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Item Stable Isotope-Assisted Untargeted Metabolomics Identifies ALDH1A1-Driven Erythronate Accumulation in Lung Cancer Cells(MDPI, 2023-10-19) Zhang, Jie; Keibler, Mark A.; Dong, Wentao; Ghelfi, Jenny; Cordes, Thekla; Kanashova, Tamara; Pailot, Arnaud; Linster, Carole L.; Dittmar, Gunnar; Metallo, Christian M.; Lautenschlaeger, Tim; Hiller, Karsten; Stephanopoulos, Gregory; Radiation Oncology, School of MedicineUsing an untargeted stable isotope-assisted metabolomics approach, we identify erythronate as a metabolite that accumulates in several human cancer cell lines. Erythronate has been reported to be a detoxification product derived from off-target glycolytic metabolism. We use chemical inhibitors and genetic silencing to define the pentose phosphate pathway intermediate erythrose 4-phosphate (E4P) as the starting substrate for erythronate production. However, following enzyme assay-coupled protein fractionation and subsequent proteomics analysis, we identify aldehyde dehydrogenase 1A1 (ALDH1A1) as the predominant contributor to erythrose oxidation to erythronate in cell extracts. Through modulating ALDH1A1 expression in cancer cell lines, we provide additional support. We hence describe a possible alternative route to erythronate production involving the dephosphorylation of E4P to form erythrose, followed by its oxidation by ALDH1A1. Finally, we measure increased erythronate concentrations in tumors relative to adjacent normal tissues from lung cancer patients. These findings suggest the accumulation of erythronate to be an example of metabolic reprogramming in cancer cells, raising the possibility that elevated levels of erythronate may serve as a biomarker of certain types of cancer.Item Overexpression of FRA1 (FOSL1) Leads to Global Transcriptional Perturbations, Reduced Cellular Adhesion and Altered Cell Cycle Progression(MDPI, 2023) Al-khayyat, Wuroud; Pirkkanen, Jake; Dougherty, Jessica; Laframboise, Taylor; Dickinson, Noah; Khaper, Neelam; Lees, Simon J.; Mendonca, Marc S.; Boreham, Douglas R.; Tai, Tze Chun; Thome, Christopher; Tharmalingam, Sujeenthar; Radiation Oncology, School of MedicineFRA1 (FOSL1) is a transcription factor and a member of the activator protein-1 superfamily. FRA1 is expressed in most tissues at low levels, and its expression is robustly induced in response to extracellular signals, leading to downstream cellular processes. However, abnormal FRA1 overexpression has been reported in various pathological states, including tumor progression and inflammation. To date, the molecular effects of FRA1 overexpression are still not understood. Therefore, the aim of this study was to investigate the transcriptional and functional effects of FRA1 overexpression using the CGL1 human hybrid cell line. FRA1-overexpressing CGL1 cells were generated using stably integrated CRISPR-mediated transcriptional activation, resulting in a 2–3 fold increase in FRA1 mRNA and protein levels. RNA-sequencing identified 298 differentially expressed genes with FRA1 overexpression. Gene ontology analysis showed numerous molecular networks enriched with FRA1 overexpression, including transcription-factor binding, regulation of the extracellular matrix and adhesion, and a variety of signaling processes, including protein kinase activity and chemokine signaling. In addition, cell functional assays demonstrated reduced cell adherence to fibronectin and collagen with FRA1 overexpression and altered cell cycle progression. Taken together, this study unravels the transcriptional response mediated by FRA1 overexpression and establishes the role of FRA1 in adhesion and cell cycle progression.Item Resolution of Radiation-Induced Necrosis in Arteriovenous Malformation with Bevacizumab: A Case Report and Review of Current Literature(Karger, 2021-05-27) Kwong, Forrest; Scarpelli, Daphne B.; Barajas, Ramon F.; Monaco, Debra; Tanyi, James A.; McClelland, Shearwood; Jaboin, Jerry J.; Radiation Oncology, School of MedicineStereotactic radiosurgery (SRS) is a proven treatment modality for inoperable arteriovenous malformations (AVMs). However, the rate of radiation-induced necrosis (RIN) is as high as 10%. A 6-year-old female patient presented with severe headache, emesis, and syncope, and workup revealed a Spetzler-Martin grade 4 AVM with intraventricular hemorrhage and hydrocephalus. The patient underwent a right frontal ventriculostomy followed by a linear accelerator-based SRS of 16.9 Gy. At 19 years, she developed progressive neurological symptoms. Diagnostic magnetic resonance imaging (MRI) revealed a recurrent parietal AVM nidus. We delivered the linear accelerator-based SRS of 18.5 Gy to the AVM nidus. Within 9 months, she experienced episodic headaches and left-sided weakness and spasticity; symptoms were initially managed with dexamethasone. Follow-up MRI was notable for edema and nondetectable blood flow, consistent with RIN and AVM obliteration. The second course of steroids did not provide the symptom control. Persistent RIN was noted on MRI, and she had stigmata of steroid toxicity (centripetal obesity, depression, and sleep disorder). Two infusions of bevacizumab (5 mg/kg) were administered concurrently with a tapering dose of dexamethasone. The patient noted a near immediate improvement in her headaches, and 2 months following the second bevacizumab infusion, she reported a near-complete resolution of her symptoms and displayed improved ambulation. The development of RIN remains a noteworthy concern post-SRS of AVMs. While steroids aid with initial management of RIN, for persistent and recurrent symptoms, bevacizumab infusions serve as a viable treatment course, with the added benefit of reducing the likelihood of adverse effects resulting from prolonged steroid therapy.Item Hypoxia-driven ncRNAs in breast cancer(Frontiers Media, 2023-07-31) Al-Zuaini, Hashim H.; Rafiq Zahid, Kashif; Xiao, Xiangyan; Raza, Umar; Huang, Qiyuan; Zeng, Tao; Radiation Oncology, School of MedicineLow oxygen tension, or hypoxia is the driving force behind tumor aggressiveness, leading to therapy resistance, metastasis, and stemness in solid cancers including breast cancer, which now stands as the leading cause of cancer-related mortality in women. With the great advancements in exploring the regulatory roles of the non-coding genome in recent years, the wide spectrum of hypoxia-responsive genome is not limited to just protein-coding genes but also includes multiple types of non-coding RNAs, such as micro RNAs, long non-coding RNAs, and circular RNAs. Over the years, these hypoxia-responsive non-coding molecules have been greatly implicated in breast cancer. Hypoxia drives the expression of these non-coding RNAs as upstream modulators and downstream effectors of hypoxia inducible factor signaling in the favor of breast cancer through a myriad of molecular mechanisms. These non-coding RNAs then contribute in orchestrating aggressive hypoxic tumor environment and regulate cancer associated cellular processes such as proliferation, evasion of apoptotic death, extracellular matrix remodeling, angiogenesis, migration, invasion, epithelial-to-mesenchymal transition, metastasis, therapy resistance, stemness, and evasion of the immune system in breast cancer. In addition, the interplay between hypoxia-driven non-coding RNAs as well as feedback and feedforward loops between these ncRNAs and HIFs further contribute to breast cancer progression. Although the current clinical implications of hypoxia-driven non-coding RNAs are limited to prognostics and diagnostics in breast cancer, extensive explorations have established some of these hypoxia-driven non-coding RNAs as promising targets to treat aggressive breast cancers, and future scientific endeavors hold great promise in targeting hypoxia-driven ncRNAs at clinics to treat breast cancer and limit global cancer burden.Item Improved Pathologic response to chemoradiation in MGMT methylated locally advanced rectal cancer(Elsevier, 2023-07-24) Jensen, Garrett L.; Pourfarrokh, Niloufar; Volz, Marcus; Morales, Linden L.; Walker, Kimberly; Hammonds, Kendall P.; El-Ghamry, Moataz; Wong, Lucas; Hodjat, Parsa; Castro, Eduardo; Rao, Arundhati; Jhavar, Sameer G.; Radiation Oncology, School of MedicineBackground and purpose: With the growing interest in total neoadjuvant treatment for locally advanced rectal adenocarcinoma (LARC) there is an urgent unmet need to identify predictive markers of response to long-course neoadjuvant concurrent chemoradiotherapy (LCRT). O6-Methylguanine (O6-MG)-DNA-methyltransferase (MGMT) gene methylation has been associated in some malignancies with response to concurrent chemoradiotherapy. We attempted to find if pathologic response to LCRT was associated with MGMT promoter hypermethylation (MGMTh). Materials and methods: Patients were identified with LARC, available pre-treatment biopsy specimens, and at least 1 year of follow-up who received LCRT followed by surgical resection within 6 months. Biopsies were tested for MGMTh using a Qiagen pyrosequencing kit (Catalog number 970061). The primary outcome of LCRT responsiveness was based on tumor regression grade (TRG), with grades of 0-1 considered to have excellent response and grades of 2-3 considered to be non-responders. Secondary outcomes included overall survival (OS) and recurrence free survival (RFS). Results: Of 96 patients who met inclusion criteria, 76 had samples which produced reliable assay results. MGMTh corresponded with higher grade and age of the biopsy specimen. The percentage of responders to LCRT was higher amongst the MGMTh patients than the MGMTn patients (60.0% vs 27.5%, p value = 0.0061). MGMTh was not significantly associated with improved OS (2-year OS of 96.0% vs 98.0%, p = 0.8102) but there was a trend for improved RFS (2-year RFS of 87.6% vs 74.2%, p = 0.0903). Conclusion: Significantly greater tumor regression following LCRT was seen in MGMTh LARC. Methylation status may help identify good candidates for close observation without surgery following LCRT.Item Genomic Loss and Epigenetic Silencing of the FOSL1 Tumor Suppressor Gene in Radiation-induced Neoplastic Transformation of Human CGL1 Cells Alters the Tumorigenic Phenotype In Vitro and In Vivo(BioOne, 2023) Pirkkanen, Jake; Tharmalingam, Sujeenthar; Thome, Christopher; Chin Sinex, Helen; Benjamin, Laura V.; Losch, Adam C.; Borgmann, Anthony J.; Dhaemers, Ryan M.; Gordon, Christopher; Boreham, Douglas R.; Mendonca, Marc S.; Radiation Oncology, School of MedicineThe CGL1 human hybrid cell system has been utilized for many decades as an excellent cellular tool for investigating neoplastic transformation. Substantial work has been done previously implicating genetic factors related to chromosome 11 to the alteration of tumorigenic phenotype in CGL1 cells. This includes candidate tumor suppressor gene FOSL1, a member of the AP-1 transcription factor complex which encodes for protein FRA1. Here we present novel evidence supporting the role of FOSL1 in the suppression of tumorigenicity in segregants of the CGL1 system. Gamma-induced mutant (GIM) and control (CON) cells were isolated from 7 Gy gamma-irradiated CGL1s. Western, Southern and Northern blot analysis were utilized to assess FOSL1/FRA1 expression as well as methylation studies. GIMs were transfected to re-express FRA1 and in vivo tumorigenicity studies were conducted. Global transcriptomic microarray and RT-qPCR analysis were used to further characterize these unique cell segregants. GIMs were found to be tumorigenic in vivo when injected into nude mice whereas CON cells were not. GIMs show loss of Fosl/FRA1 expression as confirmed by Western blot. Southern and Northern blot analysis further reveals that FRA1 reduction in tumorigenic CGL1 segregants is likely due to transcriptional suppression. Results suggest that radiation-induced neoplastic transformation of CGL1 is in part due to silencing of the FOSL1 tumor suppressor gene promoter by methylation. The radiation-induced tumorigenic GIMs transfected to re-express FRA1 resulted in suppression of subcutaneous tumor growth in nude mice in vivo. Global microarray analysis and RT-qPCR validation elucidated several hundred differentially expressed genes. Downstream analysis reveals a significant number of altered pathways and enriched Gene Ontology terms genes related to cellular adhesion, proliferation, and migration. Together these findings provide strong evidence that FRA1 is a tumor suppressor gene deleted and epigenetically silenced after ionizing radiation-induced neoplastic transformation in the CGL1 human hybrid cell system.Item Cardiovascular-specific mortality and risk factors in colorectal Cancer patients: A cohort study based on registry data of over 500,000 individuals in the US(Elsevier, 2024-02) Zhang, Taolan; Zhu, Hongxia; Hu, Hongjuan; Hu, Haihong; Zhan, Wendi; Jiang, Lingxiang; Tang, Ming; Escobar, David; Huang, Wei; Feng, Yaoguang; Zhou, Junlin; Zou, Mingxiang; Radiation Oncology, School of MedicineBackground Colorectal cancer (CRC) is one of the most common cancers worldwide, and recent studies have found that CRC patients are at increased risk for cardiovascular disease (CVD). This study aimed to investigate competing causes of death and prognostic factors among a large cohort of CRC patients and to describe cardiovascular-specific mortality in relation to the US standard population. Methods This registry-based cohort study identified patients diagnosed with CRC between 1973 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database in the US. Cumulative mortality functions, conditional standardized mortality ratios, and cause-specific hazard ratios were calculated. Results Of the 563,298 eligible CRC patients included in this study, 407,545 died during the follow-up period. CRC was the leading cause of death, accounting for 49.8% of all possible competing causes of death. CVD was the most common non-cancer cause of death, accounting for 17.8% of total mortality. This study found that CRC patients have a significantly increased risk of cardiovascular-specific mortality compared to the US standard population, with the risk increasing with age and extended survival time. Conclusion This study highlights the need to develop multidisciplinary prevention and management strategies for CRC and CVD to improve CRC patients' survival and quality of life.Item Isopentyl-Deoxynboquinone Induces Mitochondrial Dysfunction and G2/M Phase Cell Cycle Arrest to Selectively Kill NQO1-Positive Pancreatic Cancer Cells(Mary Ann Liebert, Inc., 2024) Jiang, Lingxiang; Liu, Yingchun; Tumbath, Soumya; Boudreau, Matthew W.; Chatkewitz, Lindsay E.; Wang, Jiangwei; Su, Xiaolin; Zahid, Kashif Rafiq; Li, Katherine; Chen, Yaomin; Yang, Kai; Hergenrother, Paul J.; Huang, Xiumei; Radiation Oncology, School of MedicineAims: Pancreatic cancer is among the top five leading causes of cancer-related deaths worldwide, with poor overall survival rates. Current therapies for pancreatic cancer lack tumor specificity, resulting in harmful effects on normal tissues. Therefore, developing tumor-specific agents for the treatment of pancreatic cancer is critical. NAD(P)H:quinone oxidoreductase 1 (NQO1), highly expressed in pancreatic cancers but not in associated normal tissues, makes NQO1 bioactivatable drugs a potential therapy for selectively killing NQO1-positive cancer cells. Our previous studies have revealed that the novel NQO1 bioactivatable drug deoxynyboquinone (DNQ) is 10-fold more potent than the prototypic NQO1 bioactivatable drug β-lapachone in killing of NQO1-positive cancer cells. However, DNQ treatment results in high-grade methemoglobinemia, a significant side effect that limits clinical development. Results: Here, we report for the first time on a DNQ derivative, isopentyl-deoxynboquinone (IP-DNQ), which selectively kills pancreatic ductal adenocarcinoma (PDAC) cells in an NQO1-dependent manner with equal potency to the parent DNQ. IP-DNQ evokes massive reactive oxygen species (ROS) production and oxidative DNA lesions that result in poly(ADP-ribose)polymerase-1 (PARP1) hyperactivation, mitochondrial catastrophe, and G2/M phase cell cycle arrest, leading to apoptotic and necrotic programmed cell death. Importantly, IP-DNQ treatment causes only mild methemoglobinemia in vivo, with a threefold improvement in the maximum tolerated dose (MTD) compared with DNQ, while it significantly suppresses tumor growth and extends the life span of mice in subcutaneous and orthotopic pancreatic cancer xenograft models. Innovation and Conclusion: Our study demonstrates that IP-DNQ is a promising therapy for NQO1-positive pancreatic cancers and may enhance the efficacy of other anticancer drugs. IP-DNQ represents a novel approach to treating pancreatic cancer with the potential to improve patient outcomes.Item Changes in receipt of adjuvant brachytherapy for endometrial cancer patients before and after affordable care act: The impact of Medicaid expansion(Termedia Publishing, 2023) Le, Amy; Holmes, Jordan A.; Radiation Oncology, School of MedicinePurpose: For patients with high-intermediate risk (HIR) endometrial cancer, adjuvant radiation (RT) reduces the risk of recurrence, but many patients do not receive RT. Under the Affordable Care Act (ACA), most states expanded Medicaid coverage. Our hypothesis was patients would be more likely to receive indicated adjuvant RT in states that expanded Medicaid compared with patients in states that did not expand Medicaid. Material and methods: National Cancer Database (NCDB) was used to identify patients aged 40-64 years with HIR endometrial adenocarcinoma, stage IA and grade 3 or stage IB and grade 1 or 2, diagnosed from 2010-2018. We conducted a difference-in-differences (DID) cross-sectional retrospective analysis comparing receipt of adjuvant RT among patients residing in Medicaid expansion and non-expansion states before and after ACA implementation (January 2014). Results: Expansion states had higher rates of adjuvant RT prior to January 2014 compared with non-expansion states (49.21% vs. 36.46%), and the proportion of patients who received adjuvant RT increased over the study period across both Medicaid expansion and non-expansion states. After Medicaid expansion, the non-expansion states had a larger absolute increase in adjuvant radiation resulting in a non-significant change in the difference in adjuvant radiation rates compared with baseline (crude increase: 9.63% vs. 7.45%, adjusted DID: -2.68 [95% CI: -7.12-1.75], p = 0.236). Conclusions: Medicaid expansion is likely not the most significant factor affecting access or receipt of adjuvant RT for HIR endometrial cancer patients. Further study could help inform policy and efforts to ensure all patients have access to guideline-recommended RT.Item Dosimetric Impact of Source Displacement in GammaTile Surgically Targeted Radiation Therapy for Gliomas(Springer Nature, 2023-05-02) Ng, Sook Kien; Yue, Yong; Shiue, Kevin; Shah, Mitesh V.; Le, Yi; Radiation Oncology, School of MedicineBackground: This study aims to evaluate dosimetric changes that happened during the first month after GammaTile surgically targeted radiation therapy (STaRT) for gliomas due to Cesium-131 (Cs-131) seed displacement caused by cavity shrinkage in brain brachytherapy. Methodology: In this study, 10 glioma patients had 4-11 GammaTiles placed along the resection bed after maximal safe resection during craniotomy. Each GammaTile is composed of four Cs-131 seeds embedded in a biodegradable collagen sponge to minimize seed movement and maintain seed-to-cavity surface distance. The Cs-131 seed positions were identified using VariSeed on day one. On day 30, post-implant computed tomography (CT) images and dosimetry parameters were calculated. An iterative closest point (ICP) algorithm was used to compute rigid transformation between the day one and day 30 seed clouds. The seed displacement was calculated after registration. The volume receiving 100% of the prescription dose (V100), the dose received by 90% of the planning target volume (D90_PTV), the planning target volume receiving 100% of the prescription dose (V100_PTV), and the dose to organs at risk (OARs) were calculated for both CT images to determine the dosimetric changes from any seed displacement. Results: The mean seed displacement of 1.8 ± 1.0 mm for all patients was observed between day one and day 30. The maximum seed displacement for each patient ranged from 2.3 mm to 7.3 mm. The mean V100 difference between day one and day 30 was 2.5 cc (range = 0.5-6.5 cc). The mean D90_PTVs were 95.5% (range = 69.0%-131.0%) and 98.1% (range = 19.9%-149.0%) on day one and day 30, respectively. The mean V100_PTVs were 88.4% (range = 81.3%-99.1%) and 87.9% (range = 47.0%-99.7%) on day one and day 30, respectively. On day one, the brainstem dose was 63.5 Gy for one case and 28.1 Gy for another case; while on day 30, the brainstem dose was 55.8 Gy and 20.6 Gy for the same patients, contributing to 7.7 Gy (12.8%) and 7.5 Gy (12.5%) dose reductions to brainstem for these patients, respectively. Only two patients received a dose to the optic nerves (34.1 Gy and 5.2 Gy). There were small changes (1.8 Gy and 0.5 Gy, respectively) in the dose to optic nerves when comparing the dose calculated on day one and the dose calculated on day 30 CT images. The same two patients received 30.4 Gy and 6.8 Gy to the chiasm, respectively. Small changes in the dose to the chiasm (≤1.1 Gy) were noted between day one and day 30. Conclusions: A maximum seed displacement of up to 7.3 mm and a mean seed displacement of 1.8 mm caused by cavity shrinkage were observed during the first month after GammaTile STaRT for gliomas. There were noticeable changes in dosimetry parameters. Changes in the doses to OARs, particularly the brainstem, were large (up to 12.8% of the prescription dose). These changes in dosimetry should be considered when evaluating treatment outcomes and planning future GammaTile treatments.