The Department of Radiation Oncology provides radiation medicine to the region's oncology patients and serves as the academic infrastructure for radiation science at UMass Chan Medical School. The Department is one of the largest in New England, providing state-of the-art clinical treatment service to cancer patients in Worcester County. This collection showcases journal articles and other publications produced by faculty and researchers of the Department of Radiation Oncology.


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Recently Published

  • The Importance of Quality Assurance in Radiation Oncology Clinical Trials

    FitzGerald, Thomas J; Bishop-Jodoin, Maryann; Laurie, Fran; Iandoli, Matthew; Smith, Koren; Ulin, Kenneth; Ding, Linda; Moni, Janaki; Cicchetti, M Giulia; Knopp, Michael; et al. (2023-10-01)
    Clinical trials have been the center of progress in modern medicine. In oncology, we are fortunate to have a structure in place through the National Clinical Trials Network (NCTN). The NCTN provides the infrastructure and a forum for scientific discussion to develop clinical concepts for trial design. The NCTN also provides a network group structure to administer trials for successful trial management and outcome analyses. There are many important aspects to trial design and conduct. Modern trials need to ensure appropriate trial conduct and secure data management processes. Of equal importance is the quality assurance of a clinical trial. If progress is to be made in oncology clinical medicine, investigators and patient care providers of service need to feel secure that trial data is complete, accurate, and well-controlled in order to be confident in trial analysis and move trial outcome results into daily practice. As our technology has matured, so has our need to apply technology in a uniform manner for appropriate interpretation of trial outcomes. In this article, we review the importance of quality assurance in clinical trials involving radiation therapy. We will include important aspects of institution and investigator credentialing for participation as well as ongoing processes to ensure that each trial is being managed in a compliant manner. We will provide examples of the importance of complete datasets to ensure study interpretation. We will describe how successful strategies for quality assurance in the past will support new initiatives moving forward.
  • Risk of Subsequent Neoplasms in Childhood Cancer Survivors After Radiation Therapy: A Comprehensive PENTEC Review

    Casey, Dana L; Vogelius, Ivan R; Brodin, N Patrik; Roberts, Kenneth B; Avanzo, Michele; Moni, Janaki; Owens, Constance; Ronckers, Cécile M; Constine, Louis S; Bentzen, Soren M; et al. (2023-09-29)
    Purpose: A Pediatric Normal Tissue Effects in the Clinic (PENTEC) analysis of published investigations of central nervous system (CNS) subsequent neoplasms (SNs), subsequent sarcomas, and subsequent lung cancers in childhood cancer survivors who received radiation therapy (RT) was performed to estimate the effect of RT dose on the risk of SNs and the modification of this risk by host and treatment factors. Methods and materials: A systematic literature review was performed to identify data published from 1975 to 2022 on SNs after prior RT in childhood cancer survivors. After abstract review, usable quantitative and qualitative data were extracted from 83 studies for CNS SNs, 118 for subsequent sarcomas, and 10 for lung SNs with 4 additional studies (3 for CNS SNs and 1 for lung SNs) later added. The incidences of SNs, RT dose, age, sex, primary cancer diagnosis, chemotherapy exposure, and latent time from primary diagnosis to SNs were extracted to assess the factors influencing risk for SNs. The excess relative ratio (ERR) for developing SNs as a function of dose was analyzed using inverse-variance weighted linear regression, and the ERR/Gy was estimated. Excess absolute risks were also calculated. Results: The ERR/Gy for subsequent meningiomas was estimated at 0.44 (95% CI, 0.19-0.68); for malignant CNS neoplasms, 0.15 (95% CI, 0.11-0.18); for sarcomas, 0.045 (95% CI, 0.023-0.067); and for lung cancer, 0.068 (95% CI, 0.03-0.11). Younger age at time of primary diagnosis was associated with higher risk of subsequent meningioma and sarcoma, whereas no significant effect was observed for age at exposure for risk of malignant CNS neoplasm, and insufficient data were available regarding age for lung cancer. Females had a higher risk of subsequent meningioma (odds ratio, 1.46; 95% CI, 1.22-1.76; P < .0001) relative to males, whereas no statistically significant sex difference was seen in risk of malignant CNS neoplasms, sarcoma SNs, or lung SNs. There was an association between chemotherapy receipt (specifically alkylating agents and anthracyclines) and subsequent sarcoma risk, whereas there was no clear association between specific chemotherapeutic agents and risk of CNS SNs and lung SNs. Conclusions: This PENTEC systematic review shows a significant radiation dose-response relationship for CNS SNs, sarcomas, and lung SNs. Given the linear dose response, improved conformality around the target volume that limits the high dose volume might be a promising strategy for reducing the risk of SNs after RT. Other host- and treatment-related factors such as age and chemotherapy play a significant contributory role in the development of SNs and should be considered when estimating the risk of SNs after RT among childhood cancer survivors.
  • Children's Oncology Group's 2023 blueprint for research: Radiation oncology

    Kalapurakal, John A; Wolden, Suzanne L; Haas-Kogan, Daphne; Laack, Nadia N; Hua, Chia-Ho; Paulino, Arnold C; Hill-Kayser, Christine E; Hoppe, Bradford S; FitzGerald, Thomas J (2023-07-24)
    Radiation oncology is an integral part of the multidisciplinary team caring for children with cancer. The primary goal of our committee is to enable the delivery of the safest dose of radiation therapy (RT) with the maximal potential for cure, and to minimize toxicity in children by delivering lower doses to normal tissues using advanced technologies like intensity-modulated RT (IMRT) and proton therapy. We provide mentorship for y ators and are actively involved in educating the global radiation oncology community. We are leaders in the effort to discover novel radiosensitizers, radioprotectors, and advanced RT technologies that could help improve outcomes of children with cancer.
  • Editorial: Rising stars in radiation oncology 2022

    FitzGerald, Thomas J (2023-06-21)
    As patient care has matured and become increasingly complex, the fundamental skill set for the modern radiation oncologist has evolved as well. The initial generation of radiation oncologists trained in the United States and North America were taught by highly skilled mentors with expertise in surface anatomy and fluoroscopy with radiation fields designed by common understanding of the pattern of disease spread. Our first-generation mentors were critical thought leaders in applying management tools available at that time to trainees. This generation of radiation oncologists applied their expertise with the tools of the day; however, as our technology has evolved, the modern radiation oncologist requires skills commensurate with rapid technology changes. As we evolve and mature as thought leaders in the oncology practice of today, the skills required for the modern radiation oncologist both in clinical care and in basic science evolve and reach a new level of performance to match expectations of our colleagues and patients.
  • Quality improvements in radiation oncology clinical trials

    Smith, Koren; Ulin, Kenneth; Knopp, Michael; Kry, Stephan; Xiao, Ying; Rosen, Mark; Michalski, Jeff; Iandoli, Matthew; Laurie, Fran; Quigley, Jean; et al. (2023-01-26)
    Clinical trials have become the primary mechanism to validate process improvements in oncology clinical practice. Over the past two decades there have been considerable process improvements in the practice of radiation oncology within the structure of a modern department using advanced technology for patient care. Treatment planning is accomplished with volume definition including fusion of multiple series of diagnostic images into volumetric planning studies to optimize the definition of tumor and define the relationship of tumor to normal tissue. Daily treatment is validated by multiple tools of image guidance. Computer planning has been optimized and supported by the increasing use of artificial intelligence in treatment planning. Informatics technology has improved, and departments have become geographically transparent integrated through informatics bridges creating an economy of scale for the planning and execution of advanced technology radiation therapy. This serves to provide consistency in department habits and improve quality of patient care. Improvements in normal tissue sparing have further improved tolerance of treatment and allowed radiation oncologists to increase both daily and total dose to target. Radiation oncologists need to define a priori dose volume constraints to normal tissue as well as define how image guidance will be applied to each radiation treatment. These process improvements have enhanced the utility of radiation therapy in patient care and have made radiation therapy an attractive option for care in multiple primary disease settings. In this chapter we review how these changes have been applied to clinical practice and incorporated into clinical trials. We will discuss how the changes in clinical practice have improved the quality of clinical trials in radiation therapy. We will also identify what gaps remain and need to be addressed to offer further improvements in radiation oncology clinical trials and patient care.
  • Approach to Stereotactic Body Radiotherapy for the Treatment of Advanced Hepatocellular Carcinoma in Patients with Child-Pugh B-7 Cirrhosis

    Daniell, Kayla M; Banson, Kara Micah; Diamond, Brett H; Sioshansi, Shirin (2022-11-05)
    Patients with hepatocellular carcinoma (HCC) with underlying Child-Pugh B-7 cirrhosis benefit from management from an experienced, multidisciplinary team. In patients with localized disease who meet criteria for liver transplant, establishing care at a liver transplant center is crucial. For those awaiting transplant, local bridge therapies have emerged as a strategy to maintain priority status and eligibility. Multiple liver-directed therapies exist to provide locoregional tumor control. The careful selection of locoregional therapy is a multidisciplinary endeavor that takes into account patient factors including tumor resectability, underlying liver function, performance status, previous treatment, tumor location/size, and vascular anatomy to determine the optimal management strategy. Technological advances in external beam radiation therapy have allowed stereotactic body radiation therapy (SBRT) to emerge in recent years as a versatile and highly effective bridge therapy consisting of typically between 3 and 5 high dose, highly focused, and non-invasive radiation treatments. When treating cirrhotic patients with HCC, preserving liver function is of utmost importance to prevent clinical decline and decompensation. SBRT has been shown to be both safe and effective in carefully selected patients with Child-Pugh B cirrhosis; however, care must be taken to prevent radiation-induced liver disease. This review summarizes the evolving role of SBRT in the treatment of HCC in patients with Child-Pugh B-7 cirrhosis.
  • Extranodal presentation in limited-stage diffuse large Bcell lymphoma as a prognostic marker in three SWOG trials S0014, S0313 and S1001

    Stephens, Deborah M; Li, Hongli; Constine, Louis S; Fitzgerald, Thomas J; Leonard, John P; Kahl, Brad S; Song, Joo Y; LeBlanc, Michael L; Smith, Sonali M; Persky, Daniel O; et al. (2022-11-01)
    Several recent trials have changed the standard-of-care for patients with limited stage (LS) diffuse large B-cell lymphoma (DLBCL) by minimizing the number of chemoimmunotherapy cycles and/or eliminating the need for radiotherapy without compromising long-term outcomes. However, there may be patient subsets where an abbreviated-treatment approach is insufficient. With this in mind, Bobillo et al., retrospectively reviewed LS DLBCL patients treated at a single institution with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) for four to six cycles with or without radio-therapy. This group reported that an extranodal presentation had shorter progression-free (PFS) and overall survival (OS) compared with nodal presentation. In these patients, consolidative radiotherapy prolonged survival in patients with extranodal disease, especially those with a positive positron emission tomography (PET) scan at the end of chemoimmunotherapy. In response, we analyzed similar patients treated on three consecutive SWOG studies (S0014, S0313, S1001; clinicaltrails gov. Identifier: NCT00005089, NCT00070018, NCT01359592).
  • Definitive Radiation Therapy for Medically Inoperable Endometrial Carcinoma

    Shen, James L; O'Connor, Kevin W; Moni, Janaki; Zweizig, Susan; FitzGerald, Thomas J; Ko, Eric C (2022-10-25)
    Purpose: Upfront radiation therapy consisting of brachytherapy with or without external beam radiation therapy is considered standard of care for patients with endometrial carcinoma who are unable to undergo surgical intervention. This study evaluated the cancer-free survival (CFS), cancer-specific survival (CSS), and overall survival (OS) of patients with endometrial carcinoma managed with definitive-intent radiation therapy. Methods and materials: This was a single-institution retrospective analysis of medically inoperable patients with biopsy-proven endometrial carcinoma managed with up-front, definitive radiation therapy at UMass Memorial Medical Center between May 2010 and October 2021. A total of 55 cases were included for analysis. Patients were stratified as having low-risk endometrial carcinoma (LREC; uterine-confined grade 1-2 endometrioid adenocarcinoma) or high-risk endometrial carcinoma (HREC; stage III/IV and/or grade 3 endometrioid carcinoma, or any stage serous or clear cell carcinoma or carcinosarcoma). The CFS, CSS, OS, and grade ≥3 toxic effects were reported for patients with LREC and HREC. Results: The median age was 66 years (range, 42-86 years), and the median follow-up was 44 months (range, 4-135 months). Twelve patients (22%) were diagnosed with HREC. Six patients (11%) were treated with high-dose-rate brachytherapy alone and 49 patients (89%) were treated with high-dose-rate brachytherapy and external beam radiation therapy. Twelve patients (22%) were treated with radiation and chemotherapy. The 2-year CFS was 82% for patients with LREC and 80% for patients with HREC (log rank P = .0654). The 2-year CSS was 100% for both LREC and HREC patients. The 2-year OS was 92% for LREC and 80% for HREC (log P = .0064). There were no acute grade ≥3 toxic effects. There were 3 late grade ≥3 toxic effects owing to endometrial bleeding and gastrointestinal adverse effects. Conclusions: For medically inoperable patients with endometrial carcinoma, up-front radiation therapy provided excellent CFS, CSS, and OS. The CSS and OS were higher in patients with LREC than in those with HREC. Toxic effects were limited in both cohorts.
  • Prostate Cancer: Advances in Radiation Oncology, Molecular Biology, and Future Treatment Strategies

    Wang, Tao; Lewis, Brian; Ruscetti, Marcus; Mittal, Kriti; Wang, Ming-Jin; Sokoloff, Mitchell H.; Ding, Linda; Bishop-Jodoin, Maryann; FitzGerald, Thomas J. (2022-09-12)
    Prostate cancer remains an important health problem worldwide affecting one in every six men including members of vulnerable communities. Although successful treatments have been delivered to men affected with the disease resulting in improved patient outcome, process improvements including therapy titration and augmentation are needed to optimize tumor control and limit normal tissue injury from therapy. In this chapter, we describe current management strategies for optimal patient care with radiation therapy and opportunities for improvement of care moving forward with applied science to apply therapy in a strategic manner, potentially improving care and outcome for patients treated for this disease.
  • Radiation Oncology: Future Vision for Quality Assurance and Data Management in Clinical Trials and Translational Science

    Ding, Linda; Bradford, Carla; Kuo, I-Lin; Fan, Yankhua; Ulin, Kenneth; Khalifeh, Abdulnasser; Yu, Suhong; Liu, Fenghong; Saleeby, Jonathan; Bushe, Harry; et al. (2022-08-10)
    The future of radiation oncology is exceptionally strong as we are increasingly involved in nearly all oncology disease sites due to extraordinary advances in radiation oncology treatment management platforms and improvements in treatment execution. Due to our technology and consistent accuracy, compressed radiation oncology treatment strategies are becoming more commonplace secondary to our ability to successfully treat tumor targets with increased normal tissue avoidance. In many disease sites including the central nervous system, pulmonary parenchyma, liver, and other areas, our service is redefining the standards of care. Targeting of disease has improved due to advances in tumor imaging and application of integrated imaging datasets into sophisticated planning systems which can optimize volume driven plans created by talented personnel. Treatment times have significantly decreased due to volume driven arc therapy and positioning is secured by real time imaging and optical tracking. Normal tissue exclusion has permitted compressed treatment schedules making treatment more convenient for the patient. These changes require additional study to further optimize care. Because data exchange worldwide have evolved through digital platforms and prisms, images and radiation datasets worldwide can be shared/reviewed on a same day basis using established de-identification and anonymization methods. Data storage post-trial completion can co-exist with digital pathomic and radiomic information in a single database coupled with patient specific outcome information and serve to move our translational science forward with nimble query elements and artificial intelligence to ask better questions of the data we collect and collate. This will be important moving forward to validate our process improvements at an enterprise level and support our science. We have to be thorough and complete in our data acquisition processes, however if we remain disciplined in our data management plan, our field can grow further and become more successful generating new standards of care from validated datasets.
  • Stereotactic body radiation therapy for metastatic non-small cell lung cancer: a versatile treatment, repurposed

    Shen, James L; Ko, Eric C (2022-07-01)
    Comment on: Lester-Coll NH, Skelly J, Vacek PM, et al. Trends and costs of stereotactic body radiation therapy in metastatic non-small cell lung cancer. J Thorac Dis 2022;14:2579-90.
  • A Review of Concurrent Chemo/Radiation, Immunotherapy, Radiation Planning, and Biomarkers for Locally Advanced Non-small Cell Lung Cancer and Their Role in the Development of ECOG-ACRIN EA5181

    Varlotto, John Michael; Sun, Zhuoxin; Ky, Bonnie; Upshaw, Jenica; Fitzgerald, Thomas J; Diehn, Max; Lovly, Christine; Belani, Chandra; Oettel, Kurt; Masters, Gregory; et al. (2022-06-30)
    ECOG-ACRIN EA5181 is a current prospective, randomized trial that is investigating whether the addition of concomitant durvalumab to standard chemo/radiation followed by 1 year of consolidative durvalumab results in an overall survival benefit over standard chemo/radiation alone followed by 1 year of consolidative durvalumab in patients with locally advanced, unresectable non-small cell lung cancer (NSCLC). Because multiple phase I/II trials have shown the relative safety of adding immunotherapy to chemo/radiation and due to the known synergism between chemotherapy and immunotherapy, it is hoped that concomitant durvalumab can reduce the relatively high incidence of local failure (38%-46%) as seen in recent prospective, randomized trials of standard chemo/radiation in this patient population. We will review the history of radiation for LA-NSCLC and discuss the role of induction, concurrent and consolidative chemotherapy as well as the concerns for late cardiac and pulmonary toxicities associated with treatment. Furthermore, we will review the potential role of next generation sequencing, PD-L1, ctDNA and tumor mutation burden and their possible impact on this trial.
  • AAPM task group report 302: Surface-guided radiotherapy

    Al-Hallaq, Hania A; Cerviño, Laura; Gutierrez, Alonso N; Havnen-Smith, Amanda; Higgins, Susan A; Kügele, Malin; Padilla, Laura; Pawlicki, Todd; Remmes, Nicholas; Smith, Koren; et al. (2022-03-15)
    The clinical use of surface imaging has increased dramatically, with demonstrated utility for initial patient positioning, real-time motion monitoring, and beam gating in a variety of anatomical sites. The Therapy Physics Subcommittee and the Imaging for Treatment Verification Working Group of the American Association of Physicists in Medicine commissioned Task Group 302 to review the current clinical uses of surface imaging and emerging clinical applications. The specific charge of this task group was to provide technical guidelines for clinical indications of use for general positioning, breast deep-inspiration breath hold treatment, and frameless stereotactic radiosurgery. Additionally, the task group was charged with providing commissioning and on-going quality assurance (QA) requirements for surface-guided radiation therapy (SGRT) as part of a comprehensive QA program including risk assessment. Workflow considerations for other anatomic sites and for computed tomography simulation, including motion management, are also discussed. Finally, developing clinical applications, such as stereotactic body radiotherapy (SBRT) or proton radiotherapy, are presented. The recommendations made in this report, which are summarized at the end of the report, are applicable to all video-based SGRT systems available at the time of writing.
  • Practice patterns and recommendations for pediatric image-guided radiotherapy: A Children's Oncology Group report

    Hua, Chia-Ho; Ulin, Kenneth; Laurie, Frances; FitzGerald, Thomas J. (2020-10-01)
    This report by the Radiation Oncology Discipline of Children's Oncology Group (COG) describes the practice patterns of pediatric image-guided radiotherapy (IGRT) based on a member survey and provides practice recommendations accordingly. The survey comprised of 11 vignettes asking clinicians about their recommended treatment modalities, IGRT preferences, and frequency of in-room verification. Technical questions asked physicists about imaging protocols, dose reduction, setup correction, and adaptive therapy. In this report, the COG Radiation Oncology Discipline provides an IGRT modality/frequency decision tree and the expert guidelines for the practice of ionizing image guidance in pediatric radiotherapy patients.
  • The Effectiveness of Intraoperative Clip Placement in Improving Radiation Therapy Boost Targeting After Oncoplastic Surgery

    Riina, Matthew D.; Rashad, Ramy; Cohen, Stephanie; Brownlee, Zachary; Sioshansi, Shirin; Hepel, Jaroslaw; Chatterjee, Abhishek; Huber, Kathryn E. (2020-09-01)
    PURPOSE: The role of surgical clips as markers of the tumor bed cavity for radiation therapy boost targeting after oncoplastic surgery is not well understood. Therefore, we sought to evaluate whether the placement of surgical clips can reduce interobserver variability in the delineation of the tumor bed cavities of oncoplastic surgery patients and ultimately determine an optimal number of clips to place. METHODS AND MATERIALS: We reviewed records of 39 women with breast cancer who underwent oncoplastic breast surgery and adjuvant radiation therapy at our institution. Three radiation oncologists contoured tumor bed cavity volumes on planning computed tomography simulation images. Interobserver variability was measured both by a coefficient of variation of radiation oncologists contour volume and a concordance index defined as the quotient of the intersecting and aggregated volume of the contours. Patients were stratified by the number of surgical clips placed and compared by 1-way analysis of variance. Simple linear regression was used to evaluate the relationship of total excised volume and interobserver variability in patients with a sufficient quantity of surgical clips. RESULTS: Interobserver variability in the delineation of the tumor bed cavity as measured by concordance index was significantly reduced in patients who received intraoperative surgical clips (F = 5.755; P = .001). A similar trend was seen in contour volume (F = 2.616; P = .052). Results of 1-way analysis of variance and post hoc analysis showed that 4 clips are effective and sufficient for reproducible delineation of the tumor bed cavity for the radiation therapy boost. Increasing excision volume does not result in an increase in interobserver variability (r(2) = 0.00003). CONCLUSIONS: In oncoplastic surgery patients, intraoperative placement of surgical clips is beneficial and effective in improving the delineation of the tumor bed cavity for the radiation therapy boost. Four clips are necessary and sufficient for accurate boost targeting after lumpectomy with oncoplastic reconstruction.
  • Arvin S. Glicksman, MD 1924 to 2020

    FitzGerald, Thomas J. (2020-09-01)
    Arvin S. Glicksman died January 3, 2020, at his home in Uxbridge, Massachusetts. He was born in Brooklyn, New York, where he attended high school. After graduating from the University of Chicago Medical School, he served a medical internship at Kings County Hospital in Brooklyn, New York. Awarded a postdoctoral research fellowship at the Atomic Energy Commission, Arvin was recruited by physicist Leo Szilard to work in radiation science at both Brookhaven National Laboratory and Duke University. Working on the Manhattan Project introduced him to the science of radiation medicine and its potential effect on cancer management and normal tissue tolerance. He joined the Memorial Hospital and Sloan Kettering Institute (now Memorial Sloan Kettering in New York), where he worked for 15 years. He received a Research Career Development Award by the National Institute of Health and continued his research at the Institute for Cancer Research at the Royal Marsden Hospital in London, England. He was on faculty at the Mount Sinai Medical School, Mount Sinai Hospital in New York before being recruited to begin the Radiation Medicine Program at Brown University in Providence, Rhode Island, where he remained active for the rest of his life.
  • Open access image repositories: high-quality data to enable machine learning research

    Prior, Fred; Almeida, J.; Kathiravelu, P.; Kurc, T.; Smith, K.; FitzGerald, Thomas J.; Saltz, J. (2020-01-01)
    Originally motivated by the need for research reproducibility and data reuse, large-scale, open access information repositories have become key resources for training and testing of advanced machine learning applications in biomedical and clinical research. To be of value, such repositories must provide large, high-quality data sets, where quality is defined as minimising variance due to data collection protocols and data misrepresentations. Curation is the key to quality. We have constructed a large public access image repository, The Cancer Imaging Archive, dedicated to the promotion of open science to advance the global effort to diagnose and treat cancer. Drawing on this experience and our experience in applying machine learning techniques to the analysis of radiology and pathology image data, we will review the requirements placed on such information repositories by state-of-the-art machine learning applications and how these requirements can be met.
  • Treatment Toxicity: Radiation

    FitzGerald, Thomas J.; Bishop-Jodoin, Maryann; Laurie, Frances; Lukez, Alexander; O'Loughlin, Lauren; Sacher, Allison (2019-10-01)
    Intentional and unintentional radiation exposures have a powerful impact on normal tissue function and can induce short-term and long-term injury to all cell systems. Radiation effects can lead to lifetime-defining health issues for a patient and can produce complications to all organ systems. Providers need to understand acute and late effects of radiation treatment and how the fingerprints of therapy can have an impact on health care in later life. This article reviews current knowledge concerning normal tissue tolerance with therapy.
  • The VEGF receptor neuropilin 2 promotes homologous recombination by stimulating YAP/TAZ-mediated Rad51 expression

    Elaimy, Ameer L.; Amante, John J.; Zhu, Lihua Julie; Wang, Mengdie; Walmsley, Charlotte; Fitzgerald, Thomas J.; Goel, Hira Lal; Mercurio, Arthur M. (2019-07-09)
    Vascular endothelial growth factor (VEGF) signaling in tumor cells mediated by neuropilins (NRPs) contributes to the aggressive nature of several cancers, including triple-negative breast cancer (TNBC), independently of its role in angiogenesis. Understanding the mechanisms by which VEGF-NRP signaling contributes to the phenotype of such cancers is a significant and timely problem. We report that VEGF-NRP2 promote homologous recombination (HR) in BRCA1 wild-type TNBC cells by contributing to the expression and function of Rad51, an essential enzyme in the HR pathway that mediates efficient DNA double-strand break repair. Mechanistically, we provide evidence that VEGF-NRP2 stimulates YAP/TAZ-dependent Rad51 expression and that Rad51 is a direct YAP/TAZ-TEAD transcriptional target. We also discovered that VEGF-NRP2-YAP/TAZ signaling contributes to the resistance of TNBC cells to cisplatin and that Rad51 rescues the defects in DNA repair upon inhibition of either VEGF-NRP2 or YAP/TAZ. These findings reveal roles for VEGF-NRP2 and YAP/TAZ in DNA repair, and they indicate a unified mechanism involving VEGF-NRP2, YAP/TAZ, and Rad51 that contributes to resistance to platinum chemotherapy.
  • alphavbeta3 Integrin Mediates Radioresistance of Prostate Cancer Cells Through Regulation of Survivin

    Wang, Tao; Huang, Jiayi; Vue, Mai; Alavian, Michael R.; Goel, Hira Lal; Altieri, Dario C.; Languino, Lucia R.; Fitzgerald, Thomas J. (2019-02-01)
    The alphavbeta3 integrin is involved in various physiologic and pathologic processes such as wound healing, angiogenesis, tumor growth, and metastasis. The impact of alphavbeta3 integrin on the radiosensitivity of prostate cancer cells and the molecular mechanism controlling cell survival in response to ionizing radiation (IR) was investigated. Both LNCaP cells stably transfected with alphavbeta3 integrin and PC-3 cells that contain endogenous beta3 integrin were used. This study demonstrated that alphavbeta3 integrin increases survival of alphavbeta3-LNCaP cells upon IR while small hairpin RNA (shRNA)-mediated knockdown of alphavbeta3 integrin in PC-3 cells sensitizes to radiation. Expression of alphavbeta3 integrin in LNCaP cells also enhances anchorage-independent cell growth while knockdown of alphavbeta3 integrin in PC-3 cells inhibits anchorage-independent cell growth. The alphavbeta3 antagonist, cRGD, significantly increases radiosensitivity in both alphavbeta3-LNCaP and PC-3 cells. Moreover, alphavbeta3 integrin prevents radiation-induced downregulation of survivin. Inhibition of survivin expression by siRNA or shRNA enhances IR-induced inhibition of anchorage-independent cell growth. Overexpression of wild-type survivin in PC-3 cells treated with alphavbeta3 integrin shRNA increases survival of cells upon IR. These findings reveal that alphavbeta3 integrin promotes radioresistance and regulates survivin levels in response to IR. Implications: Future translational research on targeting alphavbeta3 integrin and survivin may reveal novel approaches as an adjunct to radiotherapy for patients with prostate cancer.

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