Showing papers by "Michael D. Prados published in 2018"
TL;DR: Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, Pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which may inform strategies for future therapeutic development.
1,535 citations
TL;DR: The genomic and phenotypic correlates of cancer aneuploidy are defined and genome engineering is applied to delete 3p in lung cells, causing decreased proliferation rescued in part by chromosome 3 duplication.
660 citations
TL;DR: In this article, the authors made two errors in preparation of this manuscript and corrected them in the revised Figure S7 by re-ordering the mutations by frequency for COAD and READ independently.
303 citations
TL;DR: expression analysis revealed MYC-associated pathways in tumor subtypes, such as immune response and growth factor signaling, and chromatin, translation, and DNA replication/repair were conserved pan-cancer, suggesting that MYC is a distinct oncogenic driver.
Abstract: Although the MYC oncogene has been implicated in cancer, a systematic assessment of alterations of MYC, related transcription factors, and co-regulatory proteins, forming the proximal MYC network (PMN), across human cancers is lacking. Using computational approaches, we define genomic and proteomic features associated with MYC and the PMN across the 33 cancers of The Cancer Genome Atlas. Pan-cancer, 28% of all samples had at least one of the MYC paralogs amplified. In contrast, the MYC antagonists MGA and MNT were the most frequently mutated or deleted members, proposing a role as tumor suppressors. MYC alterations were mutually exclusive with PIK3CA, PTEN, APC, or BRAF alterations, suggesting that MYC is a distinct oncogenic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such as immune response and growth factor signaling; chromatin, translation, and DNA replication/repair were conserved pan-cancer. This analysis reveals insights into MYC biology and is a reference for biomarkers and therapeutics for cancers with alterations of MYC or the PMN.
248 citations
Joshua D. Campbell1, Joshua D. Campbell2, Joshua D. Campbell3, Christina Yau4 +766 more•Institutions (23)
TL;DR: This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas from five sites associated with smoking and/or human papillomavirus.
234 citations
TL;DR: An integromic analysis of gene alterations that modulate transforming growth factor β-Smad-mediated signaling in 9,125 tumor samples across 33 cancer types in The Cancer Genome Atlas provides a broad molecular perspective relevant for future functional and therapeutic studies of the diverse cancer pathways mediated by the TGF-β superfamily.
Abstract: We present an integromic analysis of gene alterations that modulate transforming growth factor β (TGF-β)-Smad-mediated signaling in 9,125 tumor samples across 33 cancer types in The Cancer Genome Atlas (TCGA). Focusing on genes that encode mediators and regulators of TGF-β signaling, we found at least one genomic alteration (mutation, homozygous deletion, or amplification) in 39% of samples, with highest frequencies in gastrointestinal cancers. We identified mutation hotspots in genes that encode TGF-β ligands (BMP5), receptors (TGFBR2, AVCR2A, and BMPR2), and Smads (SMAD2 and SMAD4). Alterations in the TGF-β superfamily correlated positively with expression of metastasis-associated genes and with decreased survival. Correlation analyses showed the contributions of mutation, amplification, deletion, DNA methylation, and miRNA expression to transcriptional activity of TGF-β signaling in each cancer type. This study provides a broad molecular perspective relevant for future functional and therapeutic studies of the diverse cancer pathways mediated by the TGF-β superfamily.
115 citations
TL;DR: The liquid biopsy approach provides a molecularly based tool for tumor characterization, and is the first to indicate clinical utility of ctDNA for longitudinal surveillance of DMGs.
Abstract: Purpose: Pediatric diffuse midline glioma (DMG) are highly malignant tumors with poor clinical outcomes. Over 70% of patients with DMG harbor the histone 3 p.K27M (H3K27M) mutation, which correlates with a poorer clinical outcome, and is also used as a criterion for enrollment in clinical trials. Because complete surgical resection of DMG is not an option, biopsy at presentation is feasible, but rebiopsy at time of progression is rare. While imaging and clinical-based disease monitoring is the standard of care, molecular-based longitudinal characterization of these tumors is almost nonexistent. To overcome these hurdles, we examined whether liquid biopsy allows measurement of disease response to precision therapy. Experimental Design: We established a sensitive and specific methodology that detects major driver mutations associated with pediatric DMGs using droplet digital PCR (n = 48 subjects, n = 110 specimens). Quantification of circulating tumor DNA (ctDNA) for H3K27M was used for longitudinal assessment of disease response compared with centrally reviewed MRI data. Results: H3K27M was identified in cerebrospinal fluid (CSF) and plasma in 88% of patients with DMG, with CSF being the most enriched for ctDNA. We demonstrated the feasibility of multiplexing for detection of H3K27M, and additional driver mutations in patient9s tumor and matched CSF, maximizing the utility of a single source of liquid biome. A significant decrease in H3K27M plasma ctDNA agreed with MRI assessment of tumor response to radiotherapy in 83% (10/12) of patients. Conclusions: Our liquid biopsy approach provides a molecularly based tool for tumor characterization, and is the first to indicate clinical utility of ctDNA for longitudinal surveillance of DMGs. Clin Cancer Res; 1–10. ©2018 AACR.
104 citations
TL;DR: Vorinostat combined with standard chemoradiation had acceptable tolerability in newly diagnosed glioblastoma and resistance signatures had a reverse and positive association with OS/PFS, respectively.
Abstract: Background Vorinostat, a histone deacetylase (HDAC) inhibitor, has shown radiosensitizing properties in preclinical studies. This open-label, single-arm trial evaluated the maximum tolerated dose (MTD; phase I) and efficacy (phase II) of vorinostat combined with standard chemoradiation in newly diagnosed glioblastoma. Methods Patients received oral vorinostat (300 or 400 mg/day) on days 1-5 weekly during temozolomide chemoradiation. Following a 4- to 6-week rest, patients received up to 12 cycles of standard adjuvant temozolomide and vorinostat (400 mg/day) on days 1-7 and 15-21 of each 28-day cycle. Association between vorinostat response signatures and progression-free survival (PFS) and overall survival (OS) was assessed based on RNA sequencing of baseline tumor tissue. Results Phase I and phase II enrolled 15 and 107 patients, respectively. The combination therapy MTD was vorinostat 300 mg/day and temozolomide 75 mg/m2/day. Dose-limiting toxicities were grade 4 neutropenia and thrombocytopenia and grade 3 aspartate aminotransferase elevation, hyperglycemia, fatigue, and wound dehiscence. The primary efficacy endpoint in the phase II cohort, OS rate at 15 months, was 55.1% (median OS 16.1 mo), and consequently, the study did not meet its efficacy objective. Most common treatment-related grade 3/4 toxicities in the phase II component were lymphopenia (32.7%), thrombocytopenia (28.0%), and neutropenia (21.5%). RNA expression profiling of baseline tumors (N = 76) demonstrated that vorinostat resistance (sig-79) and sensitivity (sig-139) signatures had a reverse and positive association with OS/PFS, respectively. Conclusions Vorinostat combined with standard chemoradiation had acceptable tolerability in newly diagnosed glioblastoma. Although the primary efficacy endpoint was not met, vorinostat sensitivity and resistance signatures could facilitate patient selection in future trials.
84 citations
TL;DR: Despite adequate tissue PK, palbociclib monotherapy was not an effective treatment for recurrent glioblastoma, however, these were heavily pretreated patients and targeting the CDK4/6 pathway may still deserve further exploration.
Abstract: Alterations in the CDK4/6—RB signaling pathway are common causes of cell cycle dysregulation in many cancers, including glioblastoma. Palbociclib is an oral inhibitor of CDK4/6, which leads to phosphorylation of RB1 and cell-cycle arrest. We conducted a two-arm study evaluating efficacy and tissue pharmacokinetics/pharmacodynamics of palbociclib in patients with recurrent glioblastoma. Eligibility criteria included confirmation of RB1 proficiency by IHC; ≤ 3 relapses; KPS ≥ 60; no limit on prior treatments. Arm 1 received palbociclib for 7 days prior to indicated resection followed by adjuvant palbociclib. Arm 2 received palbociclib without resection. Primary objective was PFS6; secondary included toxicity, OS, and ORR. Exploratory aims included biomarker assessment and pharmacokinetic/pharmacodynamic effects in surgical patients. Total of 22 patients were enrolled; 6 on Arm 1 and 16 on Arm 2. Trial was stopped early secondary to lack of efficacy, with 95% of evaluable patients progressing within 6 months. Median PFS was 5.14 weeks (range 5 days–142 weeks) and median OS was 15.4 weeks (range 2–274 weeks). Two patients (10%) had related grade ≥ 3 AEs. In Arm 1, 5 patients had tissue concentrations of palbociclib felt to be sufficient for biological effect and paired samples available for RB1 IHC. There were no consistent changes in RB1 expression or cell proliferation in the paired tissue. In this trial, despite adequate tissue PK, palbociclib monotherapy was not an effective treatment for recurrent glioblastoma. However, these were heavily pretreated patients and targeting the CDK4/6 pathway may still deserve further exploration.
77 citations
University of California, San Francisco1, Harvard University2, Children's Memorial Hospital3, University of Louisville4, Washington University in St. Louis5, University of Washington6, Boston Children's Hospital7, University of Minnesota8, New York University9, University of Texas Southwestern Medical Center10, University of Southern California11, University of Florida12, Medical University of South Carolina13, Duke University14, Johns Hopkins University15, University of Colorado Denver16, Oregon Health & Science University17, Pennsylvania State University18, Broad Institute19
TL;DR: Surgical biopsy of DIPGs is technically feasible, associated with acceptable risks, and can provide biologic data that can inform treatment decisions, according to the authors.
Abstract: Background
Diagnosis of diffuse intrinsic pontine glioma (DIPG) has relied on imaging studies, since the appearance is pathognomonic, and surgical risk was felt to be high and unlikely to affect therapy. The DIPG Biology and Treatment Study (DIPG-BATS) reported here incorporated a surgical biopsy at presentation and stratified subjects to receive FDA-approved agents chosen on the basis of specific biologic targets.
75 citations
Children's National Medical Center1, Boston Children's Hospital2, Seattle Cancer Care Alliance3, Academy for Urban School Leadership4, New York Medical College5, Children's Memorial Hospital6, Children's Hospital of Philadelphia7, University of California, San Francisco8, Harvard University9, Institut Gustave Roussy10, Leipzig University11, Dana Corporation12
TL;DR: Consensus recommendations and response definitions for patients with medulloblastomas and other seeding tumors have been established and need to be prospectively validated in clinical trials, as with other Response Assessment in Neuro-Oncology recommendations.
Abstract: Lack of standard response criteria in clinical trials for medulloblastoma and other seeding tumors complicates assessment of therapeutic efficacy and comparisons across studies. An international working group was established to develop consensus recommendations for response assessment. The aim is that these recommendations be prospectively evaluated in clinical trials, with the goal of achieving more reliable risk stratification and uniformity across clinical trials. Current practices and literature review were performed to identify major confounding issues and justify subsequently developed recommendations; in areas lacking scientific investigations, recommendations were based on experience of committee members and consensus was reached after discussion. Recommendations apply to both adult and pediatric patients with medulloblastoma and other seeding tumors. Response should be assessed using MR imaging (brain and spine), CSF cytology, and neurologic examination. Clinical imaging standards with minimum mandatory sequence acquisition that optimizes detection of leptomeningeal metastases are defined. We recommend central review prior to inclusion in treatment cohorts to ensure appropriate risk stratification and cohort inclusion. Consensus recommendations and response definitions for patients with medulloblastomas and other seeding tumors have been established; as with other Response Assessment in Neuro-Oncology recommendations, these need to now be prospectively validated in clinical trials.
Translational Genomics Research Institute1, Mayo Clinic2, University of California, San Francisco3, University of Texas Health Science Center at San Antonio4, University of Texas MD Anderson Cancer Center5, Huntsman Cancer Institute6, Harvard University7, Brigham and Women's Hospital8, University of California, Los Angeles9, Memorial Sloan Kettering Cancer Center10, University of Southern California11
TL;DR: Use of genome-wide molecular profiling is feasible and can be informative for guiding real-time, central nervous system–penetrant, genomics-informed treatment recommendations for patients with recurrent glioblastoma.
Abstract: Purpose: Glioblastoma is an aggressive and molecularly heterogeneous cancer with few effective treatment options. We hypothesized that next-generation sequencing can be used to guide treatment recommendations within a clinically acceptable time frame following surgery for patients with recurrent glioblastoma.Experimental Design: We conducted a prospective genomics-informed feasibility trial in adults with recurrent and progressive glioblastoma. Following surgical resection, genome-wide tumor/normal exome sequencing and tumor RNA sequencing were performed to identify molecular targets for potential matched therapy. A multidisciplinary molecular tumor board issued treatment recommendations based on the genomic results, blood-brain barrier penetration of the indicated therapies, drug-drug interactions, and drug safety profiles. Feasibility of generating genomics-informed treatment recommendations within 35 days of surgery was assessed.Results: Of the 20 patients enrolled in the study, 16 patients had sufficient tumor tissue for analysis. Exome sequencing was completed for all patients, and RNA sequencing was completed for 14 patients. Treatment recommendations were provided within the study's feasibility time frame for 15 of 16 (94%) patients. Seven patients received treatment based on the tumor board recommendations. Two patients reached 12-month progression-free survival, both adhering to treatments based on the molecular profiling results. One patient remained on treatment and progression free 21 months after surgery, 3 times longer than the patient's previous time to progression. Analysis of matched nonenhancing tissue from 12 patients revealed overlapping as well as novel putatively actionable genomic alterations.Conclusions: Use of genome-wide molecular profiling is feasible and can be informative for guiding real-time, central nervous system-penetrant, genomics-informed treatment recommendations for patients with recurrent glioblastoma. Clin Cancer Res; 24(2); 295-305. ©2017 AACRSee related commentary by Wick and Kessler, p. 256.
TL;DR: Cabozantinib treatment appeared to have modest clinical activity with a 4.3% response rate in patients who had received prior antiangiogenic therapy for GBM.
Abstract: Author(s): Wen, Patrick Y; Drappatz, Jan; de Groot, John; Prados, Michael D; Reardon, David A; Schiff, David; Chamberlain, Marc; Mikkelsen, Tom; Desjardins, Annick; Holland, Jaymes; Ping, Jerry; Weitzman, Ron; Cloughesy, Timothy F | Abstract: BackgroundCabozantinib is a tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2) and MET that has demonstrated clinical activity in advanced solid tumors. This open-label, phase II trial evaluated cabozantinib in patients with recurrent or refractory glioblastoma (GBM).MethodsPatients were initially enrolled at a starting dose of 140 mg/day, but the starting dose was amended to 100 mg/day because of toxicity. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate assessed by an independent radiology facility using modified Response Assessment in Neuro-Oncology criteria. Additional endpoints included duration of response, 6-month and median progression-free survival, overall survival, and safety.ResultsAmong 152 patients naive to prior antiangiogenic therapy, the objective response rate was 17.6% and 14.5% in the 140 mg/day and 100 mg/day groups, respectively, which did not meet the predefined statistical target for success. The proportions of patients alive and progression free at 6 months were 22.3% and 27.8%, respectively. Median progression-free survival was 3.7 months in both groups, and median overall survival was 7.7 months and 10.4 months, respectively. The incidence of grade 3/4 adverse events (AEs) was 79.4% and 84.7% in the 140 mg/day and 100 mg/day groups, respectively, and dose reductions due to AEs were experienced by 61.8% and 72.0%, respectively. Common grade 3/4 AEs included fatigue, diarrhea, and palmar-plantar erythrodysesthesia syndrome.ConclusionsCabozantinib showed evidence of clinical activity in patients with recurrent GBM naive to antiangiogenic therapy, although the predefined statistical target for success was not met. At the starting doses assessed, AEs were frequently managed with dose reductions.Clinical trials registration numberNCT00704288 (https://www.clinicaltrials.gov/ct2/show/NCT00704288).
University of California, Los Angeles1, Hoffmann-La Roche2, University of California, San Francisco3, Mayo Clinic4, Aix-Marseille University5, The Royal Marsden NHS Foundation Trust6, Saitama Medical University7, Umeå University8, German Cancer Research Center9, Harvard University10, Huntsman Cancer Institute11, University of Texas MD Anderson Cancer Center12, Memorial Sloan Kettering Cancer Center13, Brigham and Women's Hospital14
TL;DR: Postoperative, residual contrast-enhancing disease significantly negatively influences survival in patients with newly diagnosed GBM treated with chemoradiation with or without concomitant experimental therapy.
Abstract: Background. In the current study, we pooled imaging data in newly diagnosed glioblastoma (GBM) patients from international multicenter clinical trials, single institution databases, and multicenter ...
University of California, Los Angeles1, Exelixis2, University of Pittsburgh3, University of Texas MD Anderson Cancer Center4, University of California, San Francisco5, Harvard University6, University of Virginia Health System7, Fred Hutchinson Cancer Research Center8, Henry Ford Health System9, Duke University10
TL;DR: T1 subtraction maps provide value in determining response in recurrent GBM treated with cabozantinib and correlated with survival benefit, and were independent predictors of overall survival (OS).
Abstract: Author(s): Ellingson, Benjamin M; Aftab, Dana T; Schwab, Gisela M; Hessel, Colin; Harris, Robert J; Woodworth, Davis C; Leu, Kevin; Chakhoyan, Ararat; Raymond, Catalina; Drappatz, Jan; de Groot, John; Prados, Michael D; Reardon, David A; Schiff, David; Chamberlain, Marc; Mikkelsen, Tom; Desjardins, Annick; Holland, Jaymes; Ping, Jerry; Weitzman, Ron; Wen, Patrick Y; Cloughesy, Timothy F | Abstract: Background:To overcome challenges with traditional response assessment in anti-angiogenic agents, the current study uses T1 subtraction maps to quantify volumetric radiographic response in monotherapy with cabozantinib, an orally bioavailable tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2), hepatocyte growth factor receptor (MET), and AXL, in an open-label, phase II trial in patients with recurrent glioblastoma (GBM) (NCT00704288). Methods:A total of 108 patients with adequate imaging data and confirmed recurrent GBM were included in this retrospective study from a phase II multicenter trial of cabozantinib monotherapy (XL184-201) at either 100 mg (N = 87) or 140 mg (N = 21) per day. Contrast enhanced T1-weighted digital subtraction maps were used to define volume of contrast-enhancing tumor at baseline and subsequent follow-up time points. Volumetric radiographic response (g65% reduction in contrast-enhancing tumor volume from pretreatment baseline tumor volume sustained for more than 4 wk) was tested as an independent predictor of overall survival (OS). Results:Volumetric response rate for all therapeutic doses was 38.9% (41.4% and 28.6% for 100 mg and 140 mg doses, respectively). A log-linear association between baseline tumor volume and OS (P = 0.0006) and a linear correlation between initial change in tumor volume and OS (P = 0.0256) were observed. A significant difference in OS was observed between responders (median OS = 20.6 mo) and nonresponders (median OS = 8.0 mo) (hazard ratio [HR] = 0.3050, P l 0.0001). Multivariable analyses showed that continuous measures of baseline tumor volume (HR = 1.0233, P l 0.0001) and volumetric response (HR = 0.2240, P l 0.0001) were independent predictors of OS. Conclusions:T1 subtraction maps provide value in determining response in recurrent GBM treated with cabozantinib and correlated with survival benefit.
University of California, Los Angeles1, Memorial Sloan Kettering Cancer Center2, Harvard University3, University of Pittsburgh4, University of Wisconsin-Madison5, University of Texas MD Anderson Cancer Center6, University of California, San Francisco7, Baptist Hospital of Miami8, University of Texas at Austin9
TL;DR: The maximum tolerated dose (MTD) for the combination of tipifarnib and sorafenib for the treatment of recurrent GBM was determined and full single agent dosages could not be achieved in combination.
Abstract: Recurrent glioblastoma (GBM) has a very low 6-month progression free survival (PFS) with currently available treatments. Combination chemotherapy to target multiple cell signaling pathways is currently being investigated in order to improve prognosis for recurrent disease. The purpose of this phase I study was to determine the maximum tolerated dose (MTD) for the combination of tipifarnib and sorafenib for the treatment of recurrent GBM. Patients with pathologically proven WHO grade IV GBM and radiographically proven tumor recurrence were eligible for this study. Treatments included sorafenib at twice daily and escalating dosages of tipifarnib. Dose-limiting toxicity (DLT) was determined over the first 28-days of treatments, and the MTD was determined in a 3 + 3 study design. We enrolled 24 patients, and 21 patients completed the MTD period. The study was stopped early with no MTD determination for excessive toxicities. The last dose level reached was sorafenib at 200 mg twice a day and tipifarnib 100 mg twice a day on an alternating week schedule. The DLTs included diarrhea, lipase elevation, hypophosphatemia, and arthralgia. The combination of sorafenib and tipifarnib has excessive toxicities and full single agent dosages could not be achieved in combination.
TL;DR: As technology continues to improve, exome and RNA sequencing will play a role in the design of clinical trials, classification of patient subgroups and identification of rare mutations that can be targeted by small-molecule inhibitors and biologic agents.
Abstract: Glioblastoma has been shown to have many different genetic mutations found both within and between tumor samples Molecular testing and genomic sequencing has helped to classify diagnoses and clarify difficult to interpret histopathological specimens Genomic information also plays a critical role in prognostication for patients, with IDH mutations and MGMT methylation having significant impact of the response to chemotherapy and overall survival of patients Unfortunately, personalized medicine and targeted therapy against specific mutations have not been shown to improve patient outcomes As technology continues to improve, exome and RNA sequencing will play a role in the design of clinical trials, classification of patient subgroups and identification of rare mutations that can be targeted by small-molecule inhibitors and biologic agents