CTNI-07. ABTC-1701: PILOT SURGICAL PK STUDY OF BGB324 (BEMCENTINIB) IN RECURRENT GLIOBLASTOMA PATIENTS – RESULTS FROM INTERIM FUTILITY ANALYSIS

Abstract BACKGROUND Glioblastoma often can relapse as mesenchymal (MES) tumors, indicating a phenotypic shift during clinical progression. Glioma spheres, when they gain MES phenotypes, develop dependence on AXL for their growth both in vitro and in vivo. The first-in-class orally bioavailable AXL kinase inhibitor bemcentinib has IC50 of 14 nM and is > 100-fold selective for AXL over other kinases. Bemcentinib is currently under evaluation as a monotherapy and in combination with other treatments across various PhII trials in several oncology indications. METHODS This is an open-label, multicenter, intratumoral pharmacokinetic study of bemcentinib in patients with recurrent glioblastoma for whom a surgical resection is medically indicated. All subjects must have had histological confirmation of glioblastoma by either biopsy or resection that is progressive or recurrent following radiation therapy ± chemotherapy. Intratumoral drug levels were analyzed by LC/MS. RESULTS A planned analysis after the first 5 patients were enrolled with glioblastoma (4 IDH WT and 1 IDH-mutant), (3m, 2f, median age 57, KPS 80). Bemcentinib concentration in contrast enhancing brain tissue ranged from 3.1 to 43.0 uM with a geometric mean concentration of 11.1 uM (% CV, 132.1). The drug concentration in contrast enhancing tumor tissue exceeded the 1.0 uM threshold in all 5 patients, satisfying the criteria of the protocol to enroll an additional 15 patients into the surgical study. Total drug levels were approximately 2-fold greater in contrast enhancing tissue as compared to tissue from a non-enhancing region of the tumor (geometric mean, 5.8 uM; % CV, 187.7). The mean ratio of the drug concentration in brain tissue to plasma was 25.9 (% CV, 92.7) for contrast enhancing tissue and 13.4 (% CV, 126.8) for non-enhancing tissue. CONCLUSIONS Bemcentinib readily distributes in brain tumor tissue following oral administration. The study continues to complete accrual for the remaining 15 patients.

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A Vascular Targeted Pan PI-3 Kinase Inhibitor, SF1126 with Activity Against Multiple Myeloma In Vivo.

Blood ◽

10.1182/blood.v108.11.244.244 ◽

2006 ◽

Vol 108 (11) ◽

pp. 244-244 ◽

Cited By ~ 2

Author(s):

Pradip De ◽

Qiong Peng ◽

Nandini Dey ◽

Breanne McDermitt ◽

Xiaodong Peng ◽

...

Keyword(s):

Multiple Myeloma ◽

Tumor Tissue ◽

Kinase Inhibitor ◽

Surrogate Marker ◽

Phase I Clinical Trials ◽

Lymphoid Malignancies ◽

Antiangiogenic Activity ◽

Density Analysis

Abstract Background: Considerable evidence suggests an important role for the PI-3 kinase and AKT signaling pathways in survival and chemoresistance in multiple myeloma (MM) and other lymphoid malignancies. Our group and others have demonstrated that downregulation of p-AKT with combination therapy (bortezomib + lonafarnib; David et al, Blood, 2005) is a surrogate marker for myeloma apoptosis. It has been demonstrated that the compound, LY294002 has significant pan PI-3 kinase inhibitory properties but is not suitable for clinical use due to PK issues. SF1126 is a novel RGD targeted derivative of LY294002 that has been shown to have activity in a number of different tumor models. Herein, we evaluated the activity of SF1126 against the MM.1S and MM.1R MM cell lines in vitro and in vivo for sensitivity to PI-3 kinase inhibition. The results demonstrate that MM.1S and MM.1R tumor cell growth is sensitive to SF1126 with IC50 of 7.5 and 10.8 uM, respectively. The effects of SF1126 on MM.1R signaling in vitro was examined with profound inhibition of HIF1a induction under hypoxia, the suppression of phosphorylation states of MDM2, ERK and RS6 kinase. The IC50 for inhibition of p-AKT in MM.1S and MM.1R cells was determined to be 2.4 and 2.8 uM, respectively. SF1126 treatment (50 mg/kg/dose sc given every other day) inhibited MM.1R tumor growth in nude mouse xenografts 95% as compared to untreated controls on day 38 (p < .01). Microvessel density analysis of MM.1R tumor tissue demonstrated that SF1126 had significant antiangiogenic activity in vivo. Conclusion: The results provide preclinical data to support SF1126 as a clinically viable antiangiogenic, pan PI-3 kinase inhibitor for Phase I clinical trials in the treatment of multiple myeloma. Further studies in primary myeloma cells and in combination with conventional agents will be presented.

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BBI608-201GBM: A phase Ib/II clinical study of napabucasin (BBI608) in combination with temozolomide (TMZ) for adult patients with recurrent glioblastoma (GBM).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e13525 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e13525-e13525 ◽

Cited By ~ 1

Author(s):

Warren P. Mason ◽

Paula de Robles ◽

Laura Borodyansky ◽

Matthew Hitron ◽

Waldo Feliu Ortuzar ◽

...

Keyword(s):

Recurrent Glioblastoma ◽

Open Label ◽

Cancer Stemness ◽

Phase Ib ◽

Anti Cancer ◽

First Recurrence ◽

Multi Center Study ◽

Anti Tumor Activity

e13525 Background: Napabucasin, a first-in-class cancer stemness inhibitor in clinical development, suppresses cancer stemness by targeting STAT3-driven gene transcription. Pre-clinically, potent and broad-spectrum anti-cancer activity was observed in vitro and in vivo, alone and in combination with other agents. PK studies demonstrated napabucasin penetration in the murine orthotopic GBM model. Methods: A phase Ib/II open-label, multi-center study in pts with GBM at first recurrence who have not received bevacizumab, was performed to determine safety and preliminary activity of napabucasin administered orally at 480mg BID po in combination with TMZ 150mg/m²/day po; days 1 through 5 of each 28 day cycle, until disease progression or unacceptable toxicity. A 6-patient safety cohort was planned to evaluate the occurrence of DLT during the first 28 days of combination treatment with napabucasin and TMZ. 4 additional patients have been enrolled under the RP2D expansion phase. Results: 11 pts have been enrolled to date; no DLT was observed in the safety cohort and the RP2D of the combination is 480 mg BID for napabucasin. The safety profile was consistent with that of each agent as monotherapy and most common AEs included grade 1/2 diarrhea, nausea, abdominal cramps, and vomiting. Two patients requested to withdraw treatment due to concurrent conditions and AE s. 9 patients were evaluable by RANO; Disease Control Rate was observed in 5 patients (55.5%) of which 4 achieved PR (44.4%) and 1 achieved SD (11.1%). The Overall response rate was 44.4% in the evaluable patients. Conclusions: This phase Ib/II study demonstrated that napabucasin at 480 mg BID can be safely combined with temozolomide at full dose and showed encouraging anti-tumor activity in patients with recurrent Glioblastoma. Clinical trial information: NCT02315534. [Table: see text]

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CTNI-16. TROTABRESIB (CC-90010, BMS-986378), A REVERSIBLE, POTENT ORAL BROMODOMAIN AND EXTRATERMINAL INHIBITOR (BETi) IN PATIENTS WITH HIGH-GRADE GLIOMAS: A PHASE 1 OPEN-LABEL ‘WINDOW OF OPPORTUNITY’ STUDY

Neuro-Oncology ◽

10.1093/neuonc/noab196.241 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi62-vi62

Author(s):

Michael Vogelbaum ◽

Juan Manuel Sepulveda ◽

David Reardon ◽

Bishoy Hanna ◽

Ellen Filvaroff ◽

...

Keyword(s):

Antitumor Activity ◽

Tumor Tissue ◽

Tissue Concentration ◽

Phase 1 ◽

Geometric Mean ◽

Study Drug ◽

Recurrent Glioblastoma ◽

Percentage Increase ◽

Open Label ◽

Salvage Resection

Abstract Trotabresib is a potent, reversible oral BETi with antitumor activity in patients with advanced malignancies (Moreno et al. ESMO 2020. Abstract 5270). The CC-90010-GBM-001 study (NCT04047303) enrolled patients with progressive or recurrent astrocytoma or recurrent glioblastoma scheduled for salvage resection. Patients were treated with trotabresib 30 mg daily for 4 days before surgery, then trotabresib 45 mg daily 4 days on/24 days off after recovery. Primary objectives were trotabresib tumor tissue concentration and plasma pharmacokinetics (PK). Secondary and exploratory objectives included safety, antitumor activity, cerebrospinal fluid concentration, and pharmacodynamics (PD). Twenty patients were enrolled; blood PK, blood PD, and tumor PD data were available for 14, 12, and 11 patients, respectively. Geometric mean peak trotabresib plasma concentration on day 4 was 1.92 μM; median time to peak concentration was 1.5 hours. At the time of resection, geometric mean trotabresib concentrations in plasma and brain tumor tissue were 1.01 and 0.68 μM, respectively. Blood CCR1 mRNA was reduced ≥ 50% from baseline after dose 4. Blood HEXIM1 mRNA increased at 72–96 hours following first dose, and at the time of surgery the percentage increase was related to plasma trotabresib concentration. Tumor HEXIM1 RNA increased in 10 of 11 patients. Eighteen patients (90%) had ≥ 1 treatment-related adverse event (TRAE). Nine patients (45%) had grade 3/4 TRAEs, most frequently thrombocytopenia (5 patients [25%]). Only 1 patient had serious TRAEs (hemiparesis and lethargy). Two patients died of intracranial hemorrhage unrelated to study drug. Of 16 patients evaluable for antitumor response, 7 had stable disease per RANO criteria, with 3 ongoing beyond data cutoff at cycles 4–11. Median progression-free survival was 1.9 months (95% CI, 1.4–3.3). Overall, trotabresib showed good tumor tissue penetration, with PD signals of response, and was well tolerated. A study of trotabresib + temozolomide in first-line glioblastoma is ongoing (NCT04324840).

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Monocytes as Carriers of Magnetic Nanoparticles for Tracking Inflammation in the Epileptic Rat Brain

Current Drug Delivery ◽

10.2174/1567201816666190619122456 ◽

2019 ◽

Vol 16 (7) ◽

pp. 637-644 ◽

Cited By ~ 4

Author(s):

Hadas Han ◽

Sara Eyal ◽

Emma Portnoy ◽

Aniv Mann ◽

Miriam Shmuel ◽

...

Keyword(s):

Brain Tissue ◽

Ex Vivo ◽

In Vivo Studies ◽

Nanoparticle Distribution ◽

Spontaneous Seizures ◽

Systemic Distribution ◽

Hippocampal Ca1 ◽

Pilocarpine Model

Background: Inflammation is a hallmark of epileptogenic brain tissue. Previously, we have shown that inflammation in epilepsy can be delineated using systemically-injected fluorescent and magnetite- laden nanoparticles. Suggested mechanisms included distribution of free nanoparticles across a compromised blood-brain barrier or their transfer by monocytes that infiltrate the epileptic brain. Objective: In the current study, we evaluated monocytes as vehicles that deliver nanoparticles into the epileptic brain. We also assessed the effect of epilepsy on the systemic distribution of nanoparticleloaded monocytes. Methods: The in vitro uptake of 300-nm nanoparticles labeled with magnetite and BODIPY (for optical imaging) was evaluated using rat monocytes and fluorescence detection. For in vivo studies we used the rat lithium-pilocarpine model of temporal lobe epilepsy. In vivo nanoparticle distribution was evaluated using immunohistochemistry. Results: 89% of nanoparticle loading into rat monocytes was accomplished within 8 hours, enabling overnight nanoparticle loading ex vivo. The dose-normalized distribution of nanoparticle-loaded monocytes into the hippocampal CA1 and dentate gyrus of rats with spontaneous seizures was 176-fold and 380-fold higher compared to the free nanoparticles (p<0.05). Seizures were associated with greater nanoparticle accumulation within the liver and the spleen (p<0.05). Conclusion: Nanoparticle-loaded monocytes are attracted to epileptogenic brain tissue and may be used for labeling or targeting it, while significantly reducing the systemic dose of potentially toxic compounds. The effect of seizures on monocyte biodistribution should be further explored to better understand the systemic effects of epilepsy.

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Characterization of LDD-2633 as a Novel RET Kinase Inhibitor with Anti-Tumor Effects in Thyroid Cancer

Pharmaceuticals ◽

10.3390/ph14010038 ◽

2021 ◽

Vol 14 (1) ◽

pp. 38

Author(s):

Hyo Jeong Lee ◽

Pyeonghwa Jeong ◽

Yeongyu Moon ◽

Jungil Choi ◽

Jeong Doo Heo ◽

...

Keyword(s):

Thyroid Cancer ◽

Thyroid Carcinoma ◽

Kinase Inhibitor ◽

Point Mutations ◽

Carcinoma Cells ◽

Medullary Thyroid ◽

Potent Inhibition ◽

Kinase Inhibitory Activity

Rearranged during transfection (RET), a receptor tyrosine kinase, is activated by glial cell line-derived neurotrophic factor family ligands. Chromosomal rearrangement or point mutations in RET are observed in patients with papillary thyroid and medullary thyroid carcinomas. Oncogenic alteration of RET results in constitutive activation of RET activity. Therefore, inhibiting RET activity has become a target in thyroid cancer therapy. Here, the anti-tumor activity of a novel RET inhibitor was characterized in medullary thyroid carcinoma cells. The indirubin derivative LDD-2633 was tested for RET kinase inhibitory activity. In vitro, LDD-2633 showed potent inhibition of RET kinase activity, with an IC50 of 4.42 nM. The growth of TT thyroid carcinoma cells harboring an RET mutation was suppressed by LDD-2633 treatment via the proliferation suppression and the induction of apoptosis. The effects of LDD-2633 on the RET signaling pathway were examined; LDD-2633 inhibited the phosphorylation of the RET protein and the downstream molecules Shc and ERK1/2. Oral administration of 20 or 40 mg/kg of LDD-2633 induced dose-dependent suppression of TT cell xenograft tumor growth. The in vivo and in vitro experimental results supported the potential use of LDD-2633 as an anticancer drug for thyroid cancers.

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Regorafenib-Attenuated, Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms22041985 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1985

Author(s):

Xiaohe Li ◽

Ling Ma ◽

Kai Huang ◽

Yuli Wei ◽

Shida Long ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Signaling Pathway ◽

Transforming Growth Factor ◽

Kinase Inhibitor ◽

In Vivo Experiments ◽

Age Related ◽

And Migration ◽

Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a fatal and age-related pulmonary disease. Nintedanib is a receptor tyrosine kinase inhibitor, and one of the only two listed drugs against IPF. Regorafenib is a novel, orally active, multi-kinase inhibitor that has similar targets to nintedanib and is applied to treat colorectal cancer and gastrointestinal stromal tumors in patients. In this study, we first identified that regorafenib could alleviate bleomycin-induced pulmonary fibrosis in mice. The in vivo experiments indicated that regorafenib suppresses collagen accumulation and myofibroblast activation. Further in vitro mechanism studies showed that regorafenib inhibits the activation and migration of myofibroblasts and extracellular matrix production, mainly through suppressing the transforming growth factor (TGF)-β1/Smad and non-Smad signaling pathways. In vitro studies have also indicated that regorafenib could augment autophagy in myofibroblasts by suppressing TGF-β1/mTOR (mechanistic target of rapamycin) signaling, and could promote apoptosis in myofibroblasts. In conclusion, regorafenib attenuates bleomycin-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway.

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Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia

Nature Communications ◽

10.1038/s41467-020-20259-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Hu Lei ◽

Han-Zhang Xu ◽

Hui-Zhuang Shan ◽

Meng Liu ◽

Ying Lu ◽

...

Keyword(s):

Tyrosine Kinase ◽

Progenitor Cells ◽

Chronic Myelogenous Leukemia ◽

Drug Targets ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Myelogenous Leukemia ◽

Tki Resistance

AbstractIdentifying novel drug targets to overcome resistance to tyrosine kinase inhibitors (TKIs) and eradicating leukemia stem/progenitor cells are required for the treatment of chronic myelogenous leukemia (CML). Here, we show that ubiquitin-specific peptidase 47 (USP47) is a potential target to overcome TKI resistance. Functional analysis shows that USP47 knockdown represses proliferation of CML cells sensitive or resistant to imatinib in vitro and in vivo. The knockout of Usp47 significantly inhibits BCR-ABL and BCR-ABLT315I-induced CML in mice with the reduction of Lin−Sca1+c-Kit+ CML stem/progenitor cells. Mechanistic studies show that stabilizing Y-box binding protein 1 contributes to USP47-mediated DNA damage repair in CML cells. Inhibiting USP47 by P22077 exerts cytotoxicity to CML cells with or without TKI resistance in vitro and in vivo. Moreover, P22077 eliminates leukemia stem/progenitor cells in CML mice. Together, targeting USP47 is a promising strategy to overcome TKI resistance and eradicate leukemia stem/progenitor cells in CML.

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Integrin α6 mediates the drug resistance of acute lymphoblastic B-cell leukemia

Blood ◽

10.1182/blood.2019001417 ◽

2020 ◽

Vol 136 (2) ◽

pp. 210-223 ◽

Cited By ~ 2

Author(s):

Eun Ji Gang ◽

Hye Na Kim ◽

Yao-Te Hsieh ◽

Yongsheng Ruan ◽

Heather A. Ogana ◽

...

Keyword(s):

Drug Resistance ◽

Tyrosine Kinase ◽

B Cell ◽

Kinase Inhibitor ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Underlying Mechanism ◽

Conditional Knockout

Abstract Resistance to multimodal chemotherapy continues to limit the prognosis of acute lymphoblastic leukemia (ALL). This occurs in part through a process called adhesion-mediated drug resistance, which depends on ALL cell adhesion to the stroma through adhesion molecules, including integrins. Integrin α6 has been implicated in minimal residual disease in ALL and in the migration of ALL cells to the central nervous system. However, it has not been evaluated in the context of chemotherapeutic resistance. Here, we show that the anti-human α6-blocking Ab P5G10 induces apoptosis in primary ALL cells in vitro and sensitizes primary ALL cells to chemotherapy or tyrosine kinase inhibition in vitro and in vivo. We further analyzed the underlying mechanism of α6-associated apoptosis using a conditional knockout model of α6 in murine BCR-ABL1+ B-cell ALL cells and showed that α6-deficient ALL cells underwent apoptosis. In vivo deletion of α6 in combination with tyrosine kinase inhibitor (TKI) treatment was more effective in eradicating ALL than treatment with a TKI (nilotinib) alone. Proteomic analysis revealed that α6 deletion in murine ALL was associated with changes in Src signaling, including the upregulation of phosphorylated Lyn (pTyr507) and Fyn (pTyr530). Thus, our data support α6 as a novel therapeutic target for ALL.

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USP29-mediated HIF1α stabilization is associated with Sorafenib resistance of hepatocellular carcinoma cells by upregulating glycolysis

Oncogenesis ◽

10.1038/s41389-021-00338-7 ◽

2021 ◽

Vol 10 (7) ◽

Author(s):

Ruize Gao ◽

David Buechel ◽

Ravi K. R. Kalathur ◽

Marco F. Morini ◽

Mairene Coto-Llerena ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Transcriptional Activity ◽

Kinase Inhibitor ◽

Aerobic Glycolysis ◽

Hypoxia Inducible Factor ◽

Aberrant Expression ◽

Key Enzyme ◽

Hcc Cells

AbstractUnderstanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In hepatocellular carcinoma (HCC), aberrant expression of hypoxia-inducible factor 1 α (HIF1α) and increased aerobic glycolysis metabolism are drivers of resistance to therapy with the multi-kinase inhibitor Sorafenib. However, it has remained unknown how HIF1α is activated and how its activity and the subsequent induction of aerobic glycolysis promote Sorafenib resistance in HCC. Here, we report the ubiquitin-specific peptidase USP29 as a new regulator of HIF1α and of aerobic glycolysis during the development of Sorafenib resistance in HCC. In particular, we identified USP29 as a critical deubiquitylase (DUB) of HIF1α, which directly deubiquitylates and stabilizes HIF1α and, thus, promotes its transcriptional activity. Among the transcriptional targets of HIF1α is the gene encoding hexokinase 2 (HK2), a key enzyme of the glycolytic pathway. The absence of USP29, and thus of HIF1α transcriptional activity, reduces the levels of aerobic glycolysis and restores sensitivity to Sorafenib in Sorafenib-resistant HCC cells in vitro and in xenograft transplantation mouse models in vivo. Notably, the absence of USP29 and high HK2 expression levels correlate with the response of HCC patients to Sorafenib therapy. Together, the data demonstrate that, as a DUB of HIF1α, USP29 promotes Sorafenib resistance in HCC cells, in parts by upregulating glycolysis, thereby opening new avenues for therapeutically targeting Sorafenib-resistant HCC in patients.

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Differentiated glioblastoma cells accelerate tumor progression by shaping the tumor microenvironment via CCN1-mediated macrophage infiltration

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01124-7 ◽

2021 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Atsuhito Uneda ◽

Kazuhiko Kurozumi ◽

Atsushi Fujimura ◽

Kentaro Fujii ◽

Joji Ishida ◽

...

Keyword(s):

Tumor Microenvironment ◽

Tumor Progression ◽

Tumor Cells ◽

In Silico ◽

Tumor Tissue ◽

The Cancer Genome Atlas ◽

Macrophage Infiltration ◽

Macrophage Migration

AbstractGlioblastoma (GBM) is the most lethal primary brain tumor characterized by significant cellular heterogeneity, namely tumor cells, including GBM stem-like cells (GSCs) and differentiated GBM cells (DGCs), and non-tumor cells such as endothelial cells, vascular pericytes, macrophages, and other types of immune cells. GSCs are essential to drive tumor progression, whereas the biological roles of DGCs are largely unknown. In this study, we focused on the roles of DGCs in the tumor microenvironment. To this end, we extracted DGC-specific signature genes from transcriptomic profiles of matched pairs of in vitro GSC and DGC models. By evaluating the DGC signature using single cell data, we confirmed the presence of cell subpopulations emulated by in vitro culture models within a primary tumor. The DGC signature was correlated with the mesenchymal subtype and a poor prognosis in large GBM cohorts such as The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project. In silico signaling pathway analysis suggested a role of DGCs in macrophage infiltration. Consistent with in silico findings, in vitro DGC models promoted macrophage migration. In vivo, coimplantation of DGCs and GSCs reduced the survival of tumor xenograft-bearing mice and increased macrophage infiltration into tumor tissue compared with transplantation of GSCs alone. DGCs exhibited a significant increase in YAP/TAZ/TEAD activity compared with GSCs. CCN1, a transcriptional target of YAP/TAZ, was selected from the DGC signature as a candidate secreted protein involved in macrophage recruitment. In fact, CCN1 was secreted abundantly from DGCs, but not GSCs. DGCs promoted macrophage migration in vitro and macrophage infiltration into tumor tissue in vivo through secretion of CCN1. Collectively, these results demonstrate that DGCs contribute to GSC-dependent tumor progression by shaping a mesenchymal microenvironment via CCN1-mediated macrophage infiltration. This study provides new insight into the complex GBM microenvironment consisting of heterogeneous cells.

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