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Article ; Online: A clinical decision support system for AI-assisted decision-making in response-adaptive radiotherapy (ARCliDS)

Dipesh Niraula / Wenbo Sun / Jionghua Jin / Ivo D. Dinov / Kyle Cuneo / Jamalina Jamaluddin / Martha M. Matuszak / Yi Luo / Theodore S. Lawrence / Shruti Jolly / Randall K. Ten Haken / Issam El Naqa

Scientific Reports, Vol 13, Iss 1, Pp 1-

2023 Volume 14

Abstract: Abstract Involvement of many variables, uncertainty in treatment response, and inter-patient heterogeneity challenge objective decision-making in dynamic treatment regime (DTR) in oncology. Advanced machine learning analytics in conjunction with ... ...

Abstract	Abstract Involvement of many variables, uncertainty in treatment response, and inter-patient heterogeneity challenge objective decision-making in dynamic treatment regime (DTR) in oncology. Advanced machine learning analytics in conjunction with information-rich dense multi-omics data have the ability to overcome such challenges. We have developed a comprehensive artificial intelligence (AI)-based optimal decision-making framework for assisting oncologists in DTR. In this work, we demonstrate the proposed framework to Knowledge Based Response-Adaptive Radiotherapy (KBR-ART) applications by developing an interactive software tool entitled Adaptive Radiotherapy Clinical Decision Support (ARCliDS). ARCliDS is composed of two main components: Artifcial RT Environment (ARTE) and Optimal Decision Maker (ODM). ARTE is designed as a Markov decision process and modeled via supervised learning. Given a patient’s pre- and during-treatment information, ARTE can estimate treatment outcomes for a selected daily dosage value (radiation fraction size). ODM is formulated using reinforcement learning and is trained on ARTE. ODM can recommend optimal daily dosage adjustments to maximize the tumor local control probability and minimize the side effects. Graph Neural Networks (GNN) are applied to exploit the inter-feature relationships for improved modeling performance and a novel double GNN architecture is designed to avoid nonphysical treatment response. Datasets of size 117 and 292 were available from two clinical trials on adaptive RT in non-small cell lung cancer (NSCLC) patients and adaptive stereotactic body RT (SBRT) in hepatocellular carcinoma (HCC) patients, respectively. For training and validation, dense data with 297 features were available for 67 NSCLC patients and 110 features for 71 HCC patients. To increase the sample size for ODM training, we applied Generative Adversarial Networks to generate 10,000 synthetic patients. The ODM was trained on the synthetic patients and validated on the original dataset. We found ...
Keywords	Medicine ; R ; Science ; Q
Subject code	006
Language	English
Publishing date	2023-03-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Metabolic Tumor Volume Response Assessment Using (11)C-Methionine Positron Emission Tomography Identifies Glioblastoma Tumor Subregions That Predict Progression Better Than Baseline or Anatomic Magnetic Resonance Imaging Alone

Sean Miller, BS / Pin Li, MS / Matthew Schipper, PhD / Larry Junck, MD / Morand Piert, MD / Theodore S. Lawrence, MD, PhD / Christina Tsien, MD / Yue Cao, PhD / Michelle M. Kim, MD

Advances in Radiation Oncology, Vol 5, Iss 1, Pp 53-

2020 Volume 61

Abstract: Purpose: To evaluate whether response assessment of newly diagnosed glioblastoma at 3 months using 11C-methionine-positron emission tomography (MET-PET) is better associated with patient outcome compared with baseline MET-PET or anatomic magnetic ... ...

Abstract	Purpose: To evaluate whether response assessment of newly diagnosed glioblastoma at 3 months using 11C-methionine-positron emission tomography (MET-PET) is better associated with patient outcome compared with baseline MET-PET or anatomic magnetic resonance imaging alone. Methods and Materials: Patients included were participants in a phase I/II trial of dose-escalated chemoradiation based on anatomic magnetic resonance imaging. Automated segmentation of metabolic tumor volume (MTV) was performed at a threshold of 1.5 times mean cerebellar uptake. Progression-free (PFS) and overall survival were estimated with the Kaplan-Meier method and compared with log-rank tests. Multivariate analysis for PFS and overall survival was performed using Cox proportional hazards, and spatial overlap between imaging and recurrence volumes were analyzed. Results: Among 37 patients, 15 had gross total resection, of whom 10 (67%) had residual MTV, 16 subtotal resection, and 6 biopsy alone. Median radiation therapy dose was 75 Gy (range, 66-81). Median baseline T1 Gd-enhanced tumor volume (GTV-Gd) was 38.0 cm3 (range, 8.0-81.5). Median pre-CRT MTV was 4.9 cm3 (range, 0-43.8). Among 25 patients with 3-month MET-PET, MTV was only 2.4 cm3 (range, 0.004-18.0) in patients with uptake. Patients with MTV = 0 cm3 at 3 months had superior PFS (18.2 vs 10.1 months, P = .03). On multivariate analysis, larger 3-month MTV (hazard ratio [HR] 2.4, 95% confidence interval [CI], 1.4-4.3, P = .03), persistent MET-PET subvolume (overlap of pre-CRT and 3 month MTV; HR 2.0, 95% CI, 1.2-3.4, P = .06), and increase in MTV (HR 1.8, 95% CI, 1.1-3.1, P = .09) were the only imaging factors significant for worse PFS. GTV-Gd at recurrence encompassed 97% of the persistent MET-PET subvolume (interquartile range 72%-100%), versus 71% (interquartile range 39%-93%) of baseline MTV, 54% of baseline GTV-Gd (18%-87%), and 78% of 3-month MTV (47%-95%). Conclusions: The majority of patients with apparent gross total resection of glioblastoma have measurable postoperative ...
Keywords	Medical physics. Medical radiology. Nuclear medicine ; R895-920 ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282
Subject code	610 ; 616
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: FBXW7 Facilitates Nonhomologous End-Joining via K63-Linked Polyubiquitylation of XRCC4

Zhang, Qiang / David Karnak / Meredith A. Morgan / Mingjia Tan / Theodore S. Lawrence / Yi Sun

Molecular cell. 2016 Feb. 04, v. 61, no. 3

2016

Abstract: FBXW7 is a haploinsufficient tumor suppressor with loss-of-function mutations occurring in human cancers. FBXW7 inactivation causes genomic instability, but the mechanism remains elusive. Here we show that FBXW7 facilitates nonhomologous end-joining ( ... ...

Abstract	FBXW7 is a haploinsufficient tumor suppressor with loss-of-function mutations occurring in human cancers. FBXW7 inactivation causes genomic instability, but the mechanism remains elusive. Here we show that FBXW7 facilitates nonhomologous end-joining (NHEJ) repair and that FBXW7 depletion causes radiosensitization. In response to ionizing radiation, ATM phosphorylates FBXW7 at serine 26 to recruit it to DNA double-strand break (DSB) sites, whereas activated DNA-PKcs phosphorylates XRCC4 at serines 325/326, which promotes binding of XRCC4 to FBXW7. SCFFBXW7 E3 ligase then promotes polyubiquitylation of XRCC4 at lysine 296 via lysine 63 linkage for enhanced association with the Ku70/80 complex to facilitate NHEJ repair. Consistent with these findings, a small-molecule inhibitor that abrogates XRCC4 polyubiquitylation reduces NHEJ repair. Our study demonstrates one mechanism by which FBXW7 contributes to genome integrity and implies that inactivated FBXW7 in human cancers could be a strategy for increasing the efficacy of radiotherapy.
Keywords	DNA ; genome ; humans ; ionizing radiation ; loss-of-function mutation ; lysine ; neoplasms ; radiotherapy ; serine ; ubiquitin-protein ligase
Language	English
Dates of publication	2016-0204
Size	p. 419-433.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2015.12.010
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Inducing Oncoprotein Degradation to Improve Targeted Cancer Therapy

Dipankar Ray / Kyle C. Cuneo / Alnawaz Rehemtulla / Theodore S. Lawrence / Mukesh K. Nyati

Neoplasia : An International Journal for Oncology Research, Vol 17, Iss 9, Pp 697-

2015 Volume 703

Abstract: Over the past decade, inhibition of the kinase activities of oncogenic proteins using small molecules and antibodies has been a mainstay of our anticancer drug development effort, resulting in several Food and Drug Administration–approved cancer ... ...

Abstract	Over the past decade, inhibition of the kinase activities of oncogenic proteins using small molecules and antibodies has been a mainstay of our anticancer drug development effort, resulting in several Food and Drug Administration–approved cancer therapies. The clinical effectiveness of kinase-targeted agents has been inconsistent, mostly because of the development of resistance. The expression and function of oncoproteins and tumor suppressors are regulated by numerous posttranslational protein modifications including phosphorylation, ubiquitination, and acetylation; hence, targeting specific posttranslational protein modifications provides for an attractive strategy for anticancer drug development. The present review discusses the hypothesis that targeted degradation of an oncoprotein may overcome many of the shortcomings seen with kinase inhibitors and that the approach would enable targeted inhibition of oncogenic proteins previously thought to be undruggable.
Keywords	Medicine ; R ; Internal medicine ; RC31-1245 ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282
Publishing date	2015-09-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: RB expression confers sensitivity to CDK4/6 inhibitor–mediated radiosensitization across breast cancer subtypes

Andrea M. Pesch / Nicole H. Hirsh / Anna R. Michmerhuizen / Kassidy M. Jungles / Kari Wilder-Romans / Benjamin C. Chandler / Meilan Liu / Lynn M. Lerner / Charles A. Nino / Connor Ward / Erin F. Cobain / Theodore S. Lawrence / Lori J. Pierce / James M. Rae / Corey W. Speers

JCI Insight, Vol 7, Iss

2022 Volume 3

Abstract: Standard radiation therapy (RT) does not reliably provide locoregional control for women with multinode-positive breast cancer and triple-negative breast cancer (TNBC). We hypothesized that CDK4/6 inhibition (CDK4/6i) would increase the radiosensitivity ... ...

Abstract	Standard radiation therapy (RT) does not reliably provide locoregional control for women with multinode-positive breast cancer and triple-negative breast cancer (TNBC). We hypothesized that CDK4/6 inhibition (CDK4/6i) would increase the radiosensitivity not only of estrogen receptor–positive (ER+) cells, but also of TNBC that expresses retinoblastoma (RB) protein. We found that CDK4/6i radiosensitized RB WT TNBC (n = 4, radiation enhancement ratio [rER]: 1.49–2.22) but failed to radiosensitize RB-null TNBC (n = 3, rER: 0.84–1.00). RB expression predicted response to CDK4/6i + RT (R2 = 0.84), and radiosensitization was lost in ER+/TNBC cells (rER: 0.88–1.13) after RB1 knockdown in isogenic and nonisogenic models. CDK4/6i suppressed homologous recombination (HR) in RB WT cells but not in RB-null cells or isogenic models of RB1 loss; HR competency was rescued with RB reexpression. Radiosensitization was independent of nonhomologous end joining and the known effects of CDK4/6i on cell cycle arrest. Mechanistically, RB and RAD51 interact in vitro to promote HR repair. CDK4/6i produced RB-dependent radiosensitization in TNBC xenografts but not in isogenic RB1-null xenografts. Our data provide the preclinical rationale for a clinical trial expanding the use of CDK4/6i + RT to difficult-to-control RB-intact breast cancers (including TNBC) and nominate RB status as a predictive biomarker of therapeutic efficacy.
Keywords	Oncology ; Medicine ; R
Subject code	616
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: PD-L1 Expression in Circulating Tumor Cells Increases during Radio(chemo)therapy and Indicates Poor Prognosis in Non-small Cell Lung Cancer

Yang Wang / Tae Hyun Kim / Shamileh Fouladdel / Zhuo Zhang / Payal Soni / Angel Qin / Lili Zhao / Ebrahim Azizi / Theodore S. Lawrence / Nithya Ramnath / Kyle C. Cuneo / Sunitha Nagrath

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 9

Abstract: Abstract Preclinical studies demonstrated that radiation up-regulates PD-L1 expression in tumor cells, providing a rationale for combining PD-1/PD-L1 inhibitors with radiation. However this has not been validated in patients with non-small cell lung ... ...

Abstract	Abstract Preclinical studies demonstrated that radiation up-regulates PD-L1 expression in tumor cells, providing a rationale for combining PD-1/PD-L1 inhibitors with radiation. However this has not been validated in patients with non-small cell lung cancer due to the difficulty to obtain serial biopsies. Measuring PD-L1 expression in circulating tumor cells (CTCs), may allow real-time monitoring of immune activation in tumor. In this study, whole blood from non-metastatic NSCLC patients was collected before, during, and after radiation or chemoradiation using a microfluidic chip. PD-L1 expression in CTCs was assessed by immunofluorescence and qPCR and monitored through the course of treatment. Overall, PD-L1(+) CTCs were detected in 25 out of 38 samples (69.4%) with an average of 4.5 cells/ml. After initiation of radiation therapy, the proportion of PD-L1(+) CTCs increased significantly (median 0.7% vs. 24.7%, P < 0.01), indicating up-regulation of PD-L1 in tumor cells in response to radiation. In addition, patients positive for PD-L1 (≥5% of CTCs positive for PD-L1) at baseline had shorter PFS. Gene expression analysis revealed that higher levels of PD-L1 were associated with poor prognosis. Therefore, CTCs can be used to monitor dynamic changes of PD-L1 during radiation therapy which is potentially prognostic of response to treatment.
Keywords	Medicine ; R ; Science ; Q
Subject code	610 ; 616
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Regional variation in brain white matter diffusion index changes following chemoradiotherapy

Christopher H Chapman / Mohammad Nazem-Zadeh / Oliver E Lee / Matthew J Schipper / Christina I Tsien / Theodore S Lawrence / Yue Cao

PLoS ONE, Vol 8, Iss 3, p e

a prospective study using tract-based spatial statistics.

2013 Volume 57768

Abstract: There is little known about how brain white matter structures differ in their response to radiation, which may have implications for radiation-induced neurocognitive impairment. We used diffusion tensor imaging (DTI) to examine regional variation in ... ...

Abstract	There is little known about how brain white matter structures differ in their response to radiation, which may have implications for radiation-induced neurocognitive impairment. We used diffusion tensor imaging (DTI) to examine regional variation in white matter changes following chemoradiotherapy.Fourteen patients receiving two or three weeks of whole-brain radiation therapy (RT) ± chemotherapy underwent DTI pre-RT, at end-RT, and one month post-RT. Three diffusion indices were measured: fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD). We determined significant individual voxel changes of diffusion indices using tract-based spatial statistics, and mean changes of the indices within fourteen white matter structures of interest.Voxels of significant FA decreases and RD increases were seen in all structures (p<0.05), with the largest changes (20-50%) in the fornix, cingula, and corpus callosum. There were highly significant between-structure differences in pre-RT to end-RT mean FA changes (p<0.001). The inferior cingula had a mean FA decrease from pre-RT to end-RT significantly greater than 11 of the 13 other structures (p<0.00385).Brain white matter structures varied greatly in their response to chemoradiotherapy as measured by DTI changes. Changes in FA and RD related to white matter demyelination were prominent in the cingula and fornix, structures relevant to radiation-induced neurocognitive impairment. Future research should evaluate DTI as a predictive biomarker of brain chemoradiotherapy adverse effects.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Fbxw7 Deletion Accelerates KrasG12D-Driven Pancreatic Tumorigenesis via Yap Accumulation

Qiang Zhang / Yaqing Zhang / Joshua D. Parsels / Ines Lohse / Theodore S. Lawrence / Marina Pasca di Magliano / Yi Sun / Meredith A. Morgan

Neoplasia: An International Journal for Oncology Research, Vol 18, Iss 11, Pp 666-

2016 Volume 673

Abstract: Pancreatic cancers driven by KRAS mutations require additional mutations for tumor progression. The tumor suppressor FBXW7 is altered in pancreatic cancers, but its contribution to pancreatic tumorigenesis is unknown. To determine potential cooperation ... ...

Abstract	Pancreatic cancers driven by KRAS mutations require additional mutations for tumor progression. The tumor suppressor FBXW7 is altered in pancreatic cancers, but its contribution to pancreatic tumorigenesis is unknown. To determine potential cooperation between Kras mutation and Fbxw7 inactivation in pancreatic tumorigenesis, we generated P48-Cre;LSL-KrasG12D;Fbxw7fl/fl (KFCfl/fl) compound mice. We found that KFCfl/fl mice displayed accelerated tumorigenesis: all mice succumbed to pancreatic ductal adenocarcinoma (PDA) by 40 days of age, with PDA onset occurring by 2 weeks of age. PDA in KFCfl/fl mice was preceded by earlier onset of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions, and associated with chromosomal instability and the accumulation of Fbxw7 substrates Yes-associated protein (Yap), c-Myc, and Notch. Using KFCfl/fl and FBXW7-deficient human pancreatic cancer cells, we found that Yap silencing attenuated growth promotion by Fbxw7 deletion. Our data demonstrate that Fbxw7 is a potent suppressor of KrasG12D-induced pancreatic tumorigenesis due, at least in part, to negative regulation of Yap.
Keywords	Medicine ; R ; Internal medicine ; RC31-1245 ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282
Language	English
Publishing date	2016-11-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Sensitization of Pancreatic Cancers to Gemcitabine Chemoradiation by WEE1 Kinase Inhibition Depends on Homologous Recombination Repair

Tasneem Kausar / Jason S. Schreiber / David Karnak / Leslie A. Parsels / Joshua D. Parsels / Mary A. Davis / Lili Zhao / Jonathan Maybaum / Theodore S. Lawrence / Meredith A. Morgan

Neoplasia : An International Journal for Oncology Research, Vol 17, Iss 10, Pp 757-

2015 Volume 766

Abstract: To improve the efficacy of chemoradiation therapy for locally advanced pancreatic cancer and begin to establish patient selection criteria, we investigated the combination of the WEE1 inhibitor AZD1775 with gemcitabine-radiation in homologous ... ...

Abstract	To improve the efficacy of chemoradiation therapy for locally advanced pancreatic cancer and begin to establish patient selection criteria, we investigated the combination of the WEE1 inhibitor AZD1775 with gemcitabine-radiation in homologous recombination (HR) repair proficient and deficient pancreatic cancers. Sensitization to gemcitabine-radiation by AZD1775 was assessed in pancreatic cancer cells by clonogenic survival and in patient-derived xenografts by tumor growth. The contributions of HR repair inhibition and G2 checkpoint abrogation to sensitization were assessed by γH2AX, BRCA2 manipulation, and RAD51 focus formation and pHistone H3 flow cytometry, respectively. We found that AZD1775 sensitized to gemcitabine-radiation in BRCA2 wild-type but not BRCA2 mutant pancreatic cancer cells. In all cells, AZD1775 caused inhibition of CDK1 phosphorylation and G2 checkpoint abrogation. However, sensitization by AZD1775 was associated with persistent γH2AX and inhibition of RAD51 focus formation. In HR-proficient (BRCA2 wild-type) or -deficient (BRAC2 null) isogenic cells, AZD1775 sensitized to gemcitabine-radiation in BRCA2 wild-type, but not in BRCA2 null cells, despite significant G2 checkpoint abrogation. In patient-derived pancreatic tumor xenografts, AZD1775 significantly inhibited tumor growth and impaired RAD51 focus formation in response to gemcitabine-radiation. In conclusion, WEE1 inhibition by AZD1775 is an effective strategy for sensitizing pancreatic cancers to gemcitabine chemoradiation. Although this sensitization is accompanied by inhibition of CDK1 phosphorylation and G2 checkpoint abrogation, this mechanism is not sufficient for sensitization. Our findings demonstrate that sensitization to chemoradiation by WEE1 inhibition results from inhibition of HR repair and suggest that patient tumors without underlying HR defects would benefit most from this therapy.
Keywords	Medicine ; R ; Internal medicine ; RC31-1245 ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282
Subject code	610
Publishing date	2015-10-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Development and validation of a novel platform-independent metastasis signature in human breast cancer.

Shuang G Zhao / Mark Shilkrut / Corey Speers / Meilan Liu / Kari Wilder-Romans / Theodore S Lawrence / Lori J Pierce / Felix Y Feng

PLoS ONE, Vol 10, Iss 5, p e

2015 Volume 0126631

Abstract: PURPOSE:The molecular drivers of metastasis in breast cancer are not well understood. Therefore, we sought to identify the biological processes underlying distant progression and define a prognostic signature for metastatic potential in breast cancer. ... ...

Abstract	PURPOSE:The molecular drivers of metastasis in breast cancer are not well understood. Therefore, we sought to identify the biological processes underlying distant progression and define a prognostic signature for metastatic potential in breast cancer. EXPERIMENTAL DESIGN:In vivo screening for metastases was performed using Chick Chorioallantoic Membrane assays in 21 preclinical breast cancer models. Expressed genes associated with metastatic potential were identified using high-throughput analysis. Correlations with biological function were determined using the Database for Annotation, Visualization and Integrated Discovery. RESULTS:We identified a broad range of metastatic potential that was independent of intrinsic breast cancer subtypes. 146 genes were significantly associated with metastasis progression and were linked to cancer-related biological functions, including cell migration/adhesion, Jak-STAT, TGF-beta, and Wnt signaling. These genes were used to develop a platform-independent gene expression signature (M-Sig), which was trained and subsequently validated on 5 independent cohorts totaling nearly 1800 breast cancer patients with all p-values < 0.005 and hazard ratios ranging from approximately 2.5 to 3. On multivariate analysis accounting for standard clinicopathologic prognostic variables, M-Sig remained the strongest prognostic factor for metastatic progression, with p-values < 0.001 and hazard ratios > 2 in three different cohorts. CONCLUSION:M-Sig is strongly prognostic for metastatic progression, and may provide clinical utility in combination with treatment prediction tools to better guide patient care. In addition, the platform-independent nature of the signature makes it an excellent research tool as it can be directly applied onto existing, and future, datasets.
Keywords	Medicine ; R ; Science ; Q
Subject code	610 ; 616
Language	English
Publishing date	2015-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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