Beth Neilsen

All Publications

• Dosimetric analysis of post-radiotherapy sexual dysfunction in patients receiving definitive stereotactic body radiotherapy (SBRT) for prostate cancer: a secondary analysis of MIRAGE RADIOTHERAPY AND ONCOLOGY Massachi, J., Jiang, T., Neilsen, B. K., Wilhalme, H., Ruan, D., Casado, M., Chong, N., Zello, L., Lamb, J. M., Ma, T., Valle, L. F., Cao, M., Steinberg, M. L., Kishan, A. U. 2026; 222: 111683

  Abstract

  The etiology of the improved long-term sexual function seen following MRI-guided stereotactic body radiotherapy (SBRT) with aggressive margin reduction for prostate cancer remains unknown.To investigate potential explanatory mechanisms for this finding, we conducted a secondary analysis of data collected for the prospective, randomized phase III MIRAGE trial. Dosimetric data for the structures hypothesized to drive sexual function decline (neurovascular bundles (NVB) and internal pudendal arteries (IPA)) were retrospectively collected and analyzed for correlations with treatment arm or clinically significant sexual function decline as measured by patient reported outcome (PRO) surveys focused on sexual function, namely the EPIC26-SF and SHIM scores.One-hundred-and-seventeen participants from the MIRAGE trial (CT-arm: 58, MRI-arm: 59), corresponding to 75 % of the overall cohort, had complete sexual function PRO survey responses at 24 months. Baseline SHIM score was slightly higher in the MRI arm although EPIC26-SF was the same. No significant differences were noted in treatment characteristics (such as hydrogel spacer, GTV boost, or ADT use) between the study arms. Patients in the MRI group were noted to have significantly lower V36Gy and V20Gy for the NVBs and IPAs. Maximum dose to the right NVB was associated with increased likelihood of sexual function decline (p < 0.05).Although this analysis is limited in its exploratory nature, the data suggest that the unintentional sparing effect of aggressive margin reduction may be associated with a reduction in volume of the NVBs and IPAs receiving intermediate- or low-dose radiation. This, in turn, could explain the reduced rates of sexual function decline experienced by patients receiving MRgSBRT.

  View details for DOI 10.1016/j.radonc.2026.111683

  View details for Web of Science ID 001826222100001

  View details for PubMedID 42435817

• Metapipeline-DNA: A comprehensive germline and somatic genomics Nextflow pipeline. Cell reports methods Patel, Y., Zhu, C., Yamaguchi, T. N., Wang, N. K., Wiltsie, N., Zeltser, N., Gonzalez, A. E., Winata, H. K., Pan, Y., Mootor, M. F., Sanders, T., Fitz-Gibbon, S. T., Kandoth, C., Livingstone, J., Liu, L. Y., Carlin, B., Holmes, A., Oh, J., Sahrmann, J., Tao, S., Eng, S., Hugh-White, R., Pashminehazar, K., Beshlikyan, A., Jordan, M., Wu, S., Tian, M., Arbet, J., Neilsen, B., Haas, R., Bugh, Y. Z., Kim, G., Salmingo, J., Zhang, W., Anand, A., Hwang, E., Neiman-Golden, A., Steinberg, P., Zhao, W., Anand, P., Agrawal, R., Tsai, B. L., Boutros, P. C. 2026: 101340

  Abstract

  The price, quality, and throughput of DNA sequencing continue to improve. Algorithmic innovations have allowed inference of a growing range of features from DNA sequencing data, quantifying nuclear, mitochondrial, and evolutionary aspects of both germline and somatic genomes. To automate analyses of the full range of genomic characteristics, we created an extensible Nextflow metapipeline called metapipeline-DNA. It analyzes targeted and whole-genome sequencing data from raw reads through preprocessing, feature detection by multiple algorithms, quality control, and data-visualization. Each step can be run independently and is supported by robust software engineering including automated failure-recovery, granular testing, and consistent verifications of inputs, outputs, and parameters. Metapipeline-DNA is cloud-compatible and highly configurable, with options to subset and optimize each analysis. Metapipeline-DNA facilitates high-scale, comprehensive analysis of DNA sequencing data, and is open-source under the GPLv2 license.

  View details for DOI 10.1016/j.crmeth.2026.101340

  View details for PubMedID 41850291

• Genomic and Transcriptomic Profiling of Radiation-Resistant, Locally Recurrent Prostate Cancer. International journal of radiation oncology, biology, physics Neilsen, B. K., Huang, R. R., Valle, L. F., Proudfoot, J. A., Davicioni, E., Zhang, L., Ryg, U., Schulz-Jaavall, M., Weidhaas, J. B., Santoso, M., Parmisano, S., Calais, J., Reiter, R. E., Rettig, M. B., Steinberg, M. L., Sisk, A., Brisbane, W., Marks, L. S., Boutros, P. C., Lilleby, W. H., Kishan, A. U. 2025

  Abstract

  PURPOSE: The biology of locally radiorecurrent prostate cancer (LRR-PCa) is poorly understood.METHODS AND MATERIALS: We sought to explore the genomic and transcriptomic landscape of LRR-PCa with targeted DNA sequencing and RNA expression analysis from 41 biopsy-proven LRR-PCa tumors from 36 unique patients who had a recurrence at a median interval of 84 months (IQR, 70-124 months). Genomic alteration frequencies and transcriptomic data were compared between the LRR-PCa cohort and treatment-naive patients from the Cancer Genome Atlas (genomic; n = 496) and Gleason grade-at-recurrence-matched patients from the Decipher Genomics Resource for Intelligent Discovery (transcriptomic; n = 22,320).RESULTS: Twenty-five patients (69%) had pathologic upgrading at recurrence (17% vs 64% with Gleason grade 4-5 disease; P < .001). The LRR-PCa cohort demonstrated significantly greater single-nucleotide variations in 29 genes known to be associated with prostate cancer, including several associated with increased aggressiveness and DNA repair: FAT1 (58.5% vs 1.0%), RAD51B (36.6% vs 0.4%), POLQ (34.1% vs 1.4%), KMT2C (34.1% vs 4.9%), BRCA2 (29.3% vs 1.8%), ATRX (26.8% vs 0.8%), and BRCA1 (24.4% vs 0.4%) (Pvalues < .001 for all). The LRR-PCa cohort had a significantly higher Decipher score (median, 0.80 vs 0.66; P = .05) and demonstrated significantly greater basal subtype based on PAM50 (56% vs 20%; P < .001) and lower androgen receptor activity (61% for LRR vs 9%; P < .001).CONCLUSIONS: Overall, these results suggest that LRR-PCa has a distinct genomic and transcriptomic landscape from de novo prostate cancer. Specifically, LRR-PCa has an enrichment in SNVs in genes associated with tumor aggressiveness and/or DNA repair, has higher Decipher scores, a more basal subtype, and has transcriptomic evidence of lower androgen receptor activity and loss of tumor suppressor genes.

  View details for DOI 10.1016/j.ijrobp.2025.09.035

  View details for PubMedID 41105052

• Validation and Derivation of miRNA-Based Germline Signatures Predicting Radiation Toxicity in Prostate Cancer CLINICAL CANCER RESEARCH Kishan, A. U., McGreevy, K., Valle, L., Steinberg, M., Neilsen, B., Casado, M., Cao, M., Telesca, D., Weidhaas, J. B. 2025; 31 (12): 2530-2538

  Abstract

  Although radiotherapy (RT) is one of the primary treatment modalities used in the treatment of cancer, patients often experience toxicity during or after treatment. RT-induced genitourinary (GU) toxicity is a significant survivorship challenge for patients with prostate cancer, but identifying those at risk has been challenging. Herein, we attempt (i) to validate a previously identified biomarker of late RT-induced GU toxicity, PROSTOX, consisting primarily of miRNA-based germline biomarkers (mirSNPs), and (ii) investigate the possibility of temporally and genetically defining other forms of RT-associated GU toxicity.We included 148 patients enrolled in Magnetic Resonance Imaging-Guided Stereotactic Body Radiotherapy for Prostate Cancer (MIRAGE; NCT04384770), a trial comparing MRI- versus CT-guided prostate stereotactic body RT. Linear regression was used to evaluate the association between PROSTOX score and late GU grade toxicity. Machine learning approaches were used to develop predictive models for acute toxicity and chronic GU toxicity, and the accuracy of all models was assessed using AUC metrics. A comparative Gene Ontology analysis was performed.PROSTOX accurately predicts late GU toxicity, achieving an AUC of 0.76, and demonstrates strong correlation with GU toxicity grade (p-1.2E-9). mirSNP-based signatures can distinguish acute RT-associated GU toxicity and chronic RT-associated GU toxicity (AUCs of 0.770 and 0.763, respectively). Finally, Gene Ontology analysis identifies unique pathways involved in each form of GU toxicity: acute, chronic, and late.These findings provide strong evidence for the continued application of mirSNPs to predict toxicity to RT and act as a path for the continued personalization of RT with improved patient outcomes.

  View details for DOI 10.1158/1078-0432.CCR-24-3951

  View details for Web of Science ID 001507961400001

  View details for PubMedID 40192540

  View details for PubMedCentralID PMC12163599

• Magnetic Resonance Imaging Versus Computed Tomography Guidance for Stereotactic Body Radiotherapy in Prostate Cancer: 2-year Outcomes from the MIRAGE Randomized Clinical Trial EUROPEAN UROLOGY Kishan, A. U., Lamb, J. M., Wilhalme, H., Casado, M., Chong, N., Zello, L., Juarez, J. E., Jiang, T., Neilsen, B. K., Low, D. A., Yang, Y., Neylon, J., Basehart, V., Ma, T., Valle, L. F., Cao, M., Steinberg, M. L. 2025; 87 (6): 622-625

  Abstract

  It has been shown that magnetic resonance imaging (MRI) guidance versus computed tomography (CT) guidance for aggressive margin-reduction (AMR) for stereotactic body radiotherapy (SBRT) in prostate cancer reduces acute toxicity, but the longer-term benefits are unknown. We performed a secondary analysis of MIRAGE, a phase 3 randomized clinical trial of MRI-guided SBRT for prostate cancer, to determine whether AMR with MRI guidance significantly reduced 2-yr physician-scored or patient-reported toxic effects in comparison to CT guidance. The cumulative incidence of 2-yr physician-scored toxicity, defined as grade ≥2 genitourinary (GU) and gastrointestinal (GI) toxic effects according to Common Terminology Criteria for Adverse Events v4.03, were lower with MRI guidance. Cumulative incidence rates of late grade ≥2 toxicity at 2 yr with MRI-guided versus CT-guided SBRT were 27% (95% confidence interval [CI] 19-39%)] versus 51% (95% CI 41-63%) for GU toxicity (p = 0.004), and 1.4% (95% CI 0.2-9.6) versus 9.5% (95% CI 4.6-19) for GI toxicity (p = 0.025). Cumulative logistic regression revealed that MRI-guided SBRT was associated with significantly lower odds of a clinically relevant deterioration in bowel function according to the Expanded Prostate Cancer Index Composite-26 score (odds ratio 0.444, 95% CI 0.209-0.942; p = 0.035) and in the Sexual Health Inventory in Men score (odds ratio 0.366, 95% CI 0.148-0.906; p = 0.03). There were no significant differences in the odds of a deterioration for other quality-of-life metrics. These findings support the hypothesis that aggressive planning for margin reduction for prostate SBRT using MRI leads to continued reductions in toxic effects over 2-yr follow-up. This trial is registered on ClinicalTrials.gov Identifier as NCT04384770.

  View details for DOI 10.1016/j.eururo.2024.10.026

  View details for Web of Science ID 001505109200002

  View details for PubMedID 39537438

• A clustering-based approach to address correlated features in predicting genitourinary toxicity from MRI-guided prostate SBRT MEDICAL PHYSICS Rezapoor, P., Pham, J., Neilsen, B., Liu, H., Cao, M., Yang, Y., Sheng, K., Ma, T., Lamb, J., Steinberg, M., Kishan, A. U., Taylor, Z., Ruan, D. 2025; 52 (6): 5104-5114

  Abstract

  It is common in outcome analysis to work with a large set of candidate prognostic features. However, such high-dimensional input and relatively small sample size leads to risk of overfitting, low generalizability, and correlation bias.This study addresses the issue of correlation bias mitigation in the context of predicting genitourinary (GU) toxicity in prostate cancer patients underwent MRI-guided stereotactic body radiation therapy (SBRT).Typical dimension reduction or feature selection methods include regularization for sparsity or information criterion. However, when heavy correlation occurs with (subsets of) input features, the assigned weights of correlated features can be diluted to an extent that the corresponding features are no more effective in the prediction, leading to suboptimal feature discovery and prediction. We propose to perform advanced hierarchical clustering and then apply regression modeling to cluster centroids. This approach addresses the challenges posed by high dimensionality and ill-conditioning, and improves accuracy and reliability of the resulting prediction models. Performance of the proposed method was evaluated on typical regression models with intrinsic feature reduction methods, namely Least Absolute Shrinkage and Selection Operator (LASSO) regularized logistic regression (LR), support vector machine (SVM), and decision trees (DT).Extensive experiments show that introducing cluster-based feature compaction and representation improves all regression models under fair hyperparameter tuning conditions. Although LASSO and LR with clustered features had similar performance during training and validation, with LASSO-LR being slightly better, the cluster-based feature method achieved significantly better performance on the test set by achieving 0.91 AUC and 0.86 accuracy, demonstrating its advantage in stability and robustness. The overall best test performance is achieved by combining feature clustering to five representatives with SVM. Additional correlation study identified individual features closely representing the cluster centroids as exposure volume of rectum at 2 Gy rectum, trigone exposure at 2 Gy and 41 Gy, urethra at 42 Gy urethra, and rectal wall at 42 Gy rectal wall. This indicates the importance of hot spot control of urethra, trigone, and rectal wall for toxicity control.These findings underscore the superiority of the clustering method in mitigating correlation bias and enhancing predictive model accuracy. The current model also achieves state of the art (SOTA) performance in predicting GU toxicity in MRI-guided prostate SBRT. Correlating dose features to feature cluster centroids reveals the importance of hot spot control on urethra, trigone, and rectal wall to reduce toxicity risk.

  View details for DOI 10.1002/mp.17834

  View details for Web of Science ID 001472720100001

  View details for PubMedID 40268686

• Synchronous Double Primary Malignancy of Non-Small Cell Lung Cancer and Glioblastoma: A Case Report and Literature Review. Case reports in oncology Carmicheal, J., Johnson, K. C., Neilsen, B. K., Shonka, N., Zhang, C., Baine, M. 2025; 18 (1): 330-338

  Abstract

  Non-small cell lung cancer (NSCLC) is the most common form of lung cancer and has a propensity to metastasize to the brain. It is incredibly difficult to distinguish between a primary brain lesions and a solitary metastasis from distant occult disease using current imaging techniques. Further, complications arise from the shifting paradigm in how medicine views NSCLC brain metastasis due to contemporary nonsurgical curative treatments and the recent increase in the number of multiple primary malignancy (MPM) diagnoses associated with NSCLC. There is a dearth of reports regarding synchronous double primary malignancies involving separate lung and brain pathologies. Importantly, understanding the underlying cancer etiology is necessary for efficacious treatment strategy.A 65-year-old white male patient presented with node-positive NSCLC and a solitary intracranial lesion. The lung mass responded favorably to chemoradiotherapy while the brain lesion continued to progress despite stereotactic radiosurgery treatment. Subsequent resection of the brain lesion, conducted 8 months after initial presentation, surprisingly revealed a second primary cancer diagnosis of glioblastoma (GB). Unfortunately, despite revision of systemic therapeutic strategy, the patient continued to progress through treatment and ultimately died 16 months after the initial diagnosis.Herein is the third report regarding synchronous double primary malignancies involving non-small cell lung cancer (NSCLC) and GB. This report of an assumed metastatic NSCLC patient with a solitary brain lesion, history of smoking, and COPD underscores the need for pathological confirmation of all new presentations of metastatic disease via biopsy and highlights the importance of including the possibility of a second primary in the differential diagnosis. Additional reports of NSCLC and synchronous solitary brain lesions are needed to further elucidate pertinent patient characteristics and better inform clinical decision making.

  View details for DOI 10.1159/000543770

  View details for PubMedID 40881968

  View details for PubMedCentralID PMC11908813

• The Proteogenomics of Prostate Cancer Radioresistance CANCER RESEARCH COMMUNICATIONS Haas, R., Frame, G., Khan, S., Neilsen, B. K., Hong, B., Yeo, C. P. X., Yamaguchi, T. N., Ong, E. H. W., Zhao, W., Carlin, B., Yeo, E. L. L., Tan, K., Bugh, Y., Zhu, C., Hugh-White, R., Livingstone, J., Poon, D. J. J., Chu, P., Patel, Y., Tao, S., Ignatchenko, V., Kurganovs, N. J., Higgins, G. S., Downes, M. R., Loblaw, A., Vesprini, D., Kishan, A. U., Chua, M. L. K., Kislinger, T., Boutros, P. C., Liu, S. K. 2024; 4 (9): 2463-2479

  Abstract

  Prostate cancer is frequently treated with radiotherapy. Unfortunately, aggressive radioresistant relapses can arise, and the molecular underpinnings of radioresistance are unknown. Modern clinical radiotherapy is evolving to deliver higher doses of radiation in fewer fractions (hypofractionation). We therefore analyzed genomic, transcriptomic, and proteomic data to characterize prostate cancer radioresistance in cells treated with both conventionally fractionated and hypofractionated radiotherapy. Independent of fractionation schedule, resistance to radiotherapy involved massive genomic instability and abrogation of DNA mismatch repair. Specific prostate cancer driver genes were modulated at the RNA and protein levels, with distinct protein subcellular responses to radiotherapy. Conventional fractionation led to a far more aggressive biomolecular response than hypofractionation. Testing preclinical candidates identified in cell lines, we revealed POLQ (DNA Polymerase Theta) as a radiosensitizer. POLQ-modulated radioresistance in model systems and was predictive of it in large patient cohorts. The molecular response to radiation is highly multimodal and sheds light on prostate cancer lethality.Radiation is standard of care in prostate cancer. Yet, we have little understanding of its failure. We demonstrate a new paradigm that radioresistance is fractionation specific and identified POLQ as a radioresistance modulator.

  View details for DOI 10.1158/2767-9764.CRC-24-0292

  View details for Web of Science ID 001348320900003

  View details for PubMedID 39166898

  View details for PubMedCentralID PMC11411600

• Analysis of Oncology and Radiation Therapy Representation on the National Board of Medical Examiners Official Practice Material for the United States National Standardized Medical Board Examinations JOURNAL OF CANCER EDUCATION Mahoney, M. T., Linkowski, L. C., Wu, T. C., Chen, J., Neilsen, B. K., Thompson, P. S., Mix, M. D., Sura, K. T., Mattes, M. D. 2025; 40 (1): 79-87

  Abstract

  Radiation therapy (RT) is a critical component of multidisciplinary cancer care, but has inconsistent curricular exposure. We characterize the radiation oncology (RO) content on the standardized undergraduate medical examinations by comparing its context and prevalence with other domains in oncology. National Board of Medical Examiners (NBME) self-assessments and sample questions for the United States Medical Licensing Exam (USMLE) Steps 1-3 and NBME clinical science shelf examinations were accessed (n = 3878). Questions were inductively analyzed for content pertaining to oncology and treatment modalities of RT, systemic therapy (ST), and surgical intervention (SI). Questions were coded using USMLE Physician Tasks/Competencies and thematic analysis. Descriptive statistics and analyses using the Kruskal-Wallis test are reported. A total of 337 questions (8.6%) within the USMLE and shelf exams included oncology content, with 101 questions (2.6%) referencing at least one cancer treatment modality (n = 35 RT, 45 ST, 57 SI). Treatment questions were more common on USMLE Step 2 CK (n = 35/101, 32%) compared to Step 1 (n = 23/101, 23%) and Step 3 (n = 8/101, 8%) (p < 0.001). RT was significantly less likely to be the correct answer (2/35, 6%) compared to ST (4/45, 9%) and SI (18/57, 32%) (p = 0.003). Therapeutic oncology questions are uncommon on the examination material, with an under-representation of radiation-related content, and contextual bias favoring surgical approaches. We advocate for greater RO involvement in the content creation of such examinations to help trainees better understand multidisciplinary cancer care.

  View details for DOI 10.1007/s13187-024-02475-0

  View details for Web of Science ID 001271490500001

  View details for PubMedID 38997529

  View details for PubMedCentralID PMC11846759

• Effectiveness of Single-Fraction, Low-Dose, Bilateral Whole Lung Radiation Therapy for Diffuse Alveolar Hemorrhage Secondary to Extramedullary Hematopoiesis: A Case Report and Review of the Literature ADVANCES IN RADIATION ONCOLOGY Neilsen, B. K., Sleightholm, R. L., Gower, A., Tsai, S. C., Schiller, G. J., Oliai, C., Lee, A., Raldow, A., Tenn, S., Venkat, P. S. 2024; 9 (7): 101506

  View details for DOI 10.1016/j.adro.2024.101506

  View details for Web of Science ID 001337912700001

  View details for PubMedID 38799111

  View details for PubMedCentralID PMC11127181

• Impact of Interfractional Bladder and Trigone Displacement and Deformation on Radiation Exposure and Subsequent Acute Genitourinary Toxicity: A Post Hoc Analysis of Patients Treated with Magnetic Resonance Imaging -Guided Prostate Stereotactic Body Radiation Therapy in a Phase 3 Randomized Trial INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Neilsen, B. K., Ma, T., Akingbemi, W. O., Neylon, J., Casado, M. C., Sharma, S., Sheng, K., Ruan, D., Low, D. A., Yang, Y., Valle, L. F., Steinberg, M. L., Lamb, J. M., Cao, M., Kishan, A. U. 2024; 118 (4): 986-997

  Abstract

  Emerging data suggest that trigone dosimetry may be more associated with poststereotactic body radiation therapy (SBRT) urinary toxicity than whole bladder dosimetry. We quantify the dosimetric effect of interfractional displacement and deformation of the whole bladder and trigone during prostate SBRT using on-board, pretreatment 0.35T magnetic resonance images (MRI).Seventy-seven patients treated with MRI-guided prostate SBRT (40 Gy/5 fractions) on the MRI arm of a phase 3 single-center randomized trial were included. Bladder and trigone structures were contoured on images obtained from a 0.35T simulation MRI and 5 on-board pretreatment MRIs. Dice similarity coefficient (DSC) scores and changes in volume between simulation and daily treatments were calculated. Dosimetric parameters including Dmax, D0.03 cc, Dmean, V40 Gy, V39 Gy, V38 Gy, and V20 Gy for the bladder and trigone for the simulation and daily treatments were collected. Both physician-scored (Common Terminology Criteria for Adverse Events, version 4.03 scale) as well as patient-reported (International Prostate Symptom Scores and the Expanded Prostate Cancer Index Composite-26 scores) acute genitourinary (GU) toxicity outcomes were collected and analyzed.The average treatment bladder volume was about 30% smaller than the simulation bladder volume; however, the trigone volume remained fairly consistent despite being positively correlated with total bladder volume. Overall, the trigone accounted for <2% of the bladder volume. Median DSC for the bladder was 0.79, whereas the median DSC of the trigone was only 0.33. No statistically significant associations between our selected bladder and trigonal dosimetric parameters and grade ≥2 GU toxicity were identified, although numerically, patients with GU toxicity (grade ≥2) had higher intermediate doses to the bladder (V20 Gy and Dmean) and larger volumes exposed to higher doses in the trigone (V40 Gy, V39 Gy, and V38 Gy).The trigone exhibits little volume change, but considerable interfractional displacement/deformation. As a result, the relative volume of the trigone receiving high doses during prostate SBRT varies substantially between fractions, which could influence GU toxicity and may not be predicted by radiation planning dosimetry.

  View details for DOI 10.1016/j.ijrobp.2023.10.015

  View details for Web of Science ID 001194557100001

  View details for PubMedID 37871887

• Accelerated Hypofractionated Chemoradiation Followed by Stereotactic Ablative Radiotherapy Boost for Locally Advanced, Unresectable Non-Small Cell Lung Cancer A Nonrandomized Controlled Trial JAMA ONCOLOGY Wu, T. C., Luterstein, E., Neilsen, B. K., Goldman, J. W., Garon, E. B., Lee, J. M., Felix, C., Cao, M., Tenn, S. E., Low, D. A., Kupelian, P. A., Steinberg, M. L., Lee, P. 2024; 10 (3): 352-359

  Abstract

  Intrathoracic progression remains the predominant pattern of failure in patients treated with concurrent chemoradiation followed by a consolidation immune checkpoint inhibitor for locally advanced, unresectable non-small cell lung cancer (NSCLC).To determine the maximum tolerated dose (MTD) and use of hypofractionated concurrent chemoradiation with an adaptive stereotactic ablative radiotherapy (SABR) boost.This was an early-phase, single-institution, radiation dose-escalation nonrandomized controlled trial with concurrent chemotherapy among patients with clinical stage II (inoperable/patient refusal of surgery) or III NSCLC (American Joint Committee on Cancer Staging Manual, seventh edition). Patients were enrolled and treated from May 2011 to May 2018, with a median patient follow-up of 18.2 months. Patients advanced to a higher SABR boost dose if dose-limiting toxic effects (any grade 3 or higher pulmonary, gastrointestinal, or cardiac toxic effects, or any nonhematologic grade 4 or higher toxic effects) occurred in fewer than 33% of the boost cohort within 90 days of follow-up. The current analyses were conducted from January to September 2023.All patients first received 4 Gy × 10 fractions followed by an adaptive SABR boost to residual metabolically active disease, consisting of an additional 25 Gy (low, 5 Gy × 5 fractions), 30 Gy (intermediate, 6 Gy × 5 fractions), or 35 Gy (high, 7 Gy × 5 fractions) with concurrent weekly carboplatin/paclitaxel.The primary outcome was to determine the MTD.Data from 28 patients (median [range] age, 70 [51-88] years; 16 [57%] male; 24 [86%] with stage III disease) enrolled across the low- (n = 10), intermediate- (n = 9), and high- (n = 9) dose cohorts were evaluated. The protocol-specified MTD was not exceeded. The incidences of nonhematologic acute and late (>90 days) grade 3 or higher toxic effects were 11% and 7%, respectively. No grade 3 toxic effects were observed in the intermediate-dose boost cohort. Two deaths occurred in the high-dose cohort. Two-year local control was 74.1%, 85.7%, and 100.0% for the low-, intermediate-, and high-dose cohorts, respectively. Two-year overall survival was 30.0%, 76.2%, and 55.6% for the low-, intermediate-, and high-dose cohorts, respectively.This early-phase, dose-escalation nonrandomized controlled trial showed that concurrent chemoradiation with an adaptive SABR boost to 70 Gy in 15 fractions with concurrent chemotherapy is a safe and effective regimen for patients with locally advanced, unresectable NSCLC.ClinicalTrials.gov Identifier: NCT01345851.

  View details for DOI 10.1001/jamaoncol.2023.6033

  View details for Web of Science ID 001143290900005

  View details for PubMedID 38206614

  View details for PubMedCentralID PMC10784998

• Dosimetric predictors for genitourinary toxicity in MR-guided stereotactic body radiation therapy (SBRT): Substructure with fraction-wise analysis MEDICAL PHYSICS Pham, J., Neilsen, B. K., Liu, H., Cao, M., Yang, Y., Sheng, K., Ma, T., Kishan, A. U., Ruan, D. 2024; 51 (1): 612-621

  Abstract

  MR-guided radiation therapy (MRgRT) systems provide superior soft tissue contrast than x-ray based systems and can acquire real-time cine for treatment gating. These features allow treatment planning margins to be reduced, allowing for improved critical structure sparing and reduced treatment toxicity. Despite this improvement, genitourinary (GU) toxicity continues to affect many patients.(1) To identify dosimetric predictors, potentially in combination with clinical parameters, of GU toxicity following SBRT by leveraging MRgRT to accurately monitor daily dose, beyond predicted dose calculated during planning. (2) Improve awareness of toxicity-sensitive bladder substructures, specifically the trigone and urethra.Sixty-nine prostate cancer patients (NCT04384770 clinical trial) were treated on a ViewRay MRIdian MRgRT system, with 40 Gy prescribed to 95% of the PTV in over five fractions. Overall, 17 (24.6%) prostate patients reported acute grade 2 GU toxicity. The CTV, PTV, bladder, bladder wall, trigone, urethra, rectum, and rectal wall were contoured on the planning and daily treatment MRIs. Planning and daily treatment DVHs (0.1 Gy increments), organ doses (min, max, mean), and organ volumes were recorded. Daily dose was estimated by transferring the planning dose distributions to the daily MRI based on the daily setup alignment. Patients were partitioned into a training (55) and testing set (14). Dose features were pre-filtered using a t-test followed by maximum relevance minimum redundancy (MRMR) algorithm. Logistic regression was investigated with regularization to select dosimetric predictors. Specifically, two approaches: time-group least absolute shrinkage and selection (LASSO), and interactive grouped greedy algorithm (IGA) were investigated. Shared features across the planning and five treatment fractions were grouped to encourage consistency and stability. The conventional flat non-temporally grouped LASSO was also evaluated to provide a solid benchmark. After feature selection, a final logistic regression model was trained. Dosimetric regression models were compared to a clinical regression model with only clinical parameters (age, baseline IPSS, prostate gland size, ADT usage, etc.) and a hybrid model, combining the best performing dosimetric features with the clinical parameters, was evaluated. Final model performance was evaluated on the testing set using accuracy, sensitivity, and specificity determined by the optimal threshold of the training set.IGA had the best testing performance with an accuracy/sensitivity/specificity of 0.79/0.67/0.82, selecting 12 groups covering the bladder (V19.8 Gy, V20.5 Gy), bladder wall (19.7 Gy), trigone (15.9, 18.2, 43.3 Gy), urethra (V41.4 Gy, V41.7 Gy), CTV (V41.9 Gy), rectum (V8.5 Gy), and rectal wall (1.2, 44.1 Gy) dose features. Absolute bladder V19.8 Gy and V20.5 Gy were the most important features, followed by relative trigone 15.9  and 18.2 Gy. Inclusion of clinical parameters in the hybrid model with IGA did not significantly change regression performance.Overall, IGA feature selection resulted in the best GU toxicity prediction performance. This exploratory study demonstrated the feasibility of identification and analysis of dosimetric toxicity predictors with awareness to sensitive substructures and daily dose to potentially provide consistent and stable dosimetric metrics to guide treatment planning. Further patient accruement is warranted to further assess dosimetric predictor and perform validation.

  View details for DOI 10.1002/mp.16878

  View details for Web of Science ID 001113997600001

  View details for PubMedID 38055353

• Biochemical Recurrence Surrogacy for Clinical Outcomes After Radiotherapy for Adenocarcinoma of the Prostate JOURNAL OF CLINICAL ONCOLOGY Roy, S., Romero, T., Michalski, J. M., Feng, F. Y., Efstathiou, J. A., Lawton, C. A. F., Bolla, M., Maingon, P., de Reijke, T., Joseph, D., Ong, W., Sydes, M. R., Dearnaley, D. P., Tree, A. C., Carrier, N., Nabid, A., Souhami, L., Incrocci, L., Heemsbergen, W. D., Pos, F. J., Zapatero, A., Guerrero, A., Alvarez, A., San-Segundo, C., Maldonado, X., Reiter, R. E., Rettig, M. B., Nickols, N. G., Steinberg, M. L., Valle, L. F., Ma, T., Farrell, M. J., Neilsen, B. K., Juarez, J. E., Deng, J., Vangala, S., Avril, N., Jia, A. Y., Zaorsky, N. G., Sun, Y., Spratt, D., Kishan, A. U., Meta-Anal Ranomized Trials Canc 2023; 41 (32): 5005-+

  Abstract

  The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods.Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the R2). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed.Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The R2 values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively.BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events.

  View details for DOI 10.1200/JCO.23.00617

  View details for Web of Science ID 001101730300009

  View details for PubMedID 37639648

  View details for PubMedCentralID PMC10642893

• Radiation Therapy Improves Local Control in Juvenile Nasopharyngeal Angiofibroma following Disease Progression after Embolization and Surgical Resection: A Case Report CASE REPORTS IN ONCOLOGY Blank, Z., Sleightholm, R., Neilsen, B., Baine, M., Lin, C. 2021; 14 (2): 739-745

  Abstract

  Juvenile nasopharyngeal angiofibroma (JNA) is a relatively uncommon, benign neoplasm of the nasopharynx that can be very difficult to diagnose early due to inconspicuous and seemingly harmless presenting symptoms. Early diagnosis and treatment of JNA are essential for a good prognosis. JNA typically responds well to radiation therapy (RT), but when it does not, the most appropriate next course of action has not been readily defined due to the limited occurrence and experience with this neoplasm. Herein, we describe a JNA patient, who continued to progress after surgery and 36 Gy of adjuvant radiation, but after an additional 14.4 Gy, he has remained in remission for over 2 years. An 11-year-old boy who presented with JNA underwent treatment with embolization and surgical resection. Unfortunately, the tumor progressed within 2 months of surgical intervention and he required RT for adequate local control. While undergoing RT, he again demonstrated signs of progression; so his radiation regimen was increased from 3,600 cGy in 20 fractions to 5,040 cGy in 28 fractions. Since completing RT, the tumor has continued to decrease in size, and the patient is stable and has been without signs of disease progression for over 24 months now. Thus, escalating the radiation regimen to 5,040 cGy may improve local control in rapidly progressive JNA.

  View details for DOI 10.1159/000512061

  View details for Web of Science ID 000692155100006

  View details for PubMedID 34177524

  View details for PubMedCentralID PMC8215977

• Percentage of Hormone Receptor Positivity in Breast Cancer Provides Prognostic Value: A Single-Institute Study JOURNAL OF CLINICAL MEDICINE RESEARCH-CANADA Sleightholm, R., Neilsen, B. K., Elkhatib, S., Flores, L., Dukkipati, S., Zhao, R., Choudhury, S., Gardner, B., Carmichael, J., Smith, L., Bennion, N., Wahl, A., Baine, M. 2021; 13 (1): 9-19

  Abstract

  A majority of breast cancer tumors express estrogen receptor (ER) and/or progesterone receptor (PR); however, the percentage of cancer cells expressing these receptors can range from 0-100%. The prognostic and therapeutic impact of the percentage of cells expressing hormone receptors in breast cancer is not fully understood.A retrospective analysis of 411 breast cancer patients who were treated at the University of Nebraska Medical Center between 2010 and 2017 was performed. Patient tumors were evaluated for percentage of cells expressing ER and PR in conjunction with clinical outcomes.Patient tumors demonstrated a highly bimodal pattern of ER and PR staining with a majority of tumors demonstrating either a high percentage (> 80% of cells) or lack of cells (0%) staining for ER or PR. An increase in the percentage of ER positivity correlated with decreased local recurrence and improved overall survival. An increase in the percentage of PR positivity demonstrated a trend towards decreased local recurrence and improved overall survival, but was not statistically significant.Results based on both continuous and categorical evaluation of ER expression revealed that increasing expression correlated with improved patient outcomes. Similar evaluation of PR expression demonstrated a trend towards improved patient outcomes though not statistically significant. These findings suggest that the degree of hormone receptor positivity and not a Boolean representation of positivity could provide additional prognostic value in the treatment and management of breast cancer.

  View details for DOI 10.14740/jocmr4398

  View details for Web of Science ID 001111080600002

  View details for PubMedID 33613796

  View details for PubMedCentralID PMC7869562

• Diffuse lesions secondary to sarcoidosis mimicking widespread metastatic breast cancer: A case report CLINICAL CASE REPORTS Vieira, H., Neilsen, B. K., Sleightholm, R., Hankins, J., Freifeld, A., Moore, G., Wahl, A., Baine, M. J. 2021; 9 (1): 477-481

  Abstract

  This case of sarcoidosis mimicking metastatic breast cancer serves as a reminder of the need to consider differential diagnoses even when the clinical scenario and imaging findings are highly suggestive of metastases.

  View details for DOI 10.1002/ccr3.3561

  View details for Web of Science ID 000594373900001

  View details for PubMedID 33489200

  View details for PubMedCentralID PMC7813063

• A Gene Expression High-Throughput Screen (GE-HTS) for Coordinated Detection of Functionally Similar Effectors in Cancer CANCERS Rao, C., Huisman, D. H., Vieira, H. M., Frodyma, D. E., Neilsen, B. K., Chakraborty, B., Hight, S. K., White, M. A., Fisher, K. W., Lewis, R. E. 2020; 12 (11)

  Abstract

  Genome-wide, loss-of-function screening can be used to identify novel vulnerabilities upon which specific tumor cells depend for survival. Functional Signature Ontology (FUSION) is a gene expression-based high-throughput screening (GE-HTS) method that allows researchers to identify functionally similar proteins, small molecules, and microRNA mimics, revealing novel therapeutic targets. FUSION uses cell-based high-throughput screening and computational analysis to match gene expression signatures produced by natural products to those produced by small interfering RNA (siRNA) and synthetic microRNA libraries to identify putative protein targets and mechanisms of action (MoA) for several previously undescribed natural products. We have used FUSION to screen for functional analogues to Kinase suppressor of Ras 1 (KSR1), a scaffold protein downstream of Ras in the Raf-MEK-ERK kinase cascade, and biologically validated several proteins with functional similarity to KSR1. FUSION incorporates bioinformatics analysis that may offer higher resolution of the endpoint readout than other screens which utilize Boolean outputs regarding a single pathway activation (i.e., synthetic lethal and cell proliferation). Challenges associated with FUSION and other high-content genome-wide screens include variation, batch effects, and controlling for potential off-target effects. In this review, we discuss the efficacy of FUSION to identify novel inhibitors and oncogene-induced changes that may be cancer cell-specific as well as several potential pitfalls within FUSION and best practices to avoid them.

  View details for DOI 10.3390/cancers12113143

  View details for Web of Science ID 000592898600001

  View details for PubMedID 33120942

  View details for PubMedCentralID PMC7692652

• Correction: Characterization of CDK(5) inhibitor, 20-223 (aka CP668863) for colorectal cancer therapy. Oncotarget Robb, C. M., Kour, S., Contreras, J. I., Agarwal, E., Barger, C. J., Rana, S., Sonawane, Y., Neilsen, B. K., Taylor, M., Kizhake, S., Thakare, R. N., Chowdhury, S., Wang, J., Black, J. D., Hollingsworth, M. A., Brattain, M. G., Natarajan, A. 2020; 11 (25): 2462-2463

  Abstract

  [This corrects the article DOI: 10.18632/oncotarget.23749.].

  View details for DOI 10.18632/oncotarget.27403

  View details for PubMedID 32637035

• High-throughput identification of protein functional similarities using a gene-expression-based siRNA screen SCIENTIFIC DATA Neilsen, B. K., Kelly, D. L., Chakraborty, B., Kim, H., White, M. A., Lewis, R. E., Fisher, K. W. 2020; 7 (1): 27

  Abstract

  A gene expression-based siRNA screen was used to evaluate functional similarity between genetic perturbations to identify functionally similar proteins. A siRNA library (siGenome library, Dharmacon) consisting of multiple siRNAs per gene that have been pooled in to one well per gene was arrayed in a 384-well format and used to individually target 14,335 proteins for depletion in HCT116 colon cancer cells. For each protein depletion, the gene expression of eight genes was quantified using the multiplexed Affymetrix Quantigene 2.0 assay in technical triplicate. As a proof of concept, six genes (BNIP3, NDRG1, ALDOC, LOXL2, ACSL5, BNIP3L) whose expression pattern reliably reflect the disruption of the molecular scaffold KSR1 were measured upon each protein depletion. The remaining two genes (PPIB and HPRT) are housekeeping genes used for normalization. The gene expression signatures from this screen can be used to estimate the functional similarity between any two proteins and successfully identified functional relationships for specific proteins such as KSR1 and more generalized processes, such as autophagy.

  View details for DOI 10.1038/s41597-020-0365-2

  View details for Web of Science ID 000511439400004

  View details for PubMedID 31964871

  View details for PubMedCentralID PMC6972743

• A preliminary report of gonadal-sparing TBI using a VMAT technique. Practical radiation oncology Blomain, E. S., Kovalchuk, N. n., Neilsen, E. n., Skinner, L. n., Hoppe, R. T., Hiniker, S. M. 2020

  Abstract

  Reproductive toxicity is common following total body irradiation and has major quality of life implications for patients. In that context, this is the first report of gonadal-sparing VMAT TBI, successfully delivered in a boy and a girl with aplastic anemia. Both patients' VMAT TBI plans demonstrated improved gonadal sparing versus simulated conventional 2D approach (mean testes dose 0.45 Gy VMAT versus 0.72 Gy 2D; mean ovary dose 0.64 Gy VMAT versus 1.47 Gy 2D). PTV coverage was also improved for both cases with the VMAT plan versus conventional 2D plan (2 Gy D90% versus 1.9 Gy D90%, respectively). Given these dosimetric advantages, the present study can serve as a proof-of-concept for further prospective studies evaluating this technique for wider applications in populations receiving TBI.

  View details for DOI 10.1016/j.prro.2020.07.006

  View details for PubMedID 32795616

• A Genome-wide Functional Signature Ontology Map and Applications to Natural Product Mechanism of Action Discovery CELL CHEMICAL BIOLOGY McMillan, E. A., Kwon, G., Clemenceau, J. R., Fisher, K. W., Vaden, R. M., Shaikh, A. F., Neilsen, B. K., Kelly, D., Potts, M. B., Sung, Y., Mendiratta, S., Hight, S. K., Lee, Y., MacMillan, J. B., Lewis, R. E., Kim, H., White, M. A. 2019; 26 (10): 1380-+

  Abstract

  Gene expression signature-based inference of functional connectivity within and between genetic perturbations, chemical perturbations, and disease status can lead to the development of actionable hypotheses for gene function, chemical modes of action, and disease treatment strategies. Here, we report a FuSiOn-based genome-wide integration of hypomorphic cellular phenotypes that enables functional annotation of gene network topology, assignment of mechanistic hypotheses to genes of unknown function, and detection of cooperativity among cell regulatory systems. Dovetailing genetic perturbation data with chemical perturbation phenotypes allowed simultaneous generation of mechanism of action hypotheses for thousands of uncharacterized natural products fractions (NPFs). The predicted mechanism of actions span a broad spectrum of cellular mechanisms, many of which are not currently recognized as "druggable." To enable use of FuSiOn as a hypothesis generation resource, all associations and analyses are available within an open source web-based GUI (http://fusion.yuhs.ac).

  View details for DOI 10.1016/j.chembiol.2019.07.008

  View details for Web of Science ID 000490904200007

  View details for PubMedID 31378711

  View details for PubMedCentralID PMC9161285

• Acute Carbon Monoxide Poisoning Secondary to Cigarette Smoking in a 40-Year-Old Man: A Case Report AMERICAN JOURNAL ON ADDICTIONS Neilsen, B. K., Aloi, J., Sharma, A. 2019; 28 (5): 413-415

  Abstract

  Carbon monoxide is one of the most common causes of fatal intoxications in the United States, and multiple previous studies have demonstrated that cigarette smokers have higher levels of carbon monoxide in their blood. However, the potential negative effects due to acute carbon monoxide poisoning from excessive cigarette smoking have not been well established.This is a single patient case report.In this case report, a 40-year-old male with a past medical history of depression, anxiety, panic attacks, and substance use disorder developed symptomatic, acute carbon monoxide poisoning secondary to heavy cigarette smoking in a confined space. In this patient, the cessation of clonazepam therapy coincided with increasing anxiety and panic disorder with agoraphobia triggering an escalation in his cigarette smoking. The patient smoked three packs of cigarettes in 3 hours and developed worsening of his symptoms. He required inpatient treatment with benzodiazepines and hyperbaric oxygen.Therefore, it is important to recognize cigarette smoke as a significant source of carbon monoxide exposure.While the negative effects of cigarette smoking are often perceived as being chronic and only coming to fruition after numerous years of exposure, it is important for both physicians and patients to recognize the possibility for potentially life-threatening acute toxicity secondary to carbon monoxide exposure. (Am J Addict 2019;28:413-415).

  View details for DOI 10.1111/ajad.12939

  View details for Web of Science ID 000479661900001

  View details for PubMedID 31348564

• Stereotactic Body Radiation Therapy Versus Nonradiotherapeutic Ablative Procedures (Laser/Cryoablation and Electrocautery) for Early-Stage Non-Small Cell Lung Cancer JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Baine, M. J., Sleightholm, R., Neilsen, B. K., Oupicky, D., Smith, L. M., Verma, V., Lin, C. 2019; 17 (5): 450-458

  Abstract

  Despite the fact that stereotactic body radiation therapy (SBRT) is the only recommended first-line therapy for inoperable early-stage non-small cell lung cancer (NSCLC), several thermal ablative procedures (TAPs; defined herein as laser/cryoablation and electrocautery) are available. Studies showing outcomes of these procedures and how they compare with SBRT are scarce. We sought to evaluate the comparative efficacy of SBRT versus TAPs using the National Cancer Database (NCDB).The NCDB was queried for patients with early-stage NSCLC who did not undergo surgical resection. Treatment-specific inclusion criteria were applied to select for patients receiving either TAPs or SBRT. Univariate logistic regression and Cox proportional hazards modeling were performed, and Kaplan-Meier curves were generated. Serial propensity matches were performed using a modified greedy 8→n matching 1:1 algorithm.A total of 27,734 patients were analyzed; 26,725 underwent SBRT and 1,009 underwent TAPs. Patients who received SBRT were older and more likely to have clinical stage IB (vs IA) disease. Despite this, SBRT was associated with longer median overall survival (mOS; 37.7 vs 33.5 months; P=.001) and 1-, 2-, and 5-year OS rates compared with the TAPs cohort (86.7% vs 83.1%, 67.5% vs 62.7%, and 30.6% vs 26.9%, respectively; P=.001). Upon propensity matching, improved OS with SBRT remained, with a mOS of 40.4 versus 33.4 months and 1-, 2-, and 5-year OS rates of 89.0% versus 82.9%, 69.7% versus 62.7%, and 34.4% versus 26.4%, respectively (P=.003).Despite being associated with more higher-risk factors, SBRT was associated with higher OS compared with TAPs for treatment of nonoperative patients diagnosed with early-stage NSCLC. However, causation cannot be implied owing to the inherent limitations of large heterogeneous datasets such as the NCDB.

  View details for DOI 10.6004/jnccn.2018.7269

  View details for Web of Science ID 000468989400007

  View details for PubMedID 31085762

  View details for PubMedCentralID PMC6664794

• A 47-year-old woman with nuclear protein in testis midline carcinoma masquerading as a sinus infection: a case report and review of the literature JOURNAL OF MEDICAL CASE REPORTS Elkhatib, S. K., Neilsen, B. K., Sleightholm, R. L., Baine, M. J., Zhen, W. 2019; 13 (1): 57

  Abstract

  Nuclear protein in testis midline carcinoma is a rare, highly metastatic undifferentiated carcinoma that typically arises in midline structures and is characterized by having a fusion involving the nuclear protein in testis, NUT, gene. Nuclear protein in testis midline carcinoma has been identified in patients of all ages and is often initially misdiagnosed due to the rapid timeline of symptom onset.Here we report the case of a 47-year-old Caucasian woman with a nuclear protein in testis midline carcinoma that was initially mistaken for a sinus infection. After symptom progression while on an aggressive antibiotic regimen, the source of her symptoms was correctly identified as a sella mass. Comprehensive analysis of the tumor was performed, and standard cytogenetic analysis identified a translocation of 15q and 19p. Further testing identified a NUT-BRD4 fusion and confirmed the diagnosis of nuclear protein in testis midline carcinoma. Despite definitive diagnosis and surgical, radiation, and, ultimately, systemic therapy, she progressed rapidly, developing widespread metastases, and ultimately died from the disease 5 months after diagnosis.Based on this and other previous reports, aggressive therapy should be initiated once nuclear protein in testis midline carcinoma is diagnosed and close surveillance employed in an attempt to prevent and/or recognize metastases as early as possible. Aggressive therapy has shown little efficacy such that the average overall survival for patients with nuclear protein in testis midline carcinoma is very short, often less than 6 months. Thus, early enrollment into clinical trials testing novel therapies for the treatment of nuclear protein in testis midline carcinoma should be considered. Finally, additional reports of nuclear protein in testis midline carcinoma are needed to fully characterize this rare and highly aggressive cancer.

  View details for DOI 10.1186/s13256-019-2015-x

  View details for Web of Science ID 000704833700001

  View details for PubMedID 30853030

  View details for PubMedCentralID PMC6410502

• Comprehensive genetic alteration profiling in primary and recurrent glioblastoma JOURNAL OF NEURO-ONCOLOGY Neilsen, B. K., Sleightholm, R., McComb, R., Ramkissoon, S. H., Ross, J. S., Corona, R. J., Miller, V. A., Cooke, M., Aizenberg, M. R. 2019; 142 (1): 111-118

  Abstract

  Glioblastoma (GBM) is heterogeneous and underlying genomic profiles influence evolution, resistance, and therapeutic responses. While extensive knowledge regarding genomic profiling of primary GBM exists, there remains a lack of understanding of genomic differences in recurrent GBM.We used the FoundationOne® comprehensive genomic profiling assay (CGP) to analyze ten matched primary and recurrent GBM. Genomic alterations (GA) were compared to the cancer database Catalogue of Somatic Mutations in Cancer (COSMIC).All matched tumor pairs demonstrated differences in GA between the primary and recurrence including one resected without any intervening therapy. This suggests that time and/or therapeutic intervention contribute to GA. Although mutations were common to both the primary and recurrence, the percent reads varied substantially suggesting clonal expansions and contractions. For example, EGFR mutations were significantly expanded in three patients, and CNAs were increased in two patients at recurrence. Four genes that were commonly altered in both primary and recurrent GBM were more prevalent in our cohort than reported in COSMIC: CDKN2A (86% vs. 53%) and CDKN2B (86% vs. 54%) deletions, EGFR activating mutation (52% vs. 10%) or amplification (81% vs. 45%), and TERT mutation (95% vs. 51%). Lastly, PI3K pathway activating mutations were also commonly seen in our cohort (67%).CGP revealed that GA identified in GBM changed over time and with treatment. Mutations in TERT, CDKN2A/CDKN2B, EGFR, and PI3K pathway were commonly observed in both primary and recurrent GBM revealing their prognostic and therapeutic potential. This may have important implications for individualized therapies and needs further evaluation.

  View details for DOI 10.1007/s11060-018-03070-2

  View details for Web of Science ID 000461075200011

  View details for PubMedID 30535594

• eERK-mediated TIMELESS expression suppresses G2/M arrest in colon cancer cells PLOS ONE Neilsen, B. K., Frodyma, D. E., McCall, J. L., Fisher, K. W., Lewis, R. E. 2019; 14 (1): e0209224

  Abstract

  The cell cycle is under circadian regulation. Oncogenes can dysregulate circadian-regulated genes to disrupt the cell cycle, promoting tumor cell proliferation. As a regulator of G2/M arrest in response to DNA damage, the circadian gene Timeless Circadian Clock (TIMELESS) coordinates this connection and is a potential locus for oncogenic manipulation. TIMELESS expression was evaluated using RNASeq data from TCGA and by RT-qPCR and western blot analysis in a panel of colon cancer cell lines. TIMELESS expression following ERK inhibition was examined via western blot. Cell metabolic capacity, propidium iodide, and CFSE staining were used to evaluate the effect of TIMELESS depletion on colon cancer cell survival and proliferation. Cell metabolic capacity following TIMELESS depletion in combination with Wee1 or CHK1 inhibition was assessed. TIMELESS is overexpressed in cancer and required for increased cancer cell proliferation. ERK activation promotes TIMELESS expression. TIMELESS depletion increases γH2AX, a marker of DNA damage, and triggers G2/M arrest via increased CHK1 and CDK1 phosphorylation. TIMELESS depletion in combination with Wee1 or CHK1 inhibition causes an additive decrease in cancer cell metabolic capacity with limited effects in non-transformed human colon epithelial cells. The data show that ERK activation contributes to the overexpression of TIMELESS in cancer. Depletion of TIMELESS increases γH2AX and causes G2/M arrest, limiting cell proliferation. These results demonstrate a role for TIMELESS in cancer and encourage further examination of the link between circadian rhythm dysregulation and cancer cell proliferation.

  View details for DOI 10.1371/journal.pone.0209224

  View details for Web of Science ID 000455483000021

  View details for PubMedID 30629587

  View details for PubMedCentralID PMC6328106

• Highly Aggressive and Radiation-Resistant, "Atypical" and Silent Pituitary Corticotrophic Carcinoma: A Case Report and Review of the Literature CASE REPORTS IN ONCOLOGY Flores, L., Sleightholm, R., Neilsen, B., Baine, M., Drincic, A., Thorell, W., Shonka, N., Oupicky, D., Zhang, C. 2019; 12 (1): 139-146

  Abstract

  Pituitary tumors typically remain silent unless interaction with nearby structures occurs. Rare subsets of pituitary tumors display aggressive phenotypes: highly mitotic, locally invasive, metastatic, chemotherapy and radiation resistant, etc. Disease progression and response to therapy is ill-defined in these subtypes, and their true prognostic potential is debated. Thus, identifying tumor characteristics with prognostic value and efficacious treatment options remains a challenge in aggressive pituitary tumors.A 45-year-old female presented with a nonfunctioning corticotropic pituitary macroadenoma with biomarkers suggestive of an "atypical" subtype: Ki-67 of 8-12%, increased mitosis, and locally invasive. Despite resections and radiation, growth continued, eventually affecting her vision. Although histologically ACTH positive, the patient remained clinically asymptomatic. Twelve months later, an episode of Cushing's disease-induced psychosis prompted a PET-CT scan, identifying sites of metastasis. Temozolomide was added to her medical regimen, and her metastatic liver lesions and boney metastases were treated with radiofrequency ablation and stereotactic body radiation therapy, respectively. Systemic treatment resulted in a drop in her ACTH levels, with her most recent scans/labs at 12 months following RFA suggesting remission.This is a unique presentation of a pituitary tumor, displaying characteristics of both clinically silent corticotropic and "atypical" macroadenoma subtypes. Although initially ACTH positive while clinically silent, the patient's disease ultimately recurred metastatically with manifestations of Cushing's disease and psychosis. With the addition of temozolomide to her treatment plan, her primary and metastatic sites have responded favorably to radiation therapy. Thus, the addition of temozolomide may be beneficial in the treatment of aggressive pituitary tumors.

  View details for DOI 10.1159/000496019

  View details for Web of Science ID 000467643700023

  View details for PubMedID 31043952

  View details for PubMedCentralID PMC6477470

• Morbidity and Mortality Rates Following Cytoreductive Surgery Combined With Hyperthermic Intraperitoneal Chemotherapy Compared With Other High-Risk Surgical Oncology Procedures JAMA NETWORK OPEN Foster, J. M., Sleightholm, R., Patel, A., Shostrom, V., Hall, B., Neilsen, B., Bartlett, D., Smith, L. 2019; 2 (1): e186847

  Abstract

  Currently, rates of referral of patients with peritoneal metastasis in the United States who qualify for cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) are low, in part because of the misperception of high morbidity and mortality rates. However, patients requiring major gastrointestinal surgical procedures with similar complication rates are routinely referred.To evaluate the relative safety of CRS/HIPEC.Retrospective cohort study of 34 114 patients who underwent CRS/HIPEC, right lobe hepatectomy, trisegmental hepatectomy, pancreaticoduodenectomy, and esophagectomy between January 1, 2005, and December 31, 2015, included in the American College of Surgeons National Surgical Quality Improvement Project (NSQIP) database. Data analysis was performed in 2018.Data from the NSQIP database were used to compare perioperative and 30-day postoperative morbidity and mortality rates of CRS/HIPEC (1822 patients) with other, well-accepted, high-risk surgical oncology procedures: right lobe hepatectomy (5109 patients), trisegmental hepatectomy (2449 patients), pancreaticoduodenectomy (Whipple) (16 793 patients), and esophagectomy (7941 patients).For 34 114 patients, median (interquartile range [IQR]) age was 63 (55-71) years and 42% were female. Patients undergoing CRS/HIPEC tended to be younger, with a median age of 57 years, and esophagectomy had the highest median (IQR) American Society of Anesthesiologists classification (3 [3-3]). When compared with CRS/HIPEC, higher complication rates were reported in the following categories: (1) superficial incisional infection in Whipple and esophagectomy (5.4% [95% CI, 4.4%-6.4%] vs 9.7% [95% CI, 9.3%-10.1%] and 7.2% [95% CI, 6.6%-7.8%], respectively; P < .001); (2) deep incisional infection in Whipple (1.7% [95% CI, 1.1%-2.3%] vs 2.7% [95% CI, 2.5%-2.9%]; P < .01); (3) organ space infection in right lobe hepatectomy (7.2% [95% CI, 6.0%-8.4%] vs 9.0% [95% CI, 8.2%-9.8%]; P = .02), trisegmental hepatectomy (12.4% [95% CI, 11.1%-13.7%]; P < .001), and Whipple (12.9% [95% CI, 12.4%-13.4%]; P < .001); and (4) return to the operating room for esophagectomy (6.8% [95% CI, 5.6%-8.0%] vs 14.4% [95% CI, 13.6%-15.2%]; P < .001). Median (IQR) length of hospital stay was lower in CRS/HIPEC (8 [5-11] days) than Whipple (10 [7-15] days) and esophagectomy (10 [8-16] days) (P < .001). Overall 30-day mortality was lower in CRS/HIPEC (1.1%; 95% CI, 0.6%-1.6%) compared with Whipple (2.5%; 95% CI, 2.3%-2.7%), right lobe hepatectomy (2.9%; 95% CI, 2.4%-3.4%), esophagectomy (3.0%; 95% CI, 2.6%-3.4%), and trisegmental hepatectomy (3.9%; 95% CI, 3.1%-4.7%) (P < .001).Comparative analysis revealed CRS/HIPEC to be safe, often safer across the spectrum of NSQIP safety metrics when compared with similar-risk oncologic procedures. Patient selection was important in achieving observed outcomes. High complication rates are a misperception from early CRS/HIPEC experience and should no longer deter referral of patients to experienced centers or impede clinical trial development in the United States.

  View details for DOI 10.1001/jamanetworkopen.2018.6847

  View details for Web of Science ID 000465422700023

  View details for PubMedID 30646202

  View details for PubMedCentralID PMC6484874

• WDR5 supports colon cancer cells by promoting methylation of H3K4 and suppressing DNA damage BMC CANCER Neilsen, B. K., Chakraborty, B., McCall, J. L., Frodyma, D. E., Sleightholm, R. L., Fisher, K. W., Lewis, R. E. 2018; 18: 673

  Abstract

  KMT2/MLL proteins are commonly overexpressed or mutated in cancer and have been shown to support cancer maintenance. These proteins are responsible for methylating histone 3 at lysine 4 and promoting transcription and DNA synthesis; however, they are inactive outside of a multi-protein complex that requires WDR5. WDR5 has been implicated in cancer for its role in the COMPASS complex and its interaction with Myc; however, the role of WDR5 in colon cancer has not yet been elucidated.WDR5 expression was evaluated using RT-qPCR and western blot analysis. Cell viability and colony forming assays were utilized to evaluate the effects of WDR5 depletion or inhibition in colon cancer cells. Downstream effects of WDR5 depletion and inhibition were observed by western blot.WDR5 is overexpressed in colon tumors and colon cancer cell lines at the mRNA and protein level. WDR5 depletion reduces cell viability in HCT116, LoVo, RKO, HCT15, SW480, SW620, and T84 colon cancer cells. Inhibition of the WDR5:KMT2/MLL interaction using OICR-9429 reduces cell viability in the same panel of cell lines albeit not to the same extent as RNAi-mediated WDR5 depletion. WDR5 depletion reduced H3K4Me3 and increased phosphorylation of H2AX in HCT116, SW620, and RKO colon cancer cells; however, OICR-9429 treatment did not recapitulate these effects in all cell lines potentially explaining the reduced toxicity of OICR-9429 treatment as compared to WDR5 depletion. WDR5 depletion also sensitized colon cancer cells to radiation-induced DNA damage.These data demonstrate a clear role for WDR5 in colon cancer and future studies should examine its potential to serve as a therapeutic target in cancer. Additional studies are needed to fully elucidate if the requirement for WDR5 is independent of or consistent with its role within the COMPASS complex. OICR-9429 treatment was particularly toxic to SW620 and T84 colon cancer cells, two cell lines without mutations in WDR5 and KMT2/MLL proteins suggesting COMPASS complex inhibition may be particularly effective in tumors lacking KMT2 mutations. Additionally, the ability of WDR5 depletion to amplify the toxic effects of radiation presents the possibility of targeting WDR5 to sensitize cells to DNA-damaging therapies.

  View details for DOI 10.1186/s12885-018-4580-6

  View details for Web of Science ID 000435892500003

  View details for PubMedID 29925347

  View details for PubMedCentralID PMC6011590

• A Functional Signature Ontology (FUSION) screen detects an AMPK inhibitor with selective toxicity toward human colon tumor cells SCIENTIFIC REPORTS Das, B., Neilsen, B. K., Fisher, K. W., Gehring, D., Hu, Y., Volle, D. J., Kim, H., McCall, J. L., Kelly, D. L., MacMillan, J. B., White, M. A., Lewis, R. E. 2018; 8: 3770

  Abstract

  AMPK is a serine threonine kinase composed of a heterotrimer of a catalytic, kinase-containing α and regulatory β and γ subunits. Here we show that individual AMPK subunit expression and requirement for survival varies across colon cancer cell lines. While AMPKα1 expression is relatively consistent across colon cancer cell lines, AMPKα1 depletion does not induce cell death. Conversely, AMPKα2 is expressed at variable levels in colon cancer cells. In high expressing SW480 and moderate expressing HCT116 colon cancer cells, siRNA-mediated depletion induces cell death. These data suggest that AMPK kinase inhibition may be a useful component of future therapeutic strategies. We used Functional Signature Ontology (FUSION) to screen a natural product library to identify compounds that were inhibitors of AMPK to test its potential for detecting small molecules with preferential toxicity toward human colon tumor cells. FUSION identified 5'-hydroxy-staurosporine, which competitively inhibits AMPK. Human colon cancer cell lines are notably more sensitive to 5'-hydroxy-staurosporine than are non-transformed human colon epithelial cells. This study serves as proof-of-concept for unbiased FUSION-based detection of small molecule inhibitors of therapeutic targets and highlights its potential to identify novel compounds for cancer therapy development.

  View details for DOI 10.1038/s41598-018-22090-6

  View details for Web of Science ID 000426262400023

  View details for PubMedID 29491475

  View details for PubMedCentralID PMC5830883

• Characterization of CDK(5) inhibitor, 20-223 (aka CP668863) for colorectal cancer therapy ONCOTARGET Robb, C. M., Kour, S., Contreras, J. I., Agarwal, E., Barger, C. J., Rana, S., Sonawane, Y., Neilsen, B. K., Taylor, M., Kizhake, S., Thakare, R. N., Chowdhury, S., Wang, J., Black, J. D., Hollingsworth, M. A., Brattain, M. G., Natarajan, A. 2018; 9 (4): 5216-5232

  Abstract

  Colorectal cancer (CRC) remains one of the leading causes of cancer related deaths in the United States. Currently, there are limited therapeutic options for patients suffering from CRC, none of which focus on the cell signaling mechanisms controlled by the popular kinase family, cyclin dependent kinases (CDKs). Here we evaluate a Pfizer developed compound, CP668863, that inhibits cyclin-dependent kinase 5 (CDK5) in neurodegenerative disorders. CDK5 has been implicated in a number of cancers, most recently as an oncogene in colorectal cancers. Our lab synthesized and characterized CP668863 - now called 20-223. In our established colorectal cancer xenograft model, 20-223 reduced tumor growth and tumor weight indicating its value as a potential anti-CRC agent. We subjected 20-223 to a series of cell-free and cell-based studies to understand the mechanism of its anti-tumor effects. In our hands, in vitro 20-223 is most potent against CDK2 and CDK5. The clinically used CDK inhibitor AT7519 and 20-223 share the aminopyrazole core and we used it to benchmark the 20-223 potency. In CDK5 and CDK2 kinase assays, 20-223 was ∼3.5-fold and ∼65.3-fold more potent than known clinically used CDK inhibitor, AT7519, respectively. Cell-based studies examining phosphorylation of downstream substrates revealed 20-223 inhibits the kinase activity of CDK5 and CDK2 in multiple CRC cell lines. Consistent with CDK5 inhibition, 20-223 inhibited migration of CRC cells in a wound-healing assay. Profiling a panel of CRC cell lines for growth inhibitory effects showed that 20-223 has nanomolar potency across multiple CRC cell lines and was on an average >2-fold more potent than AT7519. Cell cycle analyses in CRC cells revealed that 20-223 phenocopied the effects associated with AT7519. Collectively, these findings suggest that 20-223 exerts anti-tumor effects against CRC by targeting CDK 2/5 and inducing cell cycle arrest. Our studies also indicate that 20-223 is a suitable lead compound for colorectal cancer therapy.

  View details for DOI 10.18632/oncotarget.23749

  View details for Web of Science ID 000422651700074

  View details for PubMedID 29435174

  View details for PubMedCentralID PMC5797045

• Emerging roles of the CXCL12/CXCR4 axis in pancreatic cancer progression and therapy PHARMACOLOGY & THERAPEUTICS Sleightholm, R. L., Neilsen, B. K., Li, J., Steele, M. M., Singh, R. K., Hollingsworth, M. A., Oupicky, D. 2017; 179: 158-170

  Abstract

  Chemokine networks regulate a variety of cellular, physiological, and immune processes. These normal functions can become appropriated by cancer cells to facilitate a more hospitable niche for aberrant cells by enhancing growth, proliferation, and metastasis. This is especially true in pancreatic cancer, where chemokine signaling is a vital component in the development of the supportive tumor microenvironment and the signaling between the cancer cells and surrounding stromal cells. Although expression patterns vary among cancer types, the chemokine receptor CXCR4 has been implicated in nearly every major malignancy and plays a prominent role in pancreatic cancer development and progression. This receptor, in conjunction with its primary chemokine ligand CXCL12, promotes pancreatic cancer development, invasion, and metastasis through the management of the tumor microenvironment via complex crosstalk with other pathways. Thus, CXCR4 likely contributes to the poor prognoses observed in patients afflicted with this malignancy. Recent exploration of combination therapies with CXCR4 antagonists have demonstrated improved outcomes, and abolishing the contribution of this pathway may prove crucial to effectively treat pancreatic cancer at both the primary tumor and metastases.

  View details for DOI 10.1016/j.pharmthera.2017.05.012

  View details for Web of Science ID 000414819600011

  View details for PubMedID 28549596

• KSR as a therapeutic target for Ras-dependent cancers EXPERT OPINION ON THERAPEUTIC TARGETS Neilsen, B. K., Frodyma, D. E., Lewis, R. E., Fisher, K. W. 2017; 21 (5): 499-509

  Abstract

  Targeting downstream effectors required for oncogenic Ras signaling is a potential alternative or complement to the development of more direct approaches targeting Ras in the treatment of Ras-dependent cancers. Areas covered: Here we review literature pertaining to the molecular scaffold Kinase Suppressor of Ras (KSR) and its role in promoting signals critical to tumor maintenance. We summarize the phenotypes in knockout models, describe the role of KSR in cancer, and outline the structure and function of the KSR1 and KSR2 proteins. We then focus on the most recent literature that describes the crystal structure of the kinase domain of KSR2 in complex with MEK1, KSR-RAF dimerization particularly in response to RAF inhibition, and novel attempts to target KSR proteins directly. Expert opinion: KSR is a downstream effector of Ras-mediated tumorigenesis that is dispensable for normal growth and development, making it a desirable target for the development of novel therapeutics with a high therapeutic index. Recent advances have revealed that KSR can be functionally inhibited using a small molecule that stabilizes KSR in an inactive conformation. The efficacy and potential for this novel approach to be used clinically in the treatment of Ras-driven cancers is still being investigated.

  View details for DOI 10.1080/14728222.2017.1311325

  View details for Web of Science ID 000399432700006

  View details for PubMedID 28333549

  View details for PubMedCentralID PMC5490495

• Assessment of vascularity in glioblastoma and its implications on patient outcomes JOURNAL OF NEURO-ONCOLOGY McGahan, B., Neilsen, B., Kelly, D., McComb, R., Kazmi, S., White, M., Zhang, Y., Aizenberg, M. 2017; 132 (1): 35-44

  Abstract

  There is little data on why glioblastomas (GBM) hemorrhage and how it may affect patient outcomes. The aim of this study was to investigate the mechanisms of hemorrhage in glioblastoma by examining molecular and genetic features by immunohistochemistry (IHC) and mRNA expression profiles in association with imaging and clinical outcomes. An observational retrospective cohort analysis was performed on 43 FFPE GBM tissue samples. MR images were assessed for the presence of hemorrhage and extent of resection. Specimens were examined for CD34 and CD105 expression using IHC. Tumor mRNA expression profiles were analyzed for 92 genes related to angiogenesis and vascularity. Forty-three specimens were analyzed, and 20 showed signs of hemorrhage, 23 did not. The average OS for patients with GBM with hemorrhage was 19.12 months (95% CI 10.39-27.84), versus 13.85 months (95% CI 8.85-18.85) in those without hemorrhage (p > 0.05). Tumors that hemorrhaged had higher IHC staining for CD34 and CD105. mRNA expression analysis revealed tumor hemorrhage was associated with increased expression of HIF1α and MDK, and decreased expression of F3. Hemorrhage in GBM was not associated with worsened OS. Increased expression of angiogenic factors and increased CD34 and CD105 IHC staining in tumors with hemorrhage suggests that increased hypoxia-induced angiogenesis and vessel density may play a role in glioblastoma hemorrhage. Characterizing tumors that are prone to hemorrhage and mechanisms behind the development of these hemorrhages may provide insights that can lead to the development of targeted, individualized therapies for glioblastoma.

  View details for DOI 10.1007/s11060-016-2350-3

  View details for Web of Science ID 000398052800005

  View details for PubMedID 28102487

  View details for PubMedCentralID PMC5479489

• Kinase Suppressor of Ras 2 (KSR2) expression in the brain regulates energy balance and glucose homeostasis MOLECULAR METABOLISM Guo, L., Costanzo-Garvey, D. L., Smith, D. R., Neilsen, B. K., MacDonald, R. G., Lewis, R. E. 2017; 6 (2): 194-205

  Abstract

  Kinase Suppressor of Ras 2 (KSR2) is a molecular scaffold coordinating Raf/MEK/ERK signaling that is expressed at high levels in the brain. KSR2 disruption in humans and mice causes obesity and insulin resistance. Understanding the anatomical location and mechanism of KSR2 function should lead to a better understanding of physiological regulation over energy balance.Mice bearing floxed alleles of KSR2 (KSR2fl/fl) were crossed with mice expressing the Cre recombinase expressed by the Nestin promoter (Nes-Cre) to produce Nes-CreKSR2fl/fl mice. Growth, body composition, food consumption, cold tolerance, insulin and free fatty acid levels, glucose, and AICAR tolerance were measured in gender and age matched KSR2-/- mice.Nes-CreKSR2fl/fl mice lack detectable levels of KSR2 in the brain. The growth and onset of obesity of Nes-CreKSR2fl/fl mice parallel those observed in KSR2-/- mice. As in KSR2-/- mice, Nes-CreKSR2fl/fl are glucose intolerant with elevated fasting and cold intolerance. Male Nes-CreKSR2fl/fl mice are hyperphagic, but female Nes-CreKSR2fl/fl mice are not. Unlike KSR2-/- mice, Nes-CreKSR2fl/fl mice respond normally to leptin and AICAR, which may explain why the degree of obesity of adult Nes-CreKSR2fl/fl mice is not as severe as that observed in KSR2-/- animals.These observations suggest that, in the brain, KSR2 regulates energy balance via control of feeding behavior and adaptive thermogenesis, while a second KSR2-dependent mechanism, functioning through one or more other tissues, modulates sensitivity to leptin and activators of the energy sensor AMPK.

  View details for DOI 10.1016/j.molmet.2016.12.004

  View details for Web of Science ID 000397024200004

  View details for PubMedID 28180061

  View details for PubMedCentralID PMC5279912

• Coordinating ERK signaling via the molecular scaffold Kinase Suppressor of Ras. F1000Research Frodyma, D., Neilsen, B., Costanzo-Garvey, D., Fisher, K., Lewis, R. 2017; 6: 1621

  Abstract

  Many cancers, including those of the colon, lung, and pancreas, depend upon the signaling pathways induced by mutated and constitutively active Ras. The molecular scaffolds Kinase Suppressor of Ras 1 and 2 (KSR1 and KSR2) play potent roles in promoting Ras-mediated signaling through the Raf/MEK/ERK kinase cascade. Here we summarize the canonical role of KSR in cells, including its central role as a scaffold protein for the Raf/MEK/ERK kinase cascade, its regulation of various cellular pathways mediated through different binding partners, and the phenotypic consequences of KSR1 or KSR2 genetic inactivation. Mammalian KSR proteins have a demonstrated role in cellular and organismal energy balance with implications for cancer and obesity. Targeting KSR1 in cancer using small molecule inhibitors has potential for therapy with reduced toxicity to the patient. RNAi and small molecule screens using KSR1 as a reference standard have the potential to expose and target vulnerabilities in cancer. Interestingly, although KSR1 and KSR2 are similar in structure, KSR2 has a distinct physiological role in regulating energy balance. Although KSR proteins have been studied for two decades, additional analysis is required to elucidate both the regulation of these molecular scaffolds and their potent effect on the spatial and temporal control of ERK activation in health and disease.

  View details for DOI 10.12688/f1000research.11895.1

  View details for PubMedID 29026529