Scholars@Duke
Matthew Waitkus

Matthew Waitkus

Assistant Professor in Neurosurgery
Neurosurgery
matthew.waitkus@duke.edu
DUMC 2600, 203 Research Drive, Room 155, Durham, NC 27710
203 Research Drive, Durham, NC 27705

Selected Publications

Mechanisms of telomere maintenance and associated therapeutic vulnerabilities in malignant gliomas.

Journal Article Neuro Oncol · June 3, 2024 A majority of cancers (~85%) activate the enzyme telomerase to maintain telomere length over multiple rounds of cellular division. Telomerase-negative cancers activate a distinct, telomerase-independent mechanism of telomere maintenance termed alternative ... Full text Link to item Cite

Interplay between ATRX and IDH1 mutations governs innate immune responses in diffuse gliomas.

Journal Article Nat Commun · January 25, 2024 Stimulating the innate immune system has been explored as a therapeutic option for the treatment of gliomas. Inactivating mutations in ATRX, defining molecular alterations in IDH-mutant astrocytomas, have been implicated in dysfunctional immune signaling. ... Full text Link to item Cite

Understanding and therapeutically exploiting cGAS/STING signaling in glioblastoma.

Journal Article J Clin Invest · January 16, 2024 Since the discovery that cGAS/STING recognizes endogenous DNA released from dying cancer cells and induces type I interferon and antitumor T cell responses, efforts to understand and therapeutically target the STING pathway in cancer have ensued. Relative ... Full text Link to item Cite

Mining cancer genomes for change-of-metabolic-function mutations.

Journal Article Commun Biol · November 10, 2023 Enzymes with novel functions are needed to enable new organic synthesis techniques. Drawing inspiration from gain-of-function cancer mutations that functionally alter proteins and affect cellular metabolism, we developed METIS (Mutated Enzymes from Tumors ... Full text Link to item Cite

Pooled genetic screens to identify vulnerabilities in TERT-promoter-mutant glioblastoma.

Journal Article Oncogene · October 2023 Pooled genetic screens represent a powerful approach to identify vulnerabilities in cancer. Here we used pooled CRISPR/Cas9-based approaches to identify vulnerabilities associated with telomerase reverse transcriptase (TERT) promoter mutations (TPMs) found ... Full text Link to item Cite

Cancer-associated SMARCAL1 loss-of-function mutations promote alternative lengthening of telomeres and tumorigenesis in telomerase-negative glioblastoma cells.

Journal Article Neuro Oncol · September 5, 2023 BACKGROUND: Telomere maintenance mechanisms are required to enable the replicative immortality of malignant cells. While most cancers activate the enzyme telomerase, a subset of cancers uses telomerase-independent mechanisms termed alternative lengthening ... Full text Link to item Cite

Interplay between ATRX and IDH1 mutations governs innate immune responses in diffuse gliomas.

Journal Article bioRxiv · April 21, 2023 Stimulating the innate immune system has been explored as a therapeutic option for the treatment of gliomas. Inactivating mutations in ATRX , defining molecular alterations in IDH -mutant astrocytomas, have been implicated in dysfunctional immune signaling ... Full text Link to item Cite

Antitumor Activity of a Mitochondrial-Targeted HSP90 Inhibitor in Gliomas.

Journal Article Clin Cancer Res · May 13, 2022 PURPOSE: To investigate the antitumor activity of a mitochondrial-localized HSP90 inhibitor, Gamitrinib, in multiple glioma models, and to elucidate the antitumor mechanisms of Gamitrinib in gliomas. EXPERIMENTAL DESIGN: A broad panel of primary and temozo ... Full text Link to item Cite

A Modified Nucleoside 6-Thio-2'-Deoxyguanosine Exhibits Antitumor Activity in Gliomas.

Journal Article Clin Cancer Res · December 15, 2021 PURPOSE: To investigate the therapeutic role of a novel telomere-directed inhibitor, 6-thio-2'-deoxyguanosine (THIO) in gliomas both in vitro and in vivo. EXPERIMENTAL DESIGN: A panel of human and mouse glioma cell lines was used to test therapeutic effica ... Full text Link to item Cite

TP53 wild-type/PPM1D mutant diffuse intrinsic pontine gliomas are sensitive to a MDM2 antagonist.

Journal Article Acta Neuropathol Commun · November 3, 2021 Diffuse intrinsic pontine gliomas (DIPGs) are high-grade tumors of the brainstem that often occur in children, with a median overall survival of less than one year. Given the fact that DIPGs are resistant to chemotherapy and are not amenable to surgical re ... Full text Link to item Cite

Targeting Isocitrate Dehydrogenase Mutations in Cancer: Emerging Evidence and Diverging Strategies.

Journal Article Clin Cancer Res · January 15, 2021 Isocitrate dehydrogenase (IDH) active-site mutations cause a neomorphic enzyme activity that results in the formation of supraphysiologic concentrations of D-2-hydroxyglutarate (D-2HG). D-2HG is thought to be an oncometabolite that drives the formation of ... Full text Link to item Cite

Targeting Mutant PPM1D Sensitizes Diffuse Intrinsic Pontine Glioma Cells to the PARP Inhibitor Olaparib.

Journal Article Mol Cancer Res · July 2020 Diffuse intrinsic pontine glioma (DIPG) is an invariably fatal brain tumor occurring predominantly in children. Up to 90% of pediatric DIPGs harbor a somatic heterozygous mutation resulting in the replacement of lysine 27 with methionine (K27M) in genes en ... Full text Link to item Cite

The integrated genomic and epigenomic landscape of brainstem glioma.

Journal Article Nature communications · June 2020 Brainstem gliomas are a heterogeneous group of tumors that encompass both benign tumors cured with surgical resection and highly lethal cancers with no efficacious therapies. We perform a comprehensive study incorporating epigenetic and genomic analyses on ... Full text Cite

CRISPR Editing of Mutant IDH1 R132H Induces a CpG Methylation-Low State in Patient-Derived Glioma Models of G-CIMP.

Journal Article Mol Cancer Res · October 2019 Mutations in isocitrate dehydrogenases 1 and 2 (IDH) occur in the majority of World Health Organization grade II and III gliomas. IDH1/2 active site mutations confer a neomorphic enzyme activity producing the oncometabolite D-2-hydroxyglutarate (D-2HG), wh ... Full text Link to item Cite

Non-invasive sensitive brain tumor detection using dual-modality bioimaging nanoprobe.

Journal Article Nanotechnology · July 5, 2019 Despite decades of efforts, non-invasive sensitive detection of small malignant brain tumors still remains challenging. Here we report a dual-modality 124I-labeled gold nanostar (124I-GNS) probe for sensitive brain tumor imaging with positron emission tomo ... Full text Link to item Cite

Hereditary brain tumor with a homozygous germline mutation in PMS2: pedigree analysis and prenatal screening in a family with constitutional mismatch repair deficiency (CMMRD) syndrome.

Journal Article Fam Cancer · April 2019 Precise genetic counseling and prenatal diagnosis are often hindered by incomplete penetrance of risk variance and complex patterns of inheritance. Here, we performed a clinical and genetic study of a five-generation Pakistani family with a history of mult ... Full text Link to item Cite

Sensitive and rapid detection of TERT promoter and IDH mutations in diffuse gliomas.

Journal Article Neuro Oncol · March 18, 2019 BACKGROUND: Mutations in telomerase reverse transcriptase promoter (TERTp) and isocitrate dehydrogenase 1 and 2 (IDH) offer objective markers to assist in classifying diffuse gliomas into genetic subgroups. However, traditional mutation detection technique ... Full text Link to item Cite

Biological Role and Therapeutic Potential of IDH Mutations in Cancer.

Journal Article Cancer Cell · August 13, 2018 Hotspot mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) occur in a variety of myeloid malignancies and solid tumors. Mutant IDH proteins acquire a neomorphic enzyme activity to produce the putative oncometabolite D-2-hy ... Full text Link to item Cite

The genomic landscape of TERT promoter wildtype-IDH wildtype glioblastoma.

Journal Article Nat Commun · May 25, 2018 The majority of glioblastomas can be classified into molecular subgroups based on mutations in the TERT promoter (TERTp) and isocitrate dehydrogenase 1 or 2 (IDH). These molecular subgroups utilize distinct genetic mechanisms of telomere maintenance, eithe ... Full text Link to item Cite

Adaptive Evolution of the GDH2 Allosteric Domain Promotes Gliomagenesis by Resolving IDH1R132H-Induced Metabolic Liabilities.

Journal Article Cancer Res · January 1, 2018 Hotspot mutations in the isocitrate dehydrogenase 1 (IDH1) gene occur in a number of human cancers and confer a neomorphic enzyme activity that catalyzes the conversion of α-ketoglutarate (αKG) to the oncometabolite D-(2)-hydroxyglutarate (D2HG). In malign ... Full text Link to item Cite

Cic Loss Promotes Gliomagenesis via Aberrant Neural Stem Cell Proliferation and Differentiation.

Journal Article Cancer Res · November 15, 2017 Inactivating mutations in the transcriptional repression factor Capicua (CIC) occur in approximately 50% of human oligodendrogliomas, but mechanistic links to pathogenesis are unclear. To address this question, we generated Cic-deficient mice and human oli ... Full text Link to item Cite

Mutant IDH1 Disrupts the Mouse Subventricular Zone and Alters Brain Tumor Progression.

Journal Article Mol Cancer Res · May 2017 IDH1 mutations occur in the majority of low-grade gliomas and lead to the production of the oncometabolite, D-2-hydroxyglutarate (D-2HG). To understand the effects of tumor-associated mutant IDH1 (IDH1-R132H) on both the neural stem cell (NSC) population a ... Full text Link to item Cite

Isocitrate dehydrogenase mutations in gliomas.

Journal Article Neuro Oncol · January 2016 Over the last decade, extraordinary progress has been made in elucidating the underlying genetic causes of gliomas. In 2008, our understanding of glioma genetics was revolutionized when mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) were identified ... Full text Link to item Cite

Mitogen-activated protein kinase phosphatase-1 promotes neovascularization and angiogenic gene expression.

Journal Article Arterioscler Thromb Vasc Biol · May 2014 OBJECTIVE: Angiogenesis is the formation of new blood vessels through endothelial cell sprouting. This process requires the mitogen-activated protein kinases, signaling molecules that are negatively regulated by the mitogen-activated protein kinase phospha ... Full text Link to item Cite

Signal integration and gene induction by a functionally distinct STAT3 phosphoform.

Journal Article Mol Cell Biol · May 2014 Aberrant activation of the ubiquitous transcription factor STAT3 is a major driver of solid tumor progression and pathological angiogenesis. STAT3 activity is regulated by numerous posttranslational modifications (PTMs), including Tyr(705) phosphorylation, ... Full text Link to item Cite

Release of nonmuscle myosin II from the cytosolic domain of tumor necrosis factor receptor 2 is required for target gene expression.

Journal Article Sci Signal · July 16, 2013 Tumor necrosis factor-α (TNF-α) elicits its biological activities through activation of TNF receptor 1 (TNFR1, also known as p55) and TNFR2 (also known as p75). The activities of both receptors are required for the TNF-α-induced proinflammatory response. T ... Full text Link to item Cite

STAT3-mediated coincidence detection regulates noncanonical immediate early gene induction.

Journal Article J Biol Chem · April 26, 2013 Signaling pathways interact with one another to form dynamic networks in which the cellular response to one stimulus may depend on the presence, intensity, timing, or localization of other signals. In rare cases, two stimuli may be simultaneously required ... Full text Link to item Cite

Synergistic induction of mitogen-activated protein kinase phosphatase-1 by thrombin and epidermal growth factor requires vascular endothelial growth factor receptor-2.

Journal Article Arterioscler Thromb Vasc Biol · October 2010 OBJECTIVE: To determine the molecular mechanism underlying the synergistic response of mitogen-activated protein kinase phosphatase-1 (MKP-1), which is induced by thrombin and epidermal growth factor (EGF). METHODS AND RESULTS: MKP-1 induction by thrombin ... Full text Link to item Cite