Publications by authors named "Ranjit S Bindra"

68 Publications

Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly.

Nat Commun 2020 11 17;11(1):5861. Epub 2020 Nov 17.

Department of Laboratory Medicine, Yale University School of Medicine, 330 Cedar St., New Haven, CT, 06520, USA.

Telomeres protect chromosome ends from inappropriately activating the DNA damage and repair responses. Primary microcephaly is a key clinical feature of several human telomere disorder syndromes, but how microcephaly is linked to dysfunctional telomeres is not known. Here, we show that the microcephalin 1/BRCT-repeats inhibitor of hTERT (MCPH1/BRIT1) protein, mutated in primary microcephaly, specifically interacts with the TRFH domain of the telomere binding protein TRF2. The crystal structure of the MCPH1-TRF2 complex reveals that this interaction is mediated by the MCPH1 YRLSP motif. TRF2-dependent recruitment of MCPH1 promotes localization of DNA damage factors and homology directed repair of dysfunctional telomeres lacking POT1-TPP1. Additionally, MCPH1 is involved in the replication stress response, promoting telomere replication fork progression and restart of stalled telomere replication forks. Our work uncovers a previously unrecognized role for MCPH1 in promoting telomere replication, providing evidence that telomere replication defects may contribute to the onset of microcephaly.
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http://dx.doi.org/10.1038/s41467-020-19674-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672075PMC
November 2020

Penetrating the brain tumor space with DNA damage response inhibitors.

Authors:
Ranjit S Bindra

Neuro Oncol 2020 12;22(12):1718-1720

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut.

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http://dx.doi.org/10.1093/neuonc/noaa228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746934PMC
December 2020

LRRC31 inhibits DNA repair and sensitizes breast cancer brain metastasis to radiation therapy.

Nat Cell Biol 2020 10 1;22(10):1276-1285. Epub 2020 Oct 1.

Department of Neurosurgery, Yale University, New Haven, CT, USA.

Breast cancer brain metastasis (BCBM) is a devastating disease. Radiation therapy remains the mainstay for treatment of this disease. Unfortunately, its efficacy is limited by the dose that can be safely applied. One promising approach to overcoming this limitation is to sensitize BCBMs to radiation by inhibiting their ability to repair DNA damage. Here, we report a DNA repair suppressor, leucine-rich repeat-containing protein 31 (LRRC31), that was identified through a genome-wide CRISPR screen. We found that overexpression of LRRC31 suppresses DNA repair and sensitizes BCBMs to radiation. Mechanistically, LRRC31 interacts with Ku70/Ku80 and the ataxia telangiectasia mutated and RAD3-related (ATR) at the protein level, resulting in inhibition of DNA-dependent protein kinase, catalytic subunit (DNA-PKcs) recruitment and activation, and disruption of the MutS homologue 2 (MSH2)-ATR module. We demonstrate that targeted delivery of the LRRC31 gene via nanoparticles improves the survival of tumour-bearing mice after irradiation. Collectively, our study suggests LRRC31 as a major DNA repair suppressor that can be targeted for cancer radiosensitizing therapy.
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http://dx.doi.org/10.1038/s41556-020-00586-6DOI Listing
October 2020

Persistent mutation despite multimodal therapy in recurrent pediatric glioblastoma.

NPJ Genom Med 2020 1;5:23. Epub 2020 Jun 1.

Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06511 USA.

Similar to their adult counterparts, the prognosis for pediatric patients with high-grade gliomas remains poor. At time of recurrence, treatment options are limited and remain without consensus. This report describes the genetic findings, obtained from whole-exome sequencing of a pediatric patient with glioblastoma who underwent multiple surgical resections and treatment with standard chemoradiation, as well as a novel recombinant poliovirus vaccine therapy. Strikingly, despite the variety of treatments, there was persistence of a tumor clone, characterized by a deleterious mutation, whose deficiency in preclinical studies can cause aneuploidy and aberrant mitotic progression, but remains understudied in the clinical setting. There was near elimination of an mutated and amplified tumor clone after gross total resection, standard chemoradiation, and poliovirus therapy, followed by the emergence of a persistently mutated clone, with rare mutations in and , the latter composed of a novel deleterious mutation previously not reported in pediatric glioblastoma (p.D594G). This was accompanied by a mutation signature shift towards one characterized by increased DNA damage repair defects, consistent with the known underlying deficiency. As such, this case represents a novel report following the clinical and genetic progression of a mutated glioblastoma, including treatment with a novel and emerging immunotherapy. Although deficiency comprises only a small subset of gliomas, this case adds clinical evidence to existing preclinical data supporting a role for mutations in gliomagenesis and resistance to standard therapies.
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http://dx.doi.org/10.1038/s41525-020-0130-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264170PMC
June 2020

Oncometabolites suppress DNA repair by disrupting local chromatin signalling.

Nature 2020 06 3;582(7813):586-591. Epub 2020 Jun 3.

Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA.

Deregulation of metabolism and disruption of genome integrity are hallmarks of cancer. Increased levels of the metabolites 2-hydroxyglutarate, succinate and fumarate occur in human malignancies owing to somatic mutations in the isocitrate dehydrogenase-1 or -2 (IDH1 or IDH2) genes, or germline mutations in the fumarate hydratase (FH) and succinate dehydrogenase genes (SDHA, SDHB, SDHC and SDHD), respectively. Recent work has made an unexpected connection between these metabolites and DNA repair by showing that they suppress the pathway of homology-dependent repair (HDR) and confer an exquisite sensitivity to inhibitors of poly (ADP-ribose) polymerase (PARP) that are being tested in clinical trials. However, the mechanism by which these oncometabolites inhibit HDR remains poorly understood. Here we determine the pathway by which these metabolites disrupt DNA repair. We show that oncometabolite-induced inhibition of the lysine demethylase KDM4B results in aberrant hypermethylation of histone 3 lysine 9 (H3K9) at loci surrounding DNA breaks, masking a local H3K9 trimethylation signal that is essential for the proper execution of HDR. Consequently, recruitment of TIP60 and ATM, two key proximal HDR factors, is substantially impaired at DNA breaks, with reduced end resection and diminished recruitment of downstream repair factors. These findings provide a mechanistic basis for oncometabolite-induced HDR suppression and may guide effective strategies to exploit these defects for therapeutic gain.
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http://dx.doi.org/10.1038/s41586-020-2363-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319896PMC
June 2020

Estimation of the carrier frequency of fumarate hydratase alterations and implications for kidney cancer risk in hereditary leiomyomatosis and renal cancer.

Cancer 2020 Aug 15;126(16):3657-3666. Epub 2020 May 15.

Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut.

Background: Hereditary leiomyomatosis and renal cancer (HLRCC) is a cancer syndrome associated with a germline mutation in fumarate hydratase (FH). The syndrome is associated with cutaneous and uterine leiomyomas, and some patients develop a lethal form of kidney cancer. This study provides estimates for the FH carrier frequency and kidney cancer penetrance.

Methods: Data sets containing sequencing data for the FH gene were used: the 1000 Genomes Project (1000GP) and the Exome Aggregation Consortium (ExAC). Alterations in the FH gene were characterized on the basis of different variant risk tiers: 1) ClinVar annotated variants, 2) loss-of-function alterations, and 3) highly impactful missense alterations. The cumulative incidence of FH alterations overall and by different world populations was evaluated in 1000GP and ExAC. A lifetime penetrance of HLRCC kidney cancer risk was generated with 3 estimates of the annual incidence.

Results: The overall allele frequencies of tier 1 to 3 FH alterations in the ExAC and 1000GP data sets were 2.54 × 10 (1 in 393) and 1.20 × 10 (1 in 835), respectively. There were differences in the allele frequencies of FH alterations between world populations. Based on various estimates of the percentage of kidney cancers with FH alterations, the lifetime kidney cancer penetrance for carrier estimate 3 in ExAC was 1.7% to 5.8%.

Conclusions: FH alterations are common and are carried by approximately 1 in 1000 individuals according to the more conservative estimates. The lifetime kidney cancer penetrance appears lower than previously estimated. Although databases are not population cohorts, they provide a useful quantitative estimate of rare variants with low penetrance.
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http://dx.doi.org/10.1002/cncr.32914DOI Listing
August 2020

Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions.

Neuro Oncol 2020 08;22(8):1073-1113

Department of Neurology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.

Glioblastomas are the most common form of malignant primary brain tumor and an important cause of morbidity and mortality. In recent years there have been important advances in understanding the molecular pathogenesis and biology of these tumors, but this has not translated into significantly improved outcomes for patients. In this consensus review from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO), the current management of isocitrate dehydrogenase wildtype (IDHwt) glioblastomas will be discussed. In addition, novel therapies such as targeted molecular therapies, agents targeting DNA damage response and metabolism, immunotherapies, and viral therapies will be reviewed, as well as the current challenges and future directions for research.
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http://dx.doi.org/10.1093/neuonc/noaa106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594557PMC
August 2020

Gray Areas in the Gray Matter: Mutations in Glioma.

Am Soc Clin Oncol Educ Book 2020 Mar;40:1-8

Departments of Therapeutic Radiology and Pathology, Yale School of Medicine, New Haven, CT.

Since the first discovery of isocitrate dehydrogenase ( mutations in cancer, considerable progress has been made in our understanding of their contribution to cancer development. For glioma, this has helped to identify two diagnostic groups of tumors (oligodendroglioma and astrocytoma ) with distinct clinical characteristics and that are now diagnosed by the presence of the mutations. The metabolic changes occurring as the consequence of the altered substrate affinity of the mutant IDH protein results in a cascade of intracellular changes, also inducing a relative sensitivity to chemotherapy and radiotherapy compared with tumors. Pharmacologic blockade of the mutant enzyme with first-in-class inhibitors has been efficacious for the treatment of mutant acute myeloid leukemia (AML) and is currently being evaluated in phase III trials for mutant glioma (INDIGO) and cholangiocarcinoma (ClarIDHy). It seems likely that acquired resistance to mutant IDH inhibitors will eventually emerge, and combination therapies to augment the antitumor activity of mutant IDH inhibitors have already been initiated. Approaches to exploit, rather than inhibit, the unique metabolism of mutant cancer cells have emerged from laboratory studies and are now also being tested in the clinic. Results of these clinical trials are eagerly awaited and will likely provide new key insights and direction of the treatment of mutant human cancer.
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http://dx.doi.org/10.1200/EDBK_280967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673204PMC
March 2020

Targeting DNA repair in gliomas.

Curr Opin Neurol 2019 12;32(6):878-885

Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.

Purpose Of Review: Gliomas represent a disparate group of malignancies with varying clinical outcomes despite a tremendous amount of time, effort, and resources dedicated to their management and understanding. The most aggressive entity, glioblastoma, has a dismal prognosis with poor local control despite intense local and systemic treatment, including radiation therapy.

Recent Findings: Given the heterogeneity in genotype, phenotype, and patient outcomes, researchers and clinicians have turned their attention toward attacking DNA damage response and repair mechanisms in gliomas in an effort to develop novel chemo and radiosensitizers. However, despite extensive work in both the laboratory and the clinic, no sensitizers have yet to emerge as clear options in the treatment of glioma, often because of meager preclinical data or an inability to penetrate the blood-brain barrier.

Summary: This review will examine current understanding of molecular DNA repair targets in glioma and their potential exploitation to improve local control and, ultimately, overall survival of patients afflicted with these diseases.
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http://dx.doi.org/10.1097/WCO.0000000000000760DOI Listing
December 2019

PPM1D mutations silence NAPRT gene expression and confer NAMPT inhibitor sensitivity in glioma.

Nat Commun 2019 08 22;10(1):3790. Epub 2019 Aug 22.

Department of Pathology, Yale University, New Haven, CT, 06520, USA.

Pediatric high-grade gliomas are among the deadliest of childhood cancers due to limited knowledge of early driving events in their gliomagenesis and the lack of effective therapies available. In this study, we investigate the oncogenic role of PPM1D, a protein phosphatase often found truncated in pediatric gliomas such as DIPG, and uncover a synthetic lethal interaction between PPM1D mutations and nicotinamide phosphoribosyltransferase (NAMPT) inhibition. Specifically, we show that mutant PPM1D drives hypermethylation of CpG islands throughout the genome and promotes epigenetic silencing of nicotinic acid phosphoribosyltransferase (NAPRT), a key gene involved in NAD biosynthesis. Notably, PPM1D mutant cells are shown to be sensitive to NAMPT inhibitors in vitro and in vivo, within both engineered isogenic astrocytes and primary patient-derived model systems, suggesting the possible application of NAMPT inhibitors for the treatment of pediatric gliomas. Overall, our results reveal a promising approach for the targeting of PPM1D mutant tumors, and define a critical link between oncogenic driver mutations and NAD metabolism, which can be exploited for tumor-specific cell killing.
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http://dx.doi.org/10.1038/s41467-019-11732-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6706443PMC
August 2019

Quantitative Profiling of Oncometabolites in Frozen and Formalin-Fixed Paraffin-Embedded Tissue Specimens by Liquid Chromatography Coupled with Tandem Mass Spectrometry.

Sci Rep 2019 08 2;9(1):11238. Epub 2019 Aug 2.

Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA.

Given the implications of oncometabolites [succinate, fumarate, and 2-hydroxyglutarate (2HG)] in cancer pathogenesis and therapeutics, quantitative determination of their tissue levels has significant diagnostic, prognostic, and therapeutic values. Here, we developed and validated a multiplex liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) platform that allows simultaneous determination of oncometabolites (including succinate, fumarate and total 2HG) and other tricarboxylic acid cycle metabolites (α-ketoglutarate, malic acid, and glutamate) in frozen and FFPE tissues specimens. In addition, by employing chiral derivatization in the sample preparation, the platform enabled separation and determination of 2HG enantiomers (D- and L-2HG) in frozen and FFPE tissues. Isotope-labeled internal standard method was used for the quantitation. Linear calibration curve ranges in aqueous solution were 0.02-10, 0.2-100, 0.002-10, and 0.002-5 µM for succinate, fumarate, total 2HG, and D/L-2HG, respectively. Intra- and inter-day precision and accuracy for individual oncometabolites were within the generally accepted criteria for bioanalytical method validation (<15%). The recovery of spiked individual oncometabolites from pooled homogenate of FFPE or frozen tissue ranged 86-112%. Method validation indicated the technical feasibility, reliability and reproducibility of the platform. Oncometabolites were notably lost during the routine FFPE process. The ratios of succinate to glutamate, fumarate to α-ketoglutarate, 2HG to glutamate, and D-2HG to L-2HG were reliable surrogate measurements for the detection of altered levels of oncometabolites in FFPE specimens. Our study laid a foundation for the utility of archival FFPE specimens for oncometabolite profiling as a valid technique in clinical research and routine medical care.
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http://dx.doi.org/10.1038/s41598-019-47669-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677826PMC
August 2019

co-mutation in an -mutant glioblastoma.

Cold Spring Harb Mol Case Stud 2019 08 1;5(4). Epub 2019 Aug 1.

Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut 06520, USA.

Glioblastomas are highly aggressive, infiltrative, and genetically heterogeneous primary brain tumors that arise de novo or secondarily progress over time from low-grade tumors. Along with well-established signature mutational profiles, emerging research suggests that the epigenetic tumor landscape plays an important role in gliomagenesis via transcriptional regulation, DNA methylation, and histone modifications. The pursuit of targeted therapeutic approaches, based not only on expression profiles but also on somatic mutations, is fundamental to the effort of improving survival in patients with glioblastoma. Here, we describe a missense p.P904S mutation in an -mutant glioblastoma. Although never previously reported in gliomas, this mutation is predicted to be pathogenic and has been reported in several other malignancies. Our report suggests that elucidating epigenetic control is important to understanding glioblastoma biology and may likely unveil targets potentially important to glioblastoma treatment in an effort to improve survival.
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http://dx.doi.org/10.1101/mcs.a004119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6672028PMC
August 2019

Role of Radiation Therapy in the Management of Diffuse Intrinsic Pontine Glioma: A Systematic Review.

Adv Radiat Oncol 2019 Jul-Sep;4(3):520-531. Epub 2019 Mar 30.

Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York.

Purpose: Diffuse intrinsic pontine glioma (DIPG) is the most aggressive primary pediatric brain tumor, with <10% of children surviving 2 years. Radiation therapy (RT) remains the mainstay of treatment, but there is a great clinical need for improvements and advancements in treatment strategies. The aim of this systematic review was to identify all available studies in which RT was used to treat patients with DIPG.

Methods And Materials: A literature search for studies published up to March 10, 2018 was conducted using the PubMed database. We identified 384 articles using search items "diffuse intrinsic pontine glioma" and 221 articles using search items "diffuse brainstem glioma radiotherapy." Included studies were prospective and retrospective series that reported outcomes of DIPG treatment with RT.

Results: We identified 49 studies (1286 patients) using upfront conventionally fractionated RT, 5 studies (92 patients) using hypofractionated RT, and 8 studies (348 patients) using hyperfractionated RT. The mean median overall survival (OS) was 12.0 months, 10.2 months, and 7.9 months in patients who received conventional, hyperfractionated, and hypofractionated RT regimens, respectively. Patients undergoing radiosensitizing therapy had a mean median OS of 11.5 months, and patients who did not receive concomitant systemic therapy had an OS of 9.4 months. In patients who received salvage RT, the mean median OS from initial diagnosis was 16.3 months.

Conclusions: As one of the largest systematic reviews examining RT for DIPG, this report may serve as a useful tool to help clinicians choose the most appropriate treatment approach, while also providing a platform for future investigations into the utility of RT and systemic therapy.
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http://dx.doi.org/10.1016/j.adro.2019.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639749PMC
March 2019

Temozolomide Sensitizes MGMT-Deficient Tumor Cells to ATR Inhibitors.

Cancer Res 2019 09 4;79(17):4331-4338. Epub 2019 Jul 4.

Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut.

O-methylguanine-DNA methyltransferase (MGMT) is an enzyme that removes alkyl groups at the O-position of guanine in DNA. MGMT expression is reduced or absent in many tumor types derived from a diverse range of tissues, most notably in glioma. Low MGMT expression confers significant sensitivity to DNA alkylating agents such as temozolomide, providing a natural therapeutic index over normal tissue. In this study, we sought to identify novel approaches that could maximally exploit the therapeutic index between tumor cells and normal tissues based on MGMT expression, as a means to enhance selective tumor cell killing. Temozolomide, unlike other alkylators, activated the ataxia telangiectasia and Rad3-related (ATR)-checkpoint kinase 1 (Chk1) axis in a manner that was highly dependent on MGMT status. Temozolomide induced growth delay, DNA double-strand breaks, and G-M cell-cycle arrest, which led to ATR-dependent phosphorylation of Chk1; this effect was dependent on reduced MGMT expression. Treatment of MGMT-deficient cells with temozolomide increased sensitivity to ATR inhibitors both and across numerous tumor cell types. Taken together, this study reveals a novel approach for selectively targeting MGMT-deficient cells with ATR inhibitors and temozolomide. As ATR inhibitors are currently being tested in clinical trials, and temozolomide is a commonly used chemotherapeutic, this approach is clinically actionable. Furthermore, this interaction potently exploits a DNA-repair defect found in many cancers. SIGNIFICANCE: Monofunctional alkylating agents sensitize MGMT-deficient tumor cells to ATR inhibitors.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6810597PMC
September 2019

Defining an Intermediate-risk Group for Low-grade Glioma: A National Cancer Database Analysis.

Anticancer Res 2019 Jun;39(6):2911-2918

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, U.S.A.

Background: RTOG 9802 identified a cohort of patients with age less than 40 years and undergoing gross total resection as having low-risk, low-grade glioma (LR-LGG). European Organization for Research and Treatment of Cancer studies have demonstrated additional prognostic features in this group. The aim of this study was to analyze clinical factors associated with overall survival (OS), identify a potentially higher risk group within LR-LGG, and investigate patterns of care for adjuvant therapy.

Materials And Methods: Patients with LR-LGG diagnosed between 2010 to 2013 were identified in the National Cancer Database. Kaplan-Meier method was used to analyze OS. Propensity score matching and multivariate analysis were utilized to adjust for differences in cohorts.

Results: A total of 1,032 patients with LR-LGG were identified. Histological breakdown was 42.0% astrocytoma, 33.2% oligodendroglioma, and 25.8% mixed. Median follow-up was 3.9 years; median pre-operative tumor size was 4.0 cm. Overall, 834 (80.8%) underwent observation and 198 (19.2%) received adjuvant therapy. Tumor size >5 cm predicted for receipt of adjuvant therapy on regression analyses (OR=2.02, p=0.001). On multivariate analysis, tumor size >5 cm (hazard ratio=1.95) and non-oligodendroglioma histology (hazard ratio=2.50) were associated with inferior OS (both p<0.05). For patients with both poor prognostic features (a subset we consider "intermediate-risk"), 5-year OS was 78.4%, compared to 94.1% for all other low-risk patients (p<0.001). After propensity score matching, the intermediate-risk group continued to be associated with worse 5-year OS: 80.5% vs. 94.0%, p=0.004.

Conclusion: Due to inferior OS for patients with LR-LGG with >5 cm, non-oligodendroglioma tumors, we propose an 'intermediate-risk' clinical classification for this subset.
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http://dx.doi.org/10.21873/anticanres.13420DOI Listing
June 2019

Pathologic Oxidation of PTPN12 Underlies ABL1 Phosphorylation in Hereditary Leiomyomatosis and Renal Cell Carcinoma.

Cancer Res 2018 12 8;78(23):6539-6548. Epub 2018 Oct 8.

Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.

: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an inherited cancer syndrome associated with a highly aggressive form of type 2 papillary renal cell carcinoma (PRCC). Germline inactivating alterations in () cause HLRCC and result in elevated levels of reactive oxygen species (ROS). Recent work indicates that PRCC cells have increased activation of ABL1, which promotes tumor growth, but how ABL1 is activated remains unclear. Given that oxidation can regulate protein-tyrosine phosphatase (PTP) catalytic activity, inactivation of an ABL-directed PTP by ROS might account for ABL1 activation in this malignancy. Our group previously developed "q-oxPTPome," a method that globally monitors the oxidation of classical PTPs. In this study, we present a refined q-oxPTPome, increasing its sensitivity by >10×. Applying q-oxPTPome to FH-deficient cell models showed that multiple PTPs were either highly oxidized (including PTPN12) or overexpressed. Highly oxidized PTPs were those with relatively high sensitivity to exogenous HO. Most PTP oxidation in FH-deficient cells was reversible, although nearly 40% of PTPN13 was irreversibly oxidized to the sulfonic acid state. Using substrate-trapping mutants, we mapped PTPs to their putative substrates and found that only PTPN12 could target ABL1. Furthermore, knockdown experiments identified PTPN12 as the major ABL1 phosphatase, and overexpression of PTPN12 inhibited ABL1 phosphorylation and HLRCC cell growth. These results show that ROS-induced oxidation of PTPN12 accounts for ABL1 phosphorylation in HLRCC-associated PRCC, revealing a novel mechanism for inactivating a tumor suppressor gene product and establishing a direct link between pathologic PTP oxidation and neoplastic disease. SIGNIFICANCE: This work identifies a novel mechanism of activation of the oncogenic kinase ABL1 via ROS-induced, oxidation-mediated inactivation of cognate protein tyrosine phosphatases.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-0901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279512PMC
December 2018

The Higher the Grade, the Bigger the Field.

Int J Radiat Oncol Biol Phys 2018 11;102(3):488-489

Department of Therapeutic Radiology Yale School of Medicine, New Haven, Connecticut.

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http://dx.doi.org/10.1016/j.ijrobp.2018.08.019DOI Listing
November 2018

Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair.

Nat Genet 2018 08 16;50(8):1086-1092. Epub 2018 Jul 16.

Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA.

The hereditary cancer syndromes hereditary leiomyomatosis and renal cell cancer (HLRCC) and succinate dehydrogenase-related hereditary paraganglioma and pheochromocytoma (SDH PGL/PCC) are linked to germline loss-of-function mutations in genes encoding the Krebs cycle enzymes fumarate hydratase and succinate dehydrogenase, thus leading to elevated levels of fumarate and succinate, respectively. Here, we report that fumarate and succinate both suppress the homologous recombination (HR) DNA-repair pathway required for the resolution of DNA double-strand breaks (DSBs) and for the maintenance of genomic integrity, thus rendering tumor cells vulnerable to synthetic-lethal targeting with poly(ADP)-ribose polymerase (PARP) inhibitors. These results identify HLRCC and SDH PGL/PCC as familial DNA-repair deficiency syndromes, providing a mechanistic basis to explain their cancer predisposition and suggesting a potentially therapeutic approach for advanced HLRCC and SDH PGL/PCC, both of which are incurable when metastatic.
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http://dx.doi.org/10.1038/s41588-018-0170-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072579PMC
August 2018

Biodegradable PEG-poly(ω-pentadecalactone-co-p-dioxanone) nanoparticles for enhanced and sustained drug delivery to treat brain tumors.

Biomaterials 2018 09 18;178:193-203. Epub 2018 Jun 18.

Department of Biomedical Engineering, Yale University, New Haven, CT, 06511, USA. Electronic address:

Intracranial delivery of therapeutic agents is limited by penetration beyond the blood-brain barrier (BBB) and rapid metabolism of the drugs that are delivered. Convection-enhanced delivery (CED) of drug-loaded nanoparticles (NPs) provides for local administration, control of distribution, and sustained drug release. While some investigators have shown that repeated CED procedures are possible, longer periods of sustained release could eliminate the need for repeated infusions, which would enhance safety and translatability of the approach. Here, we demonstrate that nanoparticles formed from poly(ethylene glycol)-poly(ω-pentadecalactone-co-p-dioxanone) block copolymers [PEG-poly(PDL-co-DO)] are highly efficient nanocarriers that provide long-term release: small nanoparticles (less than 100 nm in diameter) continuously released a radiosensitizer (VE822) over a period of several weeks in vitro, provided widespread intracranial drug distribution during CED, and yielded significant drug retention within the brain for over 1 week. One advantage of PEG-poly(PDL-co-DO) nanoparticles is that hydrophobicity can be tuned by adjusting the ratio of hydrophobic PDL to hydrophilic DO monomers, thus making it possible to achieve a wide range of drug release rates and drug distribution profiles. When administered by CED to rats with intracranial RG2 tumors, and combined with a 5-day course of fractionated radiation therapy, VE822-loaded PEG-poly(PDL-co-DO) NPs significantly prolonged survival when compared to free VE822. Thus, PEG-poly(PDL-co-DO) NPs represent a new type of versatile nanocarrier system with potential for sustained intracranial delivery of therapeutic agents to treat brain tumors.
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http://dx.doi.org/10.1016/j.biomaterials.2018.06.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082184PMC
September 2018

CDKN2A Copy Number Loss Is an Independent Prognostic Factor in HPV-Negative Head and Neck Squamous Cell Carcinoma.

Front Oncol 2018 4;8:95. Epub 2018 Apr 4.

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, United States.

Background: HPV infection is associated with high p16 expression and good prognosis in head and neck squamous cell carcinomas (HNSCCs). Analysis of CDKN2A, the gene encoding p16, may further elucidate the association between p16 expression and prognosis. We sought to determine whether CDKN2A copy number loss was associated with poor survival in HPV-negative HNSCCs.

Methods: The Cancer Genome Atlas HNSCC clinical and genomic data were obtained and integrated. Patients <80 years old with a primary tumor in the oral cavity, oropharynx, hypopharynx, or larynx were included. Stratifying by copy number loss status, CDKN2A mRNA and p16 protein expression levels were examined and overall survival (OS) and disease-free survival (DFS) were evaluated.

Results: 401 patients with HPV-negative HNSCC were identified. 146 patients demonstrated CDKN2A copy number loss. The CDKN2A copy number loss group expressed significantly lower levels of CDKN2A mRNA and p16 protein than did the non-copy number loss group. Median OS for patients with and without CDKN2A copy number loss was 16.5 and 46.6 months, respectively ( = 0.007). Median DFS for both groups was 11.6 and 19.2 months, respectively ( = 0.03). In both univariate and multivariable analyses, stage IV designation, receipt of chemotherapy and CDKN2A copy number loss were predictive of OS.

Conclusion: CDKN2A copy number loss predicted poor survival independently of other patient and treatment factors and may be a clinically useful prognostic factor.
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http://dx.doi.org/10.3389/fonc.2018.00095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893829PMC
April 2018

Response to the BRAF/MEK inhibitors dabrafenib/trametinib in an adolescent with a BRAF V600E mutated anaplastic ganglioglioma intolerant to vemurafenib.

Pediatr Blood Cancer 2018 05 30;65(5):e26969. Epub 2018 Jan 30.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Efficacy of BRAF V600E targeted therapies in brain tumors harboring the mutation has been shown in several case reports and is currently being studied in larger clinical trials. Monotherapy with vemurafenib has been associated with significant side effects, including rashes, papillomas, and squamous cell carcinomas. Here we describe an adolescent female with anaplastic ganglioglioma and significant skin reaction to vemurafenib with subsequent tumor response and tolerance to the BRAF/MEK inhibitor combination of dabrafenib and trametinib without recurrence of previous reaction.
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http://dx.doi.org/10.1002/pbc.26969DOI Listing
May 2018

Yale Cancer Center Precision Medicine Tumor Board: two patients, one targeted therapy, different outcomes.

Lancet Oncol 2018 01;19(1):23-24

Department of Medicine, Medical Oncology, Yale School of Medicine, New Haven, CT, USA. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(17)30916-6DOI Listing
January 2018

Introduction to the Yale Precision Medicine Tumor Board.

Lancet Oncol 2018 01;19(1):19-20

Department of Medicine, Medical Oncology, Yale School of Medicine, New Haven, CT 06520, USA. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(17)30919-1DOI Listing
January 2018

Residual Convolutional Neural Network for the Determination of Status in Low- and High-Grade Gliomas from MR Imaging.

Clin Cancer Res 2018 03 22;24(5):1073-1081. Epub 2017 Nov 22.

Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.

Isocitrate dehydrogenase () mutations in glioma patients confer longer survival and may guide treatment decision making. We aimed to predict the status of gliomas from MR imaging by applying a residual convolutional neural network to preoperative radiographic data. Preoperative imaging was acquired for 201 patients from the Hospital of University of Pennsylvania (HUP), 157 patients from Brigham and Women's Hospital (BWH), and 138 patients from The Cancer Imaging Archive (TCIA) and divided into training, validation, and testing sets. We trained a residual convolutional neural network for each MR sequence (FLAIR, T2, T1 precontrast, and T1 postcontrast) and built a predictive model from the outputs. To increase the size of the training set and prevent overfitting, we augmented the training set images by introducing random rotations, translations, flips, shearing, and zooming. With our neural network model, we achieved IDH prediction accuracies of 82.8% (AUC = 0.90), 83.0% (AUC = 0.93), and 85.7% (AUC = 0.94) within training, validation, and testing sets, respectively. When age at diagnosis was incorporated into the model, the training, validation, and testing accuracies increased to 87.3% (AUC = 0.93), 87.6% (AUC = 0.95), and 89.1% (AUC = 0.95), respectively. We developed a deep learning technique to noninvasively predict genotype in grade II-IV glioma using conventional MR imaging using a multi-institutional data set. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-2236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051535PMC
March 2018

Angiotensin receptor blockade: a novel approach for symptomatic radiation necrosis after stereotactic radiosurgery.

J Neurooncol 2018 Jan 9;136(2):289-298. Epub 2017 Nov 9.

Department of Therapeutic Radiology and Smilow Cancer Center, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA.

Preclinical evidence suggests angiotensin blockade therapy (ABT) decreases late radiation toxicities. This study aims to investigate the association between ABT and symptomatic radiation necrosis (SRN) following stereotactic radiosurgery (SRS). Resected brain metastases (rBM) and arteriovenous malformation (AVM) patients treated with SRS from 2002 to 2015 were identified. Patients in the ABT cohort were on therapy during SRS and at 1-month follow up. Kaplan Meier method and cumulative incidence model were used to analyze overall survival (OS) and intracranial outcomes. 228 consecutive patients were treated with SRS: 111 with rBM and 117 with AVM. Overall, 51 (22.4%) patients were in the ABT group: 32 (28.8%) in the rBM and 19 (16.2%) in AVM cohorts. Baseline characteristics were similar, except for higher Graded Prognostic Analysis (3-4) in the rBM (ABT: 25.0% vs. non-ABT: 49.0%, p = 0.033) and median age in the AVM (ABT: 51.4 vs. non-ABT: 35.4, p < 0.001) cohorts. In both populations, OS and intracranial efficacy (rBM-local control; AVM-obliteration rates) were statistically similar between the cohorts. ABT was associated with lower 1-year SRN rates in both populations: rBM, 3.1 versus 25.3% (p = 0.003); AVM, 6.7 vs. 14.6% (p = 0.063). On multivariate analysis, ABT was a significant predictive factor for rBM (HR: 0.17; 95% CI 0.03-0.88, p = 0.035), but did not reach statistical significance for AVM (HR: 0.36; 95% CI 0.09-1.52, p = 0.165). ABT use appears to be associated with a reduced risk of SRN following SRS, without detriment to OS or intracranial efficacy. A prospective trial to validate these findings is warranted.
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http://dx.doi.org/10.1007/s11060-017-2652-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784434PMC
January 2018

Patterns of care and outcomes for use of concurrent chemoradiotherapy over radiotherapy alone for anaplastic gliomas.

Radiother Oncol 2017 11 17;125(2):258-265. Epub 2017 Oct 17.

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, United States; Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, Yale University, New Haven, United States.

Background And Purpose: The role of concurrent chemoradiotherapy (CRT) for anaplastic gliomas is undefined and patterns of care are under-reported. To address the knowledge gap, we examined use of CRT for grade III gliomas compared to radiotherapy (RT) alone.

Material And Methods: In an observational study design cohort from the National Cancer Database, we identified 4437 adult patients receiving surgery followed by either CRT or RT for supratentorial anaplastic glioma in 2003-2011. Univariable and multivariable logistic regression analyses were used to assess factors associated with use of CRT. Overall survival (OS) was assessed by the Kaplan-Meier analysis with log-rank tests, Cox proportional hazards regression modeling, and propensity score matching.

Results: Receipt of CRT (vs. RT) was associated with recent year of diagnosis (OR for 2011 (vs. 2003) 3.36, 95% CI 2.49-4.54) and having astrocytoma (vs. oligodendroglioma) (OR 1.37, 95% CI 1.15-1.63). Patients receiving CRT had a lower adjusted hazard of death (hazard ratio 0.72, 95% CI 0.65-0.79). Outcomes were worse for patients ≥60 (HR 6.94, 95% CI 6.09-7.91) and astrocytomas (HR 2.08, 95% CI 1.85-2.34).

Conclusion: Use of concurrent CRT is associated with more recent year of diagnosis and improved survival relative to RT alone.
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http://dx.doi.org/10.1016/j.radonc.2017.09.027DOI Listing
November 2017

State of the art: the evolving role of RT in combined modality therapy for GBM.

J Neurooncol 2017 Sep;134(3):477-478

Miami Cancer Institute, 1575 San Ignacio Avenue, Suite 100, Coral Gables, Miami, FL, 33146, USA.

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http://dx.doi.org/10.1007/s11060-017-2596-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866384PMC
September 2017