Papers by S. Duygu Selcuklu
Targeting Aurora B kinase prevents and overcomes resistance to EGFR inhibitors in lung cancer by enhancing BIM- and PUMA-mediated apoptosis
Cancer Cell
Genome Medicine
Background Cell-free DNA (cfDNA) profiling is increasingly used to guide cancer care, yet mutatio... more Background Cell-free DNA (cfDNA) profiling is increasingly used to guide cancer care, yet mutations are not always identified. The ability to detect somatic mutations in plasma depends on both assay sensitivity and the fraction of circulating DNA in plasma that is tumor-derived (i.e., cfDNA tumor fraction). We hypothesized that cfDNA tumor fraction could inform the interpretation of negative cfDNA results and guide the choice of subsequent assays of greater genomic breadth or depth. Methods Plasma samples collected from 118 metastatic cancer patients were analyzed with cf-IMPACT, a modified version of the FDA-authorized MSK-IMPACT tumor test that can detect genomic alterations in 410 cancer-associated genes. Shallow whole genome sequencing (sWGS) was also performed in the same samples to estimate cfDNA tumor fraction based on genome-wide copy number alterations using z-score statistics. Plasma samples with no somatic alterations detected by cf-IMPACT were triaged based on sWGS-estim...
Phase 2 study of LY3023414 in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway
Cancer
Serial next generation sequencing (NGS) of cell free DNA (cfDNA) and clonal evolution of AKT1 E17K mutant tumors: Analyses from patients (pts) enrolled on a phase I basket study of an AKT inhibitor (AZD5363)
Journal of Clinical Oncology
Cancer Discovery
HER2 mutations defi ne a subset of metastatic breast cancers with a unique mechanism of oncogenic... more HER2 mutations defi ne a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversi ble pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with HER2mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER + patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating HER2 or HER3 alterations were associated with poor treatment outcome. Similarly, acquisition of multiple HER2-activating events , as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefi t from neratinib. Collectively, these data defi ne HER2 mutations as a therapeutic target in breast cancer and suggest that coexistence of additional HER signaling alterations may promote both de novo and acquired resistance to neratinib. SIGNIFICANCE: HER2 mutations defi ne a targetable breast cancer subset, although sensitivity to irreversible HER kinase inhibition appears to be modifi ed by the presence of concurrent activating genomic events in the pathway. These fi ndings have implications for potential future combinatorial approaches and broader therapeutic development for this genomically defi ned subset of breast cancer.
Tumour lineage shapes BRCA-mediated phenotypes
Nature
Abstract 1752: BRCA-mediated tumorigenesis is origin and cell-type dependent
Molecular and Cellular Biology / Genetics
Abstract 929: Paired tumor and cfDNA in patients with HER2-mutant solid tumors treated with neratinib reveals convergence of multiple on-target resistance mechanisms: Results from the SUMMIT "Basket" Trial
Experimental and Molecular Therapeutics
Non-invasive detection of acquired resistance to FGFR inhibition in patients with cholangiocarcinoma harboring FGFR2 alterations
Journal of Clinical Oncology
4096 Background: FGFR2 alterations are present in 14% of cholangiocarcinomas (CCA) and are promis... more 4096 Background: FGFR2 alterations are present in 14% of cholangiocarcinomas (CCA) and are promising targets of investigational FGFR-directed therapies. Cell-free DNA profiling has emerged as a non-invasive approach to monitor disease and longitudinally characterize tumor evolution. We describe the use of circulating tumor DNA (ctDNA) among patients (pts) with FGFR2-altered CCA receiving FGFR-targeted therapy in the identification of acquired FGFR2 mutations (mut) at resistance. Methods: Serial blood samples were collected from 8 pts with FGFR-altered CCA for ctDNA isolation and next generation sequencing. Plasma ctDNA collected at baseline and resistance to FGFR-targeted therapy were sequenced using a custom ultra-deep coverage cfDNA panel, MSK-ACCESS, incorporating dual index primers and unique molecular barcodes to enable background error suppression and high-sensitivity mut detection. The assay was enhanced to include all protein-coding exons and relevant introns of FGFR2. In 5/...
Abstract 5533: Cell-free DNA sequencing in ERBB2-mutant breast cancer patients treated with neratinib and fulvestrant: Exploratory analysis from the Phase 2 SUMMIT ‘basket' trial
Clinical Research (Excluding Clinical Trials)
Plasma KRAS as a biomarker for pancreatic ductal adenocarcinoma (PDAC)
Journal of Clinical Oncology
316 Background: PDAC needs validated diagnostic biomarkers for early detection and predictive mar... more 316 Background: PDAC needs validated diagnostic biomarkers for early detection and predictive markers for outcome. As 95% of PDACs harbor KRAS mutations (mKRAS), circulating tumor DNA (ctDNA) has potential utility in PDAC. We assessed the ability to detect and correlate mKRAS in a metastatic PDAC cohort from Memorial Sloan Kettering Cancer Center. Methods: 10 mL of whole blood was collected. cfDNA was extracted with QIAmp or QIAsymphony DNA extraction kits (Qiagen, Valencia, CA). Directed (KRAS G12D, G12R, G12V, Q61H) or multiplex (G12A, G12C, G12D, G12R, G12S, G12V, G13D) digital droplet PCR (ddPCR) was performed with Raindrop Plus (Raindance Technologies, Billerica, MA) or QX200 (BioRad, Hercules, CA) ddPCR systems. Number and size of liver, lung and lymph node metastases, peritoneal disease (mild, moderate, severe), ascites (trace, small, large) and bone mets (Y/N) were assessed by CT scan. Results: See table. 21 (55%) had detectable ctDNA (ctDNA(+)) with mean mutant allele fract...
Tracking tumour evolution in glioma through liquid biopsies of cerebrospinal fluid
Nature
Evaluating Cancer of the Central Nervous System Through Next-Generation Sequencing of Cerebrospinal Fluid
Abstract
Purpose Cancer spread to the central nervous system (CNS) often is diagnosed late and i... more Abstract
Purpose Cancer spread to the central nervous system (CNS) often is diagnosed late and is unresponsive to therapy. Mechanisms of tumor dissemination and evolution within the CNS are largely unknown because of limited access to tumor tissue.
Materials and Methods We sequenced 341 cancer-associated genes in cell-free DNA from cerebrospinal fluid (CSF) obtained through routine lumbar puncture in 53 patients with suspected or known CNS involvement by cancer.
Results We detected high-confidence somatic alterations in 63% (20 of 32) of patients with CNS metastases of solid tumors, 50% (six of 12) of patients with primary brain tumors, and 0% (zero of nine) of patients without CNS involvement by cancer. Several patients with tumor progression in the CNS during therapy with inhibitors of oncogenic kinases harbored mutations in the kinase target or kinase bypass pathways. In patients with glioma, the most common malignant primary brain tumor in adults, examination of cell-free DNA uncovered patterns of tumor evolution, including temozolomide-associated mutations.
Conclusion The study shows that CSF harbors clinically relevant genomic alterations in patients with CNS cancers and should be considered for liquid biopsies to monitor tumor evolution in the CNS.
An investigation of microRNAs mapping to breast cancer related genomic gain and loss regions
Cancer Genetics and Cytogenetics, 2009
Various regions of amplification or loss are observed in breast tumors as a manifestation of geno... more Various regions of amplification or loss are observed in breast tumors as a manifestation of genomic instability. To date, numerous oncogenes or tumor suppressors on some of these regions have been characterized. An increasing body of evidence suggests that such regions also harbor microRNA genes with crucial regulatory roles in cellular processes and disease mechanisms, including cancer. Here, we investigated 35 microRNAs localized to common genomic gain and/or loss regions in breast cancers. To examine amplification or loss of these microRNAs as a result of genomic instability, we performed semiquantitative duplex polymerase chain reaction in 20 breast cancer cell lines, 2 immortalized mammary cell lines, and 2 normal DNA controls. A comprehensive DNA fold number change data for 35 microRNA genes on chromosomal gain/loss regions are presented in breast cancer cells. A 23% (8/35) of the investigated microRNAs showed significant fold number increases (greater than fourfold) compared to GAPDH in one or more of the breast cell lines. Although no homozygous deletions were detected, fold number decreases indicating potential loss regions were observed for 26% (9/35) of the investigated microRNAs. Such fold number changes may point out some of these microRNAs as potential targets of the genomic instability regions as oncogene and tumor suppressor candidates.
An investigation of microRNAs mapping to breast cancer related genomic gain and loss regions
Cancer genetics and cytogenetics, Jan 1, 2009
Various regions of amplification or loss are observed in breast tumors as a manifestation of geno... more Various regions of amplification or loss are observed in breast tumors as a manifestation of genomic instability. To date, numerous oncogenes or tumor suppressors on some of these regions have been characterized. An increasing body of evidence suggests that such regions also harbor microRNA genes with crucial regulatory roles in cellular processes and disease mechanisms, including cancer. Here, we investigated 35 microRNAs localized to common genomic gain and/or loss regions in breast cancers. To examine amplification or loss of these microRNAs as a result of genomic instability, we performed semiquantitative duplex polymerase chain reaction in 20 breast cancer cell lines, 2 immortalized mammary cell lines, and 2 normal DNA controls. A comprehensive DNA fold number change data for 35 microRNA genes on chromosomal gain/loss regions are presented in breast cancer cells. A 23% (8/35) of the investigated microRNAs showed significant fold number increases (greater than fourfold) compared to GAPDH in one or more of the breast cell lines. Although no homozygous deletions were detected, fold number decreases indicating potential loss regions were observed for 26% (9/35) of the investigated microRNAs. Such fold number changes may point out some of these microRNAs as potential targets of the genomic instability regions as oncogene and tumor suppressor candidates.
Epigenetics, Jan 1, 2008
Cancer epigenetics research is now entering an exciting phase of translational epigenetics whereb... more Cancer epigenetics research is now entering an exciting phase of translational epigenetics whereby novel epigenome therapeutics is being developed for application in clinical settings. Epigenetics refers to all heritable and potentially reversible changes in gene or genome functioning that occurs without altering the nucleotide sequence of the DNA. A range of different epigenetic "marks" can activate or repress gene expression. While epigenetic alterations are associated with most cancers, epigenetic dysregulation can also have a causal role in cancer etiology. Epigenetically disrupted stem or progenitor cells could have an early role in neoplastic transformations, while perturbance of epigenetic regulatory mechanisms controlling gene expression in cancer-relevant pathways will also be a contribution factor. The reversibility of epigenetic marks provides the possibility that the activity of key cancer genes and pathways can be regulated as a therapeutic approach. The growing availability of a range of chemical agents which can affect epigenome functioning has led to a range of epigenetic-therapeutic approaches for cancer and intense interest in the development of second-generation epigenetic drugs (epi-drugs) which would have greater specificity and efficacy in clinical settings. The latest developments in this exciting arena of translational cancer epigenetics were presented at a recent conference on "Epigenetics and New
Regulatory interplay between miR-21,< i> JAG1</i> and 17beta-estradiol (E2) in breast cancer cells
Biochemical and …, Jan 1, 2012
Journal of Biological …, Jan 1, 2012
Background: Dysregulation of miRNAs is associated with breast cancer. Results: MiR-9 overexpressi... more Background: Dysregulation of miRNAs is associated with breast cancer. Results: MiR-9 overexpression and transcriptome analysis reveals novel miR-9 targets, including MTHFD2, which can recapitulate anti-proliferative effects of miR-9 overexpression. Conclusion: MiR-9 displays tumor-suppressor like activity in breast cancer cells, MTHFD2 contributes to this activity. Significance: Understanding miR-9 directed regulation of the breast cancer transcriptome is important for diagnosis and therapeutics.
miR-21 as a key regulator of oncogenic processes
Biochemical Society …, Jan 1, 2009
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Papers by S. Duygu Selcuklu
Purpose Cancer spread to the central nervous system (CNS) often is diagnosed late and is unresponsive to therapy. Mechanisms of tumor dissemination and evolution within the CNS are largely unknown because of limited access to tumor tissue.
Materials and Methods We sequenced 341 cancer-associated genes in cell-free DNA from cerebrospinal fluid (CSF) obtained through routine lumbar puncture in 53 patients with suspected or known CNS involvement by cancer.
Results We detected high-confidence somatic alterations in 63% (20 of 32) of patients with CNS metastases of solid tumors, 50% (six of 12) of patients with primary brain tumors, and 0% (zero of nine) of patients without CNS involvement by cancer. Several patients with tumor progression in the CNS during therapy with inhibitors of oncogenic kinases harbored mutations in the kinase target or kinase bypass pathways. In patients with glioma, the most common malignant primary brain tumor in adults, examination of cell-free DNA uncovered patterns of tumor evolution, including temozolomide-associated mutations.
Conclusion The study shows that CSF harbors clinically relevant genomic alterations in patients with CNS cancers and should be considered for liquid biopsies to monitor tumor evolution in the CNS.
Purpose Cancer spread to the central nervous system (CNS) often is diagnosed late and is unresponsive to therapy. Mechanisms of tumor dissemination and evolution within the CNS are largely unknown because of limited access to tumor tissue.
Materials and Methods We sequenced 341 cancer-associated genes in cell-free DNA from cerebrospinal fluid (CSF) obtained through routine lumbar puncture in 53 patients with suspected or known CNS involvement by cancer.
Results We detected high-confidence somatic alterations in 63% (20 of 32) of patients with CNS metastases of solid tumors, 50% (six of 12) of patients with primary brain tumors, and 0% (zero of nine) of patients without CNS involvement by cancer. Several patients with tumor progression in the CNS during therapy with inhibitors of oncogenic kinases harbored mutations in the kinase target or kinase bypass pathways. In patients with glioma, the most common malignant primary brain tumor in adults, examination of cell-free DNA uncovered patterns of tumor evolution, including temozolomide-associated mutations.
Conclusion The study shows that CSF harbors clinically relevant genomic alterations in patients with CNS cancers and should be considered for liquid biopsies to monitor tumor evolution in the CNS.