tbuckley/cabot-search huggingface dataset:
IMMU-41. GBM PLATELET HYPERACTIVITY DRIVES THE IMMUNOSUPPRESSIVE TME IN A SEX-DEPENDENT MANNER
Authors: Anthony Sloan, George Bukenya, Liza Tack, Craig Horbinski, Alok Khorana, Anirban Sen Gupta, Marvin Nieman, Scott Cameron, Justin Lathia
Journal: Neuro-Oncology (2024)

Abstract Cancer-related thrombosis is the second leading cause of death for cancer patients, including those with glioblastoma (GBM), the most common primary malignant brain tumor. Patients with GBM have a 30% risk of venous thromboembolism. Moreover, sex biases are well established in GBM, with men 1.6-fold more likely to develop GBM and exhibiting a poorer prognosis than females. GBM is extremely difficult to treat due to its highly immunosuppressive tumor microenvironment (TME), often infiltrated with suppressive myeloid populations and a reduction in T-cells intratumorally and systemically. Our group has recently demonstrated these sex-biases in survival are due to differences in the immune cell populations making up the TME. Despite these findings, there is limited information as to how a hyper-thrombotic state contribute to the immunosuppressive TME. Additionally, the role that sex biases play in these mechanisms has not been explored. Our previous work demonstrated that thrombin, a major platelet activator through PAR1 and PAR4 receptor signaling, is secreted from cancer stem cells into the tumor microenvironment. We now show that GBM patient have elevated levels of the thrombin-antithrombin complex and have increased PAR4 receptor mediated platelet activation. Similarly, we show that tumor bearing mice have elevated PAR4 receptor mediated platelet activation relative to non-tumor bearing mice. We further demonstrate pharmacologically targeting the thrombin-PAR4 signaling axis in murine GBM models prolongs survival in females but has not affect in males by preventing female platelet hyperactivity and subsequently increasing the number and function of tumor infiltrating CD8+ T-cells. These findings demonstrate how activated platelets interact and regulate immune cell populations in GBM. These results suggest that the hyper-thrombotic state seen in many GBM patients simultaneously contributes to the immunosuppressive TME. In addition, these results identify therapeutic strategies to leverage the platelet hyperactivity seen in GBM by hyperactive thrombin-PAR4 for sex-dependent therapeutic purposes.
DDDR-26. IDENTIFICATION OF MODULATORS OF IDH INHIBITOR SENSITIVITY IN<i>IDH</i>-MUTATED DIFFUSE GLIOMAS
Authors: Sumaiyah Saleek, Eric Laugesen, Poorani Ganesh Subramani, Ruxiao Tian, Annette Wu, Samah El Ghamrasni, Adrian Levine, Zoya Aamir, Kevin Petrecca, Samuel McBrayer, Mario Suvà, Cynthia Hawkins, Uri Tabori, Tak Mak, Jerome Fortin
Journal: Neuro-Oncology (2024)

Abstract Driver mutations in IDH1 and IDH2 characterize a substantial proportion of lower-grade diffuse gliomas in adults. Mutated IDH molecules cause the accumulation of D-2-hydroxyglutarate (D-2-HG), which perturbs many cellular functions, including metabolism, epigenetic regulation, and the ability to differentiate. This is notably associated with DNA and histone hyper-methylation. Recently, the newly developed IDH inhibitor, vorasidenib, was shown to delay tumor progression and the need for additional treatment in the groundbreaking INDIGO clinical trial. Nevertheless, the responses to vorasidenib were variable between patients, and so far have been established only for less aggressive disease. In addition, it is unclear to what extent vorasidenib can cause tumor regression. This highlights the need to identify molecules and pathways that control IDH inhibitor sensitivity. Towards this goal, we generated a new mouse model that combines Idh1R132H and Trp53 loss-of-function, targeted to oligodendrocyte progenitors. All the mutant mice develop diffuse gliomas that recapitulate the cardinal features of the corresponding human disease. We established multiple cell lines from these tumors, which retained expression of mutant IDH. The cells robustly produced D-2-HG, which was concentration-dependently suppressed by vorasidenib. Accordingly, vorasidenib could lower DNA methylation, and induce the expression of mature glial cell markers. To identify determinants of vorasidenib sensitivity, we performed genome-wide loss-of-function CRISPR/Cas9 functional genomics screens. In those experiments, targeting genes associated with astrocyte differentiation or Notch signaling enhanced cell fitness in the presence of vorasidenib, consistent with the anticipated effects of the drug on inducing cell differentiation. Conversely, vorasidenib-treated cells were more sensitive to the loss of regulators of cell growth and metabolism, and of some epigenetic regulators. These studies point to strategies that may enhance the efficacy of IDH inhibitors for the treatment of IDH mutated gliomas.
IMMU-39. CAR T CELLS TARGETING ICAM-1 SHOW A SURVIVAL BENEFIT IN BOTH SYNGENEIC AND XENOGRAFT GLIOMA MOUSE MODELS
Authors: Melanie Soballa, Maximilian Mastall, Danielle Villars, Lena Hänsch, Maud Mayoux, Sonia Tugues, Michael Weller, Patrick Roth
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Chimeric antigen receptor (CAR) T-cell therapy, while effective against hematological malignancies, has faced significant hurdles in its application to solid tumors. Challenges in CAR T-cell therapy for glioblastoma include the immunosuppressive tumor microenvironment, the limited infiltration of CAR T-cells into the tumor, heterogeneous target expression and antigen escape. In this study, we focused on targeting Intracellular adhesion molecule-1 (ICAM-1), a protein expressed on both glioma cells and tumor-associated cells like macrophages and endothelial cells. METHODS Glioblastoma and normal brain tissue microarray sections (TMA) were immunohistochemically analyzed for ICAM-1 expression. Second-generation human and murine ICAM-1-targeting CAR T cells were generated by lentiviral or retroviral transduction of T cells from healthy human donors or murine splenocytes. Their efficacy was evaluated in co- culture assays with human and murine glioma and endothelial cell lines. Syngeneic and xenograft orthotopic glioma mouse models were used to assess the in vivo activity of CAR T cells. Ex vivo analysis of these tumors included examination of changes in the tumor microenvironment using high-dimensional flow cytometry. RESULTS Immunohistochemical staining of TMA revealed a significant upregulation of ICAM-1 in human glioblastoma tissue compared to normal brain tissue. Single-cell RNA sequencing data from glioblastoma specimens showed a high level of ICAM-1 expression in tumor- associated macrophages. Human and murine ICAM-1-targeting CAR T cells displayed strong lysis of ICAM-1-expressing glioma and endothelial cells in vitro. Intratumoral application of CAR T cells resulted in a survival benefit in both syngeneic and xenograft glioma mouse models. Ex vivo analysis of the tumor microenvironment revealed treatment-induced changes from our CAR T cell therapy and indicates potential for further enhancements. CONCLUSION Our study demonstrates that ICAM-1-targeting CAR T cells improve survival in human and murine glioma mouse models. Flow cytometry of the tumor microenvironment reveals therapy-induced changes, for future improvements of the CAR T cell therapy.
TMET-14. ENOLASE 2 IS A UNIQUE METABOLIC VULNERABILITY INDUCED BY THE 1P19Q CODELETION IN OLIGODENDROGLIOMAS
Authors: Suresh Udutha, Georgios Batsios, Anne Marie Gillespie, Pavithra Viswanath
Journal: Neuro-Oncology (2024)

Abstract Gliomas are devastating primary brain tumors in adults. The presence of an isocitrate dehydrogenase mutation combined with a chromosomal 1p/19q codeletion discriminates oligodendrogliomas from astrocytomas. The goal of this study was to leverage metabolic vulnerabilities induced by the 1p/19q codeletion for oligodendroglioma therapy. The 1p19q codeletion results in loss of enolase 1 (ENO1), which converts 2-phosphoglycerate to phosphoenolpyruvate during glycolysis. Here, we show that enolase 2 (ENO2) is upregulated in patient-derived oligodendroglioma (SF10417, BT88, BT54) models relative to astrocytoma (BT142, SF10602) and normal human astrocytes. ENO2 is also elevated in oligodendroglioma patient biopsies relative to astrocytoma or gliosis. Mechanistic studies indicate that inhibiting MEK1 or ERK1 abrogates ENO2 expression, suggesting that the MAPK pathway upregulates ENO2 in oligodendrogliomas. Next, we examined the therapeutic potential of targeting ENO2 in oligodendrogliomas. Genetic ablation of ENO2 or pharmacological inhibition using POMHEX inhibited the viability of SF10417 and BT88 cells with IC50 values of ~50 nM. In contrast, the IC50 for BT142 and SF10602 astrocytoma cells was ~5-8 uM, highlighting the exquisite dependence of oligodendrogliomas on ENO2. However, ENO2 inhibition did not lead to cytotoxicity in patient-derived oligodendroglioma cells or intracranial tumor xenografts. To assess the metabolic consequences of ENO2 inhibition and identify potential compensatory alterations, we traced [U-13C]-glucose metabolism in vivo in mice bearing intracranial SF10417 tumors. Although POMHEX abrogated glycolytic metabolism downstream of 2-phosphoglycerate, it shunted glucose towards biosynthesis of serine, glycine, methionine and purine nucleotides, an effect that was driven by phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme for serine biosynthesis. Importantly, the novel PHGDH inhibitor PHGDH-D8 was synthetically lethal in combination with POMHEX in oligodendroglioma cells and the combination induced apoptosis in mice bearing intracranial SF10417 tumors. Collectively, we exploit a mechanistic understanding of metabolic vulnerabilities induced by the 1p19q codeletion to identify combined inhibition of ENO2 and PHGDH as a novel therapeutic opportunity for oligodendrogliomas.
CTNI-75. TRIALS IN PROGRESS: REGISTRY OF SAFETY &amp; EFFICACY IN ADULTS WITH PRIMARY &amp; METASTATIC INTRACRANIAL TUMORS TREATED WITH START (GAMMATILES (CS-131 SOURCE BRACHY-THERAPY)): NCT04427384
Authors: Erin Dunbar, Stuart Lee, Matthew Sean Peach, John Wanbo, Chris Smith, Simon Hansfit, Keith Mertitz, Aviva Berkowitz, Lindsey Sloan, Clara Ferreira, Elizabeth Neil, Rupesh Kotecha, Adam Nowlan, David McCracken, Toral Patel, Zabi Wardak, Angela Richardson, Mitesh Shah, Sajeel Chowdhary, Vincent DiNapoli, John Floyd, Mahmoud Nagib, Andrea Wasilewski, Akash Patel, Ganash Rao, Houng Pham, Roby Ryan, Colette Shen, Adam Robin, Ian Lee, Lewis Leng, Kim Hoang, Jeff Olson, Ondrej Choutka, Catherine Mercado, Rouboz Chamoun, Paul Camarata, William Smith, Harish Babu, David Piccioni, Parag Sevak, James Zhu, Devon Haydon, Michelle Aizenberg, Mark Hoeprich, Brian Williams, Lawrence Dickinson, David Baskin, Andrew Farach, alaniz rodriguez
Journal: Neuro-Oncology (2024)

Abstract INTRO This is the first observational registry study of R+STaRT, delivered by Cs-131 sources in permanently implanted resorbable collagen tile carriers, for patients with intracranial tumors. METHODS Since October 2020, 37 sites to-date have enrolled 359 patients with primary &amp; metastatic intracranial tumors into the R+STaRT registry to assess the safety &amp; efficacy of the addition of Gamma Tile to medically needed resection. Local control, overall survival, QOL, neurocognition, functional decline, and surgical and radiation associated AE’s are collected at 1, 3, 6, 9,12, 18 and 24 months, then every 6 months through 5 years. RESULTS Demographics include 359 patients, avg. age 57 y.o.. 162 malignant gliomas, 125 metastatic tumors, 38 meningiomas, and 34 rare other tumors. 197 Males (163 White, 23 Black, 5 Asian, and other races) and 157 Females (White 121, 28 Black, 0 Asian, and 8 other races). No unexpected outcomes reported in the hands of experienced providers have occurred, although close clinical-radiographic follow-up, to ensure early detection of possible treatment-effects, is paramount. Steroid-use, and above endpoints, continue to be collected. CONCLUSIONS In this observational registry of Gamma Tiles (Cs-131 source brachy-therapy) added to medically needed resections for patients with primary and metastatic intracranial tumors continues. Data will be used to benchmark clinical outcomes of R+STaRT therapy and allow for comparisons to existing standard-of-care treatments. The outcome measures captured will allow for evaluation of the potential risks and benefits of this treatment approach for patients in a real-world setting.
CTNI-48. A PHASE 1 STUDY OF ERAS-801, A POTENT, SELECTIVE, AND CENTRAL NERVOUS SYSTEM (CNS)-PENETRANT EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) INHIBITOR, FOR PATIENTS WITH RECURRENT GLIOBLASTOMA MULTIFORME (GBM)
Authors: Patrick Wen, Manmeet Ahluwalia, Yazmin Odia, Meredith McKean, James Snyder, Howard Colman, Mina Lobbous, Leia Nghiemphu, Robert Chong, Jennifer Yang, Hina Patel, Daniela Vecchio, Armend Lokku, Les Brail, Ingo Mellinghoff
Journal: Neuro-Oncology (2024)

Abstract EGFR is among the most common targets for genetic alterations in GBM. Changes in EGFR gene amplification and the extracellular domain result in receptor overexpression or constitutive activation, and enhanced oncogenic signaling. ERAS-801 is a potent, selective, and highly CNS-penetrant EGFR inhibitor being developed for the treatment of GBM, with a focus on tumors harboring EGFR genetic alterations. THUNDERBBOLT-1 is the first-in-human phase 1 dose escalation and expansion trial evaluating ERAS-801 monotherapy for patients with recurrent GBM. ERAS-801 is administered orally once daily for continuous 28-day cycles. As of April 10, 2024, a total of 52 patients were treated across 7 dose cohorts: 20 mg (n=3), 40 mg (n=5), 80 mg (n=3), 160 mg (n=6), 240 mg (n=25), 280 mg (n=4), or 320 mg (n=6). Key patient characteristics were median age of 60 years, 67% male, mostly one prior therapy, and 81% tumors with alterations. The MTD was 240 mg. Dose-limiting toxicities were observed at 320 mg (n=2, Grade 2 QT prolongation, Grade 3 rash and Grade 3 dermatitis acneiform), 280 mg (n=3, Grade 3 QT prolongation), and 240 mg (n=1, Grade 3 QT prolongation) doses. The most common treatment related adverse events (TRAEs), in &amp;gt;10% of patients, were dermatitis acneiform, diarrhea, and nausea. Electrocardiogram QT prolongation occurred in 11.5% of patients and was not associated with clinical findings. ERAS-801 showed rapid absorption; peak plasma concentration was generally achieved within 6 hours post dose. PK exposure increased in a dose-dependent manner over the doses evaluated. Across all doses there was a confirmed partial response (using mRANO) in 1 patient and 6 patients achieved a PFS of 6 months. ERAS-801 shows well behaved PK with substantial CNS penetration, preliminary safety, and tolerability in patients with recurrent GBM. The TRAEs were reversible, manageable, and consistent with known toxicities of EGFR inhibitors.
IMMU-64. SEX-SPECIFIC ROLES OF<i>YAP1</i> AND CD276/B7-H3 IN MEDULLOBLASTOMA IMMUNE SUPPRESSION
Authors: Nourhan Abdelfattah, Sivaraman Natarajan, Han Nhat Tran, Thomas Wong, Jose Maldonado, Hannah Borland, Rachael McMinimy, Shu-hsia Chen, Fernando Camargo, James Olson, Joshy George, Kyuson Yun
Journal: Neuro-Oncology (2024)

Abstract The molecular mechanism governing sex disparities in cancer prevalence, progression, and treatment outcomes represents an important yet understudied area of research with significant implications for cancer treatment. Medulloblastoma (MB), the most prevalent pediatric brain malignancy, exhibits a notable sex bias in incidence and survival rates. Males have a higher incidence rate across all age groups and have worse prognoses than their females for age groups over three years old. Here, we report an unanticipated sex-biased role of the oncogene Yap1 in SHH medulloblastoma. Our results reveal that Yap1 deletion significantly prolongs survival in male, but not female mice with SmoM2-driven SHH MB. Employing an integrated multi-omics approach, we demonstrate that YAP1 is required to maintain cancer stem cells simultaneously activating stemness genes (such as Sox2) and repressing differentiation genes (such as Neurod1 and Zic1/2) in both sexes. In contrast, Yap1 plays a more critical role in immune evasion in males than in females. Specifically, YAP1 regulates the expression of the immune checkpoint molecule Cd276/B7-H3, which suppresses cytotoxic T cell function. In males, CD276 blockade or Yap1 deletion in MB cells is enough to reverse T cell suppression effectively. In females, neither CD276 blockade nor Yap1 deletion alone in MB cells can reverse T cell suppression. Furthermore, YAP1’s direct transcriptional target gene signatures, including CD276, predict survival across multiple human cancers in male patients. These findings suggest broader implications of our findings beyond medulloblastoma and indicate a highly conserved mechanism across species. Our study provides compelling evidence for the male-biased efficacy of Yap1 or CD276 inhibitors and presents novel insights into sex-specific mechanisms of cancer immune evasion.
CTNI-43. MULTI-CENTER PHASE I STUDY OF CONCURRENT PAXALISIB AND RADIATION THERAPY (RT) IN PATIENTS WITH SOLID TUMOR BRAIN METASTASES (BM) OR LEPTOMENINGEAL METASTASES (LM) HARBORING PI3K PATHWAY ALTERATIONS
Authors: Brandon Imber, Rupesh Kotecha, Kathryn Blau, Lia Halasz, John Friend, Robert Young, Michael Offin, Ryan Mitchell, Eli Diamond, Jonathan Yang
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Partial or whole brain RT is a standard treatment for solid tumor BM and LM. However, tumors harboring PI3K pathway mutations have poorer CNS control after RT alone. Combining RT with paxalisib, a CNS-penetrant PI3K/mTOR inhibitor, may overcome radioresistance. METHODS This multi-center, phase I trial (NCT04192981) studied concurrent paxalisib with cranial RT (30Gy in 10 fractions) for PI3K pathway-altered BM/LM. Part A was a 3 + 3 dose escalation cohort of paxalisib at 45, 60 or 75mg to establish maximum tolerated dose (MTD). Part B was an expansion at MTD to further validate safety and early efficacy. CNS response was assessed using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. RESULTS From 3/2020-2/2024, 21 patients (median age 58y, n=18 with BM, n=10 with breast cancer) were enrolled. PIK3CA mutations were the most common pathway alteration (n=15, 71%) followed by PTEN deletion (n=3, 14%). Part A enrolled 12 patients of which 9 were evaluable (3 did not complete protocol therapy). There were no dose-limiting toxicities (DLTs) at 45mg, and 2 DLTs at 60mg: grade 3 nausea and grade 4 neutropenic enterocolitis. Subsequently, 9 additional patients were enrolled during Part B at MTD of 45mg, of which 1 withdrew consent prior to completion of study interventions. No additional DLTs were observed during Part B. In total, there were 14 evaluable patients who received 45mg/day paxalisib concurrently with RT, two of whom died of intercurrent extracranial progression prior to CNS restaging. Of the remaining 12, there was robust response signal. At 1-month post-treatment, 6/12 (50%) had partial response (PR) and the remaining had stable disease (SD). To date, best CNS response is 67% PR (8/12) and 33% SD (4/12). CONCLUSIONS A MTD of 45 mg/day has been confirmed for paxalisib with concurrent brain RT for PI3K pathway-altered BM/LM. Given significant unmet need, this novel therapeutic combination warrants further investigation given promising activity signal.
DDDR-27. BMP SIGNALING MODULATES APOPTOTIC AND NON-APOPTOTIC CELL DEATH IN GLIOBLASTOMA
Authors: Weaverly Colleen Lee, Jennifer Salinas, David Nathanson, Scott Dixon
Journal: Neuro-Oncology (2024)

Abstract Recurrence occurs in approximately 90% of glioblastoma (GBM) patients, in part due to the tumors becoming resistant to cell death in response to existing therapies. These therapies often trigger apoptosis; however, apoptosis is only one of several different forms of cell death. We hypothesize that activating non-canonical death mechanisms could provide a back door to killing treatment-resistant GBM cells. To test this hypothesis, we first developed a new imaging-based high-throughput method to directly quantify cell death in 3D models. Using this method, we find patient-derived GBM spheroids to be resistant to the induction of cell death in response to various standard-of-care and experimental therapeutic compounds. To further investigate mechanisms underlying this resistance, we screened a panel of extracellular protein ligands for the modulation of cell death response. We find that bone morphogenic protein (BMP) signaling increases resistance to several apoptosis-inducing compounds, including temozolomide and tyrosine kinase inhibitors. Intriguingly, BMP signaling simultaneously enhanced sensitivity to a novel non-apoptotic cell death pathway triggered by the small molecule CIL56. Efforts are ongoing to further understand how BMP signaling governs apoptotic and non-apoptotic cell death mechanisms. Nevertheless, our results suggest a novel approach to treating GBM, centered upon the modulation of BMP signaling combined with the use of agents that induce non-apoptotic cell death.
CTNI-45. PHASE 2 STUDY OF SORAFENIB, VALPROIC ACID, AND SILDENAFIL IN THE TREATMENT OF RECURRENT HIGH-GRADE GLIOMA
Authors: Palak Shah, Andrew Poklepovic, Mary Beth Tombes, Ellen Shrader, Dipankar Bandyopadhyay, Xiaoyan Deng, Catherine Roberts, Alison Ryan, Daniel Hudson, Heidi Sankala, Maciej Kmieciak, Paul Dent, Mark Malkin
Journal: Neuro-Oncology (2024)

Abstract PURPOSE Here we report the results of a single-center phase 2 clinical trial combining sorafenib tosylate, valproic acid, and sildenafil for the treatment of patients with recurrent high-grade glioma. PATIENTS AND METHODS Eligible patients were 18 years of age and older with an Eastern Cooperative Oncology Group performance status of 0-2 and pathologically confirmed high-grade glioma (WHO grade 3 or 4), with documented CT or MRI progression or recurrence and measurable or evaluable disease. The treatment schedule was a combination of sorafenib, valproic acid, and sildenafil, each agent administered orally, twice daily continuously. A cycle consisted of 4 weeks. RESULTS Clinical toxicities were grade 1 and grade 2, with one grade 3 toxicity for maculopapular rash (6.4%). For all evaluable patients, the median progression-free survival was 3.65 months and overall survival (OS) 10.0 months. There was promising evidence showing clinical activity and benefit. In the 33 evaluable patients, low protein levels of the chaperone GRP78 (HSPA5) was significantly associated with a better OS (p &amp;lt; 0.0026). A correlation between the expression of PDGFRa and OS approached significance (p &amp;lt; 0.0728). Five patients presently have a mean OS of 73.6 months and remain alive. CONCLUSIONS This is the first therapeutic intervention glioblastoma trial to significantly associate GRP78 expression to OS. Our data suggest that the combination of sorafenib tosylate, valproic acid, and sildenafil requires additional clinical development in the recurrent glioma population.