: Brendan Mullan, Tingting Qin, Ruby Siada, Ramya Ravindran, Taylor Garcia, Ashwath Muruganand, Micah Harris, Carla Danussi, Jacqueline Brosnan-Cashman, Drew Pratt, Xinyi Zhao, Alnawaz Rehemtulla, Maureen Sartor, Sriram Venneti, Alan Meeker, Jason Huse, Meredith Morgan, Pedro Lowenstein, Maria Castro, Vivekanand Yadav, Carl Koschmann
Journal: Neuro-Oncology (2019)

Abstract Gliomas are a leading cause of cancer mortality in children and adults and new targeted therapies are desperately needed. ATRX is a chromatin remodeling protein that is recurrently mutated in H3F3A-mutant pediatric GBM and IDH-mutant grade 2/3 adult glioma. We previously showed that loss of ATRX in glioma results in tumor growth and additional tumor mutations. However, the mechanism driving these phenotypes has not been fully established. We found that in ChIP-Seq datasets of mouse neuronal precursor cells (NPCs) and experimental models of human glioma cells, ATRX binds and regulates the chromatin state of promoters and enhancers for gene sets associated with regulation of the cell cycle G2/M checkpoint. In line with this, analysis of single-cell seq (sc-seq) data from IDH-mutant gliomas (n=16) shows that ATRX-mutant tumors (IDH-A) demonstrate a population of cycling cells with dysregulated cell cycle phase gene set expression when compared to ATRX-wildtype tumors (IDH-O). In glioma models, ATRX-deficient cells exhibit a seven-fold increase in mitotic index at 16 hours after sub-lethal radiation and enhanced activation of the master cell cycle regulator ATM with radiation. Treatment of ATRX-deficient gliomas with ATM inhibitors results in a selective increase in dysfunctional cell cycling and increased radio-sensitization in ATRX-deficient glioma cells. Using an ATM-luciferase reporter in orthotopically-implanted human GBM cells, both AZD0156 and AZD1390 demonstrate in vivo pathway inhibition. Mice intra-cranially implanted with ATRX-deficient GBM cells demonstrate a doubling of median survival compared to radiated controls (p=0.0018) when treated with AZD0156 combined with radiation. This study demonstrates that ATRX-deficient glioma display epigenetic dysregulation of the G2/M checkpoint, which opens a new window for therapies targeting this unique phenotype.
Steroid Metabolomic Signature of Insulin Resistance in Childhood Obesity
Authors: Aneta M. Gawlik, Michael Shmoish, Michaela F. Hartmann, Stefan A. Wudy, Ze’ev Hochberg
Journal: Diabetes Care (2019)

OBJECTIVE On the basis of urinary steroidal gas chromatography-mass spectrometry (GC-MS), we previously defined a novel concept of a disease-specific “steroid metabolomic signature” and reclassified childhood obesity into five groups with distinctive signatures. The objective of the current study was to delineate the steroidal signature of insulin resistance (IR) in obese children. RESEARCH DESIGN AND METHODS Urinary samples of 87 children (44 girls) aged 8.5–17.9 years with obesity (BMI &amp;gt;97th percentile) were quantified for 31 steroid metabolites by GC-MS. Defined as HOMA-IR &amp;gt;95th percentile and fasting glucose-to-insulin ratio &amp;gt;0.3, IR was diagnosed in 20 (of 87 [23%]) of the examined patients. The steroidal fingerprints of subjects with IR were compared with those of obese children without IR (non-IR). The steroidal signature of IR was created from the product of IR − non-IR for each of the 31 steroids. RESULTS IR and non-IR groups of children had comparable mean age (13.7 ± 1.9 and 14.6 ± 2.4 years, respectively) and z score BMI (2.7 ± 0.5 and 2.7 ± 0.5, respectively). The steroidal signature of IR was characterized by high adrenal androgens, glucocorticoids, and mineralocorticoid metabolites; higher 5α-reductase (An/Et) (P = 0.007) and 21-hydroxylase [(THE + THF + αTHF)/PT] activity (P = 0.006); and lower 11βHSD1 [(THF + αTHF)/THE] activity (P = 0.012). CONCLUSIONS The steroidal metabolomic signature of IR in obese children is characterized by enhanced secretion of steroids from all three adrenal pathways. As only the fasciculata and reticularis are stimulated by ACTH, these findings suggest that IR directly affects the adrenals. We suggest a vicious cycle model, whereby glucocorticoids induce IR, which could further stimulate steroidogenesis, even directly. We do not know whether obese children with IR and the new signature may benefit from amelioration of their hyperadrenalism.
Endothelial <i>Cdk5</i> deficit leads to the development of spontaneous epilepsy through CXCL1/CXCR2-mediated reactive astrogliosis
Authors: Xiu-xiu Liu, Lin Yang, Ling-xiao Shao, Yang He, Gang Wu, Yu-huan Bao, Nan-nan Lu, Dong-mei Gong, Ya-ping Lu, Tian-tian Cui, Ning-he Sun, Dan-yang Chen, Wei-xing Shi, Kohji Fukunaga, Hong-shan Chen, Zhong Chen, Feng Han, Ying-mei Lu
Journal: The Journal of Experimental Medicine (2019)

Blood–brain barrier (BBB) dysfunction has been suggested to play an important role in epilepsy. However, the mechanism mediating the transition from cerebrovascular damage to epilepsy remains unknown. Here, we report that endothelial cyclin-dependent kinase 5 (CDK5) is a central regulator of neuronal excitability. Endothelial-specific Cdk5 knockout led to spontaneous seizures in mice. Knockout mice showed increased endothelial chemokine (C-X-C motif) ligand 1 (Cxcl1) expression, decreased astrocytic glutamate reuptake through the glutamate transporter 1 (GLT1), and increased glutamate synaptic function. Ceftriaxone restored astrocytic GLT1 function and inhibited seizures in endothelial Cdk5-deficient mice, and these effects were also reversed after silencing Cxcl1 in endothelial cells and its receptor chemokine (C-X-C motif) receptor 2 (Cxcr2) in astrocytes, respectively, in the CA1 by AAV transfection. These results reveal a previously unknown link between cerebrovascular factors and epileptogenesis and provide a rationale for targeting endothelial signaling as a potential treatment for epilepsy.
Constitutively Activated STAT3 Induces the Production of PTX3 That Contributes to the Induction of Bone Marrow Reticulin Fibrosis in Patient with CLL
Authors: Uri Rozovski, David M. Harris, Ping Li, Zhiming Liu, Taghi Manshouri, Ivo Veletic, Preetesh Jain, Alessandra Ferrajoli, Jan A. Burger, Prithviraj Bose, Philip A. Thompson, Nitin Jain, Srdan Verstovsek, William G. Wierda, Michael J Keating, Zeev E. Estrov
Journal: Blood (2019)
High Frequencies of Mutated EZH2 and IRF8 and Other Epigenetic Genes in Primary Bone Lymphomas Are Indicative of GCB-Phenotype
Authors: Ruben A.L. De Groen, Ronald Van Eijk, Tom van Wezel, Richard Raghoo, Anne-Roos Schrader, Patty M. Jansen, Inge briaire-De Bruijn, Karin Kleiverda, Tom Vlasveld, Valeska Terpstra, Henriette Levenga, Aline Nicolae, Ward Posthuma, Isabelle Focke-Snieders, Lizan Hardi, Wietske den Hartog, Anke Van Den Berg, Arjan Diepstra, Pieternella Lugtenburg, Marie José Kersten, Steven T Pals, Hendrik Veelken, Judith Bovée, Arjen Cleven, Joost Vermaat
Journal: Blood (2019)
ABC of diabetes: The diabetic foot
Authors: Peter J Watkins
Journal: BMJ (2003)

Foot ulceration, sepsis, and amputation are known and feared by almost every person who has diabetes diagnosed. Yet these are potentially the most preventable of all diabetic complications by the simplest techniques of education and care. If lesions do occur, the majority can be cured by immediate and energetic treatment, for which good provision must be made.

This article is adapted from the 5th edition of the ABC of Diabetes , which is published by BMJ Books (www.bmjbooks.com/) 

Neuropathy and ischaemia are the principal disorders underlying foot problems. Whenever a patient presents with an active lesion, it is essential to decide at an early stage whether the foot problem is:

#### Precipitating causes of foot ulceration and infection

A combination of ulceration and sepsis in an ischaemic foot carries a higher risk of gangrene, and early arterial assessment and management are key to avoiding major amputation.

Men of low socioeconomic class are most prone to diabetic foot disorders, and Asian patients least likely to get them. Many causes are avoidable.

Patients confined to bed must have their heels elevated to avoid heel blisters and sepsis. Such wounds need weeks or months of treatment and sometimes require …
CDK4/6 Inhibitor Biomarker Research: Are We Barking Up the Wrong Tree?
Authors: Meenakshi Anurag, Svasti Haricharan, Matthew J. Ellis
Journal: Clinical Cancer Research (2019)

Abstract CDK4/6 inhibitors have emerged as a significant advance for the treatment of patients with advanced estrogen receptor–positive breast cancer. However, the identification of predictive markers that optimize their use is proving harder than expected. In this commentary we advocate for unbiased discovery and a collaborative approach across trials. See related article by Finn et al., p. 110
Ptcy + ATG Compared to Ptcy Alone As Gvhd Prophylaxis for Peripheral Blood Stem Cells Allotransplant Is Associated with Significant Lower Incidence of Acute Gvhd without Increasing Relapse or Death By Infection
Authors: Patrice Chevallier, Pierre Peterlin, Alice Garnier, Amandine Le Bourgeois, Beatrice Mahe, Viviane Dubruille, Nicolas Blin, Cyrille Touzeau, Thomas Gastinne, Anne Lok, Benoit Tessoulin, Yannick Le Bris, Marie C Bene, Steven Le Gouill, Philippe Moreau, Thierry Guillaume
Journal: Blood (2019)
Doripenem Versus Meropenem As the First-Line Mono-Therapy in High-Risk Febrile Neutropenic Patients with Acute Leukemia: A Randomized, Controlled Trial
Authors: Tatsuo Oyake, Norifumi Sugawara, Shinri Miyajima, Kazuki Kiyohara, Maki Nishiya, Tadashi Shimoyama, Yuka Takemasa-Fujisawa, Ryosei Sasaki, Wataru Izumita, Yasuhiko Tsukushi, Akihiro Otsu, Takahiro Mine, Takeshi Sugawara, Yuzo Suzuki, Yoshiaki Okano, Ichiro Hanamura, Shugo Kowata, Shigeki Ito
Journal: Blood (2019)
Benefit and Safety of Isovolemic Hemodilution Prior to Red Cell Exchange in Chronically Transfused Sickle Cell Patients
Authors: Katayoun Fomani, Cindy Xu, Swathi Ratkal, Vijay Nandi, Abena Appiah-Kubi, Banu Aygun, James Louie, Patricia Shi
Journal: Blood (2019)
DDX41 mutation in Patients with Idiopathic Cytopenia of Undetermined Significance, Myelodysplastic Syndrome, and Acute Myeloid Leukemia
Authors: Eun-Ji Choi, Young-Uk Cho, Seongsoo Jang, Chan-jeoung Park, Han-Seung Park, Jung-Hee Lee, Kyoo Hyung Lee, Eun-Hye Hur, Nayoung Kim, Hee Jeong Ouk, Je-Hwan Lee
Journal: Blood (2019)
Factors During a Child’s Illness Are Associated With Levels of Prolonged Grief Symptoms in Bereaved Mothers and Fathers
Authors: Lilian Pohlkamp, Ulrika Kreicbergs, Josefin Sveen
Journal: Journal of Clinical Oncology (2019)

PURPOSE Previous research shows that bereaved parents are at an increased risk for intense and prolonged grief responses. To offer effective support to parents during a child’s cancer treatment and after their child’s death, more knowledge is needed about factors related to the child’s illness trajectory that may contribute to prolonged grief in bereaved parents and about possible sex differences related to such factors. Therefore, we examined possible contributing factors associated with prolonged grief in cancer-bereaved mothers and fathers 1 to 5 years after their child died of cancer. METHODS We studied data from a population-based nationwide survey, including 133 mothers and 92 fathers who had lost a child to cancer 1 to 5 years earlier, using univariable and multiple regression analyses to assess the associations between prolonged grief and possible contributing variables. RESULTS The variables associated with lower levels of prolonged grief symptoms for mothers were being able to talk about feelings within the family ( P = .00) and trusting that health care professionals made every possible effort to cure the child ( P = .01). The statistically significantly associated variables for fathers were having said farewell to the deceased child in the way they wanted ( P = .00) and feeling that they had received practical support from health care professionals during the child’s illness trajectory ( P = .01). CONCLUSION We found factors during the illness of children with cancer that contributed to prolonged grief for parents; these were different for mothers and fathers. The results may have implications for design of family bereavement support within pediatric oncology care, including addressing the differing needs of mothers and fathers more effectively.
CPX-351 As Induction Chemotherapy Yields Similar Responses and Survival Outcomes in Younger Patients (&lt;60 Years Old) Compared to Older Patients (≥60 Years Old) with Acute Myeloid Leukemia
Authors: Dasom Lee, Hannah H Asghari, Yehuda E. Deutsch, Onyee Chan, Eric Padron, Andrew T Kuykendall, Alan F. List, Rami S. Komrokji, Hugo F. Fernandez, Jeffrey E. Lancet, David A Sallman, Kendra L. Sweet, Chetasi Talati
Journal: Blood (2019)
Environmental impact of bottles, teats, and packaging in maternity units
Authors: Genevieve E Becker, Yvonne Ryan-Fogarty
Journal: BMJ (2019)

Joffe and colleagues point out some of the environmental effects of infant feeding.1 Another aspect is the thousands of ready-to-use bottles, associated teats and packaging, and the volume of unconsumed breastmilk substitute that are used during the short stay in a maternity unit and need disposal.2

Research to identify environmental pressures, inform …
Venetoclax-Based Salvage Therapy for Post-Hematopoietic Cell Transplantation Relapse in Acute Myeloid Leukemia
Authors: Michael T Byrne, Nathalie Danielson, Adrianne Rasche, Rachel Hammers, Kathryn A Culos, Katie S Gatwood, Houston Wyatt, Kristin Fogo, Bhagirathbhai Dholaria, Brian G Engelhardt, Paul Brent Ferrell, Madan Jagasia, Adetola A. Kassim, Sanjay R Mohan, Bipin N. Savani, Stephen A. Strickland, Salyka M. Sengsayadeth, Michael R. Savona
Journal: Blood (2019)
Splanchnic vein thromboses associated with myeloproliferative neoplasms: An international, retrospective study on 518 cases
Authors: Emanuela Sant'Antonio, Paola Guglielmelli, Lisa Pieri, Massimo Primignani, Maria Luigia Randi, Claudia Santarossa, Elisa Rumi, Francisco Cervantes, Federica Delaini, Alessandra Carobbio, Silvia Betti, Elena Rossi, Noa Lavi, Claire N. Harrison, Natalia Curto‐Garcia, Heinz Gisslinger, Bettina Gisslinger, Giorgina Specchia, Alessandra Ricco, Nicola Vianelli, Nicola Polverelli, Maya Koren‐Michowitz, Marco Ruggeri, Francois Girodon, Martin Ellis, Alessandra Iurlo, Francesco Mannelli, Lara Mannelli, Benedetta Sordi, Giuseppe Gaetano Loscocco, Mario Cazzola, Valerio De Stefano, Tiziano Barbui, Ayalew Tefferi, Alessandro Maria Vannucchi
Journal: American Journal of Hematology (2019)

Myeloproliferative Neoplasms (MPN) course can be complicated by thrombosis involving unusual sites as the splanchnic veins (SVT). Their management is challenging, given their composite vascular risk. We performed a retrospective, cohort study in the framework of the International Working Group for MPN Research and Treatment (IWG-MRT), and AIRC-Gruppo Italiano Malattie Mieloproliferative (AGIMM). A total of 518 MPN-SVT cases were collected and compared with 1628 unselected, control MPN population, matched for disease subtype. Those with MPN-SVT were younger (median 44 years) and enriched in females compared to controls; PV (37.1%) and ET (34.4%) were the most frequent diagnoses. JAK2V617F mutation was highly prevalent (90.2%), and 38.6% of cases had an additional hypercoagulable disorder. SVT recurrence rate was 1.6 per 100 patient-years. Vitamin K-antagonists (VKA) halved the incidence of recurrence (OR 0.48), unlike cytoreduction (OR 0.96), and were not associated with overall or gastrointestinal bleeding in multivariable analysis. Esophageal varices were the only independent predictor for major bleeding (OR 17.4). Among MPN-SVT, risk of subsequent vascular events was skewed towards venous thromboses compared to controls. However, MPN-SVT clinical course was overall benign: SVT were enriched in PMF with lower IPSS, resulting in significantly longer survival than controls; survival was not affected in PV and slightly reduced in ET. MPN-U with SVT (n = 55) showed a particularly indolent phenotype, with no signs of disease evolution. In the to-date largest, contemporary cohort of MPN-SVT, VKA were confirmed effective in preventing recurrence, unlike cytoreduction, and safe; the major risk factor for bleeding was esophageal varices that therefore represent a major therapeutic target.
Outpatient Treatment with Lisocabtagene Maraleucel (liso-cel) in Three Ongoing Clinical Studies in Relapsed/Refractory (R/R) B Cell Non-Hodgkin Lymphoma (NHL), Including Second-Line Transplant Ineligible Patients: Transcend NHL 001, Outreach, and PILOT
Authors: Carlos R. Bachier, Maria Lia Palomba, Jeremy S. Abramson, Charalambos Andreadis, Alison R. Sehgal, John Godwin, Gerhard C. Hildebrandt, Tanya Siddiqi, Don Stevens, Thalia Farazi, Ana Kostic, Nikolaus S. Trede, Lei Wang, James Lymp, Tennille Thelen, Ken Ogasawara, David G. Maloney
Journal: Blood (2019)
Development and Use of the Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy Axicabtagene Ciloleucel in Large B-Cell Lymphoma
Authors: Frederick L. Locke, William Y. Go, Sattva S. Neelapu
Journal: JAMA Oncology (2019)

Axicabtagene ciloleucel, an anti-CD19-CD28-CD3ζ chimeric antigen receptor T-cell therapy, was the first US Food and Drug Administration-approved, genetically engineered T-cell therapy for adults with relapsed or refractory large B-cell lymphoma (LBCL) after 2 or more lines of systemic therapy. There has not been a US Food and Drug Administration-approved product for these cancers in more than 4 decades.Unlike traditional anticancer therapies, axicabtagene ciloleucel is a patient-specific, live-cell product that has unique requirements for manufacturing, shipping, and storage, as well as for its administration and management of its adverse events. In addition, axicabtagene ciloleucel has demonstrated efficacy in patients with refractory LBCL. This review presents a timeline of the rapid clinical development of axicabtagene ciloleucel from bench to bedside, highlights how axicabtagene ciloleucel satisfies an unmet medical need for treatment of refractory LBCL, outlines the logistics of the production process and administration of axicabtagene ciloleucel, describes its mechanism of action, and summarizes the results of the pivotal study. This review also provides a survey of adverse events, with attention to the kinetics of their clinical presentation; discusses the management of adverse events; and offers suggestions for appropriate patient selection for safe administration of axicabtagene ciloleucel.The integration of axicabtagene ciloleucel therapy into standard-of-care practice for relapsed/refractory LBCL is the beginning of a paradigm shift in the treatment of patients with LBCL and is likely to lead to improvements in their survival and curability. Timely referral to centers offering the therapy is necessary for optimal patient outcomes.
Immunotransplant: Preventing Unintended Consequences
Authors: Stephen M. Ansell
Journal: Cancer Discovery (2019)

Abstract Summary: T-cell transfer into lymphodepleted recipients results not only in homeostatic activation of the infused cells but also in T-cell inhibition due to upregulation of immune checkpoint receptors including PD-1 and CTLA4, thereby mitigating T-cell efficacy. Dual checkpoint blockade of PD-1 and CTLA4 in conjunction with lymphodepletion—an “immunotransplant”—uncouples the T-cell inhibition from activation and amplifies the T-cell antitumor immune response. See related article by Marshall et al., p. 1520.
Comprehensive Cell Specific Transcriptome Profiling of a Pediatric Hodgkin Lymphoma Cohort
Authors: Jennifer Agrusa, Elmoataz A Abdel Fattah, Howard Lin, Rikhia Chakraborty, Brooks Scull, Harshal Abhyankar, Nmazuo Wudo Ozuah, Olive S. Eckstein, Terzah M Horton, Kala Kamdar, Kenneth L. McClain, Chris Tsz-Kwong Man, Carl E. Allen
Journal: Blood (2019)
DDIS-33. SELECTIVE AND COMPLETE INHIBITION OF mTORC1 BY BI-STERIC mTOR INHIBITORS DRIVES THERAPEUTIC RESPONSE IN GLIOBLASTOMA
Authors: Qi Wen Fan, Edward Lorenzana, Xujun Luo, Robin Lea, Ozlem Aksoy, Zhenyi An, Tomoko Ozawa, Douglas Wassarman, Kevan Shokat, James Aggen, Jaqueline A M Smith, Mallika Singh, Nicholas Butowski, David Raleigh, William Weiss
Journal: Neuro-Oncology (2019)

Abstract Activation of phosphatidylinositol 3-kinase (PI3K)/PTEN pathway and oncogenic signaling via the mechanistic target of rapamycin (mTOR) occur in a majority of high-grade glial brain tumors. Allosteric mTOR inhibitors, such as rapamycin and other rapalogs, incompletely block mTORC1 by reducing phosphorylation of some substrates, including S6K1, but not 4EBP1. In contrast, ATP-competitive inhibitors, such as sapanisertib, fully inhibit mTORC1. However these inhibitors are also active against mTORC2 and lipid kinases, likely enhancing toxicity. A new class of selective mTORC1 inhibitor that interacts with both the ATP- and FKBP12/FRB-binding sites has been developed, which we term ‘bi-steric’. The prototype bi-steric inhibitor, RapaLink-1, blocks phosphorylation of many mTORC1 substrates, including 4EBP1. Importantly, RapaLink-1 showed improved efficacy in glioblastoma models in vivo as compared to rapamycin or sapanisertib (Fan et al., Cancer Cell 2017). Revolution Medicines has developed novel next-generation bi-steric mTORC1-selective inhibitors that exhibit potent and selective (&gt;10-fold) inhibition of mTORC1 over mTORC2 in vitro in cell line models. Two of these compounds, RM-001 and RM-006, showed sustained blockade of mTORC1 signaling, including dephosphorylation of 4EBP1, following weekly ip dosing in an orthotopic U87MG-Luc model of glioblastoma. Repeated weekly administration of these agents resulted in significantly greater anti-tumor efficacy, as assessed via tumor burden (bioluminescence imaging) and overall survival in comparison to daily sapanisertib and the rapalog everolimus, and weekly dosing of the first generation bi-steric RapaLink-1, all at maximally tolerated doses. In summary, our data demonstrate that bi-steric mTORC1 selective inhibitors elict marked anti-tumor efficacy at doses that are well tolerated in a preclinical model of glioblastoma. Our study emphasizes the importance of mTOR as a central target in glioblastoma, and showcases the therapeutic potential of novel and selective clinical bi-steric mTORC1 inhibitors under development as investigational new drugs.