ORCID Profile
0000-0002-2144-7157
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Publisher: MDPI AG
Date: 14-10-2021
Abstract: Acute lymphoblastic leukaemia (ALL) is the most common cancer diagnosed in children and adolescents. Approximately 70% of patients survive -years following diagnosis, however, for those that fail upfront therapies, survival is poor. Reactive oxygen species (ROS) are elevated in a range of cancers and are emerging as significant contributors to the leukaemogenesis of ALL. ROS modulate the function of signalling proteins through oxidation of cysteine residues, as well as promote genomic instability by damaging DNA, to promote chemotherapy resistance. Current therapeutic approaches exploit the pro-oxidant intracellular environment of malignant B and T lymphoblasts to cause irreversible DNA damage and cell death, however these strategies impact normal haematopoiesis and lead to long lasting side-effects. Therapies suppressing ROS production, especially those targeting ROS producing enzymes such as the NADPH oxidases (NOXs), are emerging alternatives to treat cancers and may be exploited to improve the ALL treatment. Here, we discuss the roles that ROS play in normal haematopoiesis and in ALL. We explore the molecular mechanisms underpinning overproduction of ROS in ALL, and their roles in disease progression and drug resistance. Finally, we examine strategies to target ROS production, with a specific focus on the NOX enzymes, to improve the treatment of ALL.
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/0008-5472.C.6651055
Abstract: Abstract Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9 to 11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring i PIK3CA /i mutations showed increased sensitivity to ONC201, whereas those harboring i TP53 /i mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992. Significance: PI3K/Akt signaling promotes metabolic adaptation to ONC201-mediated disruption of mitochondrial energy homeostasis in diffuse intrinsic pontine glioma, highlighting the utility of a combination treatment strategy using ONC201 and the PI3K/Akt inhibitor paxalisib. /
Publisher: American Association for Cancer Research (AACR)
Date: 17-05-2023
DOI: 10.1158/0008-5472.22892044.V1
Abstract: All Supplementary Tables
Publisher: American Association for Cancer Research (AACR)
Date: 17-05-2023
DOI: 10.1158/0008-5472.22892047.V1
Abstract: All Supplementary Figures and their captions.
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/0008-5472.23683824
Abstract: All Supplementary Tables
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/0008-5472.23683827
Abstract: All Supplementary Figures and their captions.
Publisher: American Association for Cancer Research (AACR)
Date: 05-05-2023
DOI: 10.1158/0008-5472.CAN-23-0186
Abstract: PI3K/Akt signaling promotes metabolic adaptation to ONC201-mediated disruption of mitochondrial energy homeostasis in diffuse intrinsic pontine glioma, highlighting the utility of a combination treatment strategy using ONC201 and the PI3K/Akt inhibitor paxalisib.
Publisher: American Association for Cancer Research (AACR)
Date: 17-05-2023
DOI: 10.1158/0008-5472.22892044
Abstract: All Supplementary Tables
Publisher: Springer Science and Business Media LLC
Date: 08-04-2202
Publisher: Cold Spring Harbor Laboratory
Date: 12-03-2022
DOI: 10.1101/2022.03.09.483687
Abstract: FLT3-mutations are diagnosed in 25-30% of patients with acute myeloid leukemia (AML) and are associated with a poor prognosis. AML is associated with the overproduction of reactive oxygen species (ROS), which drives genomic instability through the oxidation of DNA bases, promoting clonal evolution, treatment resistance and poor outcomes. ROS are also important second messengers, triggering cysteine oxidation in redox sensitive signaling proteins, however, the specific pathways influenced by ROS in AML remain enigmatic. Here we have surveyed the posttranslational architecture of primary AML patient s les and assessed oncogenic second messenger signaling. Signaling proteins responsible for growth and proliferation were differentially oxidized and phosphorylated between patient subtypes either harboring recuring mutation in FLT3 compared to patients expressing the wildtype-FLT3 receptor, particularly those mapping to the Src family kinases (SFKs). Patients harboring FLT3-mutations also showed increased oxidative posttranslational modifications in the GTPase Rac activated-NADPH oxidase-2 (NOX2) complex to drive autocratic ROS production. Pharmacological and molecular inhibition of NOX2 was cytotoxic specifically to FLT3-mutant AMLs, and reduced phosphorylation of the critical hematopoietic transcription factor STAT5 and MAPK/ERK to synergistically increase sensitivity to FLT3-inhibitors. NOX2 inhibition also reduced phosphorylation and cysteine oxidation of FLT3 in patient derived xenograft mouse models in vivo , highlighting an important link between oxidative stress and oncogenic signaling. Together, these data raise the promising possibility of targeting NOX2 in combination with FLT3-inhibitors to improve treatment of FLT3-mutant AML. FLT3-precision therapies have entered the clinic for AML however, their durability is limited. Here we identify the Rac-NOX2 complex as the major driver of redox second messenger signaling in FLT3-mutant AML. Molecular and pharmacological inhibition of NOX2 decreased FLT3, STAT5 and MEK/ERK signaling to delay leukemia progression, and synergistically combined with FLT3 inhibitors.
Publisher: American Association for Cancer Research (AACR)
Date: 17-05-2023
DOI: 10.1158/0008-5472.22892047
Abstract: All Supplementary Figures and their captions.
Publisher: Springer Science and Business Media LLC
Date: 12-2022
DOI: 10.1186/S12014-022-09385-7
Abstract: Global high-throughput phosphoproteomic profiling is increasingly being applied to cancer specimens to identify the oncogenic signaling cascades responsible for promoting disease initiation and disease progression pathways that are often invisible to genomics analysis. Hence, phosphoproteomic profiling has enormous potential to inform and improve in idualized anti-cancer treatment strategies. However, to achieve the adequate phosphoproteomic depth and coverage necessary to identify the activated, and hence, targetable kinases responsible for driving oncogenic signaling pathways, affinity phosphopeptide enrichment techniques are required and often coupled with offline high-pressure liquid chromatographic (HPLC) separation prior to nanoflow liquid chromatography–tandem mass spectrometry (nLC-MS/MS). These complex and time-consuming procedures, limit the utility of phosphoproteomics for the analysis of in idual cancer patient specimens in real-time, and restrict phosphoproteomics to specialized laboratories often outside of the clinical setting. To address these limitations, here we have optimized a new protocol, p hospho- h eavy-l a beled-spiketide FAIM S st e pped-CV D DA (pHASED), that employs online phosphoproteome deconvolution using high- f ield a symmetric waveform i on m obility s pectrometry (FAIMS) and internal phosphopeptide standards to provide accurate label-free quantitation (LFQ) data in real-time. Compared with traditional single-shot LFQ phosphoproteomics workflows, pHASED provided increased phosphoproteomic depth and coverage (phosphopeptides = 4617 pHASED, 2789 LFQ), whilst eliminating the variability associated with offline prefractionation. pHASED was optimized using tyrosine kinase inhibitor (sorafenib) resistant isogenic FLT3-mutant acute myeloid leukemia (AML) cell line models. Bioinformatic analysis identified differential activation of the serine/threonine protein kinase ataxia-telangiectasia mutated (ATM) pathway, responsible for sensing and repairing DNA damage in sorafenib-resistant AML cell line models, thereby uncovering a potential therapeutic opportunity. Herein, we have optimized a rapid, reproducible, and flexible protocol for the characterization of complex cancer phosphoproteomes in real-time, a step towards the implementation of phosphoproteomics in the clinic to aid in the selection of anti-cancer therapies for patients.
Publisher: American Association for Cancer Research (AACR)
Date: 27-09-2022
DOI: 10.1158/1541-7786.MCR-22-0567
Abstract: B-cell lymphoma 6 (BCL6) is a protooncogene in adult and pediatric cancers, first identified in diffuse large B-cell lymphoma (DLBCL) where it acts as a repressor of the tumor suppressor TP53, conferring survival, protection, and maintenance of lymphoma cells. BCL6 expression in normal B cells is fundamental in the regulation of humoral immunity, via initiation and maintenance of the germinal centers (GC). Its role in B cells during the production of high affinity immunoglobins (that recognize and bind specific antigens) is believed to underpin its function as an oncogene. BCL6 is known to drive the self-renewal capacity of leukemia-initiating cells (LIC), with high BCL6 expression in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and glioblastoma (GBM) associated with disease progression and treatment resistance. The mechanisms underpinning BCL6-driven therapy resistance are yet to be uncovered however, high activity is considered to confer poor prognosis in the clinical setting. BCL6’s key binding partner, BCL6 corepressor (BCOR), is frequently mutated in pediatric cancers and appears to act in concert with BCL6. Using publicly available data, here we show that BCL6 is ubiquitously overexpressed in pediatric brain tumors, inversely to BCOR, highlighting the potential for targeting BCL6 in these often lethal and untreatable cancers. In this review, we summarize what is known of BCL6 (role, effect, mechanisms) in pediatric cancers, highlighting the two sides of BCL6 function, humoral immunity, and tumorigenesis, as well as to review BCL6 inhibitors and highlight areas of opportunity to improve the outcomes of patients with pediatric cancer.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 28-03-2023
DOI: 10.1126/SCISIGNAL.ABP9586
Abstract: Mutations in the type III receptor tyrosine kinase FLT3 are frequent in patients with acute myeloid leukemia (AML) and are associated with a poor prognosis. AML is characterized by the overproduction of reactive oxygen species (ROS), which can induce cysteine oxidation in redox-sensitive signaling proteins. Here, we sought to characterize the specific pathways affected by ROS in AML by assessing oncogenic signaling in primary AML s les. The oxidation or phosphorylation of signaling proteins that mediate growth and proliferation was increased in s les from patient subtypes with FLT3 mutations. These s les also showed increases in the oxidation of proteins in the ROS-producing Rac/NADPH oxidase-2 (NOX2) complex. Inhibition of NOX2 increased the apoptosis of FLT3-mutant AML cells in response to FLT3 inhibitors. NOX2 inhibition also reduced the phosphorylation and cysteine oxidation of FLT3 in patient-derived xenograft mouse models, suggesting that decreased oxidative stress reduces the oncogenic signaling of FLT3. In mice grafted with FLT3 mutant AML cells, treatment with a NOX2 inhibitor reduced the number of circulating cancer cells, and combining FLT3 and NOX2 inhibitors increased survival to a greater extent than either treatment alone. Together, these data raise the possibility that combining NOX2 and FLT3 inhibitors could improve the treatment of FLT3 mutant AML.
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/0008-5472.C.6651055.V2
Abstract: Abstract Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9 to 11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring i PIK3CA /i mutations showed increased sensitivity to ONC201, whereas those harboring i TP53 /i mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992. Significance: PI3K/Akt signaling promotes metabolic adaptation to ONC201-mediated disruption of mitochondrial energy homeostasis in diffuse intrinsic pontine glioma, highlighting the utility of a combination treatment strategy using ONC201 and the PI3K/Akt inhibitor paxalisib. /
Publisher: American Association for Cancer Research (AACR)
Date: 17-05-2023
DOI: 10.1158/0008-5472.C.6651055.V1
Abstract: Abstract Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9 to 11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring i PIK3CA /i mutations showed increased sensitivity to ONC201, whereas those harboring i TP53 /i mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992. Significance: PI3K/Akt signaling promotes metabolic adaptation to ONC201-mediated disruption of mitochondrial energy homeostasis in diffuse intrinsic pontine glioma, highlighting the utility of a combination treatment strategy using ONC201 and the PI3K/Akt inhibitor paxalisib. /
Publisher: Cold Spring Harbor Laboratory
Date: 17-04-2023
DOI: 10.1101/2023.04.17.537256
Abstract: Diffuse midline glioma (DMG), including tumors diagnosed in the brainstem (diffuse intrinsic pontine glioma – DIPG), are uniformly fatal brain tumors that lack effective pharmacological treatment. Analysis of pooled CRISPR-Cas9 loss-of-function gene deletion screen datasets, identified PIK3CA and MTOR as targetable molecular dependencies across DIPG patient derived models, highlighting the therapeutic potential of the blood-brain barrier penetrant PI3K/Akt/mTOR inhibitor paxalisib. At the human equivalent maximum tolerated dose, mice treated with paxalisib experienced systemic feedback resulting in increased blood glucose and insulin levels, commensurate with DIPG patients in Phase 1b clinical trials who experienced hyperglycemia/hyperinsulinemia. To exploit genetic dependences, but maintain compliance and benefit, we optimized a paxalisib treatment regimen that employed reduced dosing more frequently, in combination with the anti-hyperglycemic drug, metformin. Combining optimized dosing with metformin restored glucose homeostasis and decreased phosphorylation of the insulin receptor in vivo , a common mechanism of PI3K-inhibitor resistance, extending the survival of DIPG xenograft models. RNA sequencing and phosphoproteomic profiling of DIPG models treated with paxalisib identified increased calcium-activated PKC signaling. Using the brain penetrant PKC inhibitor, enzastaurin in combination with paxalisib, we synergistically extended the survival of orthotopic xenograft models, benefits further promoted by metformin thus, identifying a clinically relevant DIPG combinatorial approach. Diffuse intrinsic pontine glioma is a lethal childhood brain tumor. Here we identify PIK3CA as a genetic dependency targeted by the brain penetrant pan-PI3K-inhibitor paxalisib.
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/0008-5472.23683824.V1
Abstract: All Supplementary Tables
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/0008-5472.23683827.V1
Abstract: All Supplementary Figures and their captions.
Publisher: MDPI AG
Date: 28-11-2019
DOI: 10.3390/IJMS20236003
Abstract: Acute myeloid leukaemia (AML) is an aggressive haematological malignancy with a poor overall survival. Reactive oxygen species (ROS) have been shown to be elevated in a wide range of cancers including AML. Whilst previously thought to be mere by-products of cellular metabolism, it is now clear that ROS modulate the function of signalling proteins through oxidation of critical cysteine residues. In this way, ROS have been shown to regulate normal haematopoiesis as well as promote leukaemogenesis in AML. In addition, ROS promote genomic instability by damaging DNA, which promotes chemotherapy resistance. The source of ROS in AML appears to be derived from members of the “NOX family” of NADPH oxidases. Most studies link NOX-derived ROS to activating mutations in the Fms-like tyrosine kinase 3 (FLT3) and Ras-related C3 botulinum toxin substrate (Ras). Targeting ROS through either ROS induction or ROS inhibition provides a novel therapeutic target in AML. In this review, we summarise the role of ROS in normal haematopoiesis and in AML. We also explore the current treatments that modulate ROS levels in AML and discuss emerging drug targets based on pre-clinical work.
No related grants have been discovered for Zacary Germon.