bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA-012: Differential immunological effects of carbon-ion versus photon radiation therapy
Authors: Drake Charles G. 
Published: April 2021

Abstract
Radiation therapy (RT) exerts multiple effects on the immune system; in particular RT can serve as an in situ vaccine to either prime new anti-tumor T cell responses, or to induce new responses. We and many others showed that these propitious effects appear to counter-balanced to some degree by immunosuppressive effects, including the expansion of regulatory T cells (Treg), recruitment of myeloid derived suppressive cells (MDSC), and induction of Trex which mitigates the pro-inflammatory effects of STING pathway activation. Carbon-ion radiation therapy (CiRT) is an emerging therapeutic modality based on data showing that heavy ions may improve dosimetry and decrease toxicity to normal tissues. Currently, CiRT is performed at a limited number of centers, thus its immunological effects remain relatively understudied. To address this knowledge gap, we used an orthotopic, syngenic murine model to compare the relative immunological effects of CiRT to conventional photon radiation therapy (PhRT). At short follow-up times post RT, PhRT decreased the prevalence of T cells in the TME at all doses examined, whilst CiRT appeared to be relatively lymphocyte sparing. Higher doses of CiRT increased the secretion of multiple pro-inflammatory cytokines to a greater degree than did PhRT. Consistent with our prior results, both modalities increased Treg infiltration; although this was less apparent with CiRT. Although these are early studies with several caveats, the results support the hypothesis that CiRT may have differential immunological effects than those mediated by PhRT.
Citation Format: Charles G. Drake. Differential immunological effects of carbon-ion versus photon radiation therapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-012.
Abstract IA-018: Molecular landmarks of tumor hypoxia across cancer types
Authors: Bhandari Vinayak , Hoey Christianne , Liu Lydia , Lalonde Emilie , Ray Jessica , Livingstone Julie , Lesurf Robert , Shiah Yu-Jia , Vujcic Tina , Huang Xiaoyong , Espiritu Shadrielle M.G. , Heisler Lawrence E. , Yousif Fouad , Huang Vincent , Yamaguchi Takafumi N. , Yao Cindy Q. , Sabelnykova Veronica Y. , Fraser Michael , Chua Melvin L.K. , van der Kwast Theodorus , Liu Stanley K. , Boutros Paul C. , Bristow Robert G. 
Published: April 2021

Abstract
Many primary tumor sub-regions have low levels of molecular oxygen, termed hypoxia. Hypoxic tumors are at elevated risk for local failure and distant metastasis, but the molecular hallmarks of tumor hypoxia remain poorly defined. To fill this gap, we quantified hypoxia in 8,006 tumors across 19 tumor types. In ten tumor types, hypoxia was associated with elevated genomic instability. In all 19 tumor types, hypoxic tumors exhibited characteristic driver mutation signatures. We observed widespread hypoxia-associated dysregulation of miRNAs across cancers and functionally validated miR-133a-3p as a hypoxia-modulated miRNA. In localized prostate cancer, hypoxia was associated with elevated rates of chromothripsis, allelic loss of PTEN and shorter telomeres. These associations are particularly enriched in polyclonal tumors, representing a constellation of features resembling tumor nimbosus – an aggressive cellular phenotype. Overall, this work establishes that tumor hypoxia may drive aggressive molecular features across cancers and shape the clinical trajectory of individual tumors.
Citation Format: Vinayak Bhandari, Christianne Hoey, Lydia Liu, Emilie Lalonde, Jessica Ray, Julie Livingstone, Robert Lesurf, Yu-Jia Shiah, Tina Vujcic, Xiaoyong Huang, Shadrielle M.G. Espiritu, Lawrence E. Heisler, Fouad Yousif, Vincent Huang, Takafumi N. Yamaguchi, Cindy Q. Yao, Veronica Y. Sabelnykova, Michael Fraser, Melvin L.K. Chua, Theodorus van der Kwast, Stanley K. Liu, Paul C. Boutros, Robert G. Bristow. Molecular landmarks of tumor hypoxia across cancer types [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-018.
Abstract IA-021: Predicting radiotherapy outcomes: Radiogenomics and risk of radiotherapy toxicity
Authors: West Catharine M.L. 
Published: April 2021

Abstract
A key challenge in radiotherapy is to maximize radiation doses to cancer while minimizing damage to surrounding healthy tissues. As toxicity in a minority of patients limits the doses that can be safely given to the majority, there is interest in developing a test to measure an individual’s radiosensitivity before treatment and predict their likelihood of developing toxicity. A biomarker that predicts a cancer patient’s risk of toxicity could be used to personalize dose prescriptions or to offer alternative treatments. Many approaches have been studied to measure radiosensitivity. The development of omics technologies underpinned genome wide association studies (GWAS) attempting to identify genetic variants reported as single nucleotide polymorphisms (SNPs). The advantages of the approach include: a genetic test will be easier to implement clinically than a functional assay; a genetic test will not suffer from the poor reproducibility associated with some radiosensitivity testing methods; and SNPs are the most common type of genetic variation and so easiest to identify. Omics technologies offer promise, but to have an impact on radiotherapy practice research must identify biomarkers that replicate across cohorts. Robust replication needs big data, which is only possible with large collaborative efforts. The need for big data was addressed by establishing an international Radiogenomics Consortium. The latest results from the consortium will be presented including the largest radiogenomics study carried out to date involved ~4,000 men with prostate cancer.
Citation Format: Catharine M.L. West. Predicting radiotherapy outcomes: Radiogenomics and risk of radiotherapy toxicity [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-021.
Abstract IA-024: Sirt2: A tumor suppressor or promotor?
Authors: Xia Fen 
Published: April 2021

Abstract
SIRT2, an NAD+-dependent histone deacetylase, has been shown to play a pivotal role in various physiological processes, however, its role in cancer is currently controversial. In recent years, SIRT2 has been described as both a tumor suppressor and oncogene with divergent expression and function in various malignancies. Using murine xenograft melanoma models, our results suggest increased systemic expression of SIRT2 promotes tumor progression. In this study, SIRT2-overexpressing mice exhibited enhanced tumor growth and larger tumor volumes compared to their wild-type littermates. Mechanistically, systemic overexpression of SIRT2 reduces the number of tumor-infiltrating natural killer (NK) cells and suppresses NK cell activation and proliferation within tumor microenvironment (TME). Furthermore, despite the effect of increased tumor growth rate and tumor volume in wild-type littermate mice, NK cell depletion does not affect that in SIRT2-overexpressing mice. Lastly, pharmacological inhibition of SIRT2 increases NK cell tumor infiltration and suppresses melanoma tumor growth in mice. The findings of this study identify a dynamic functional interaction between systemic SIRT2 and NK cell activity, which promotes melanoma tumor progression. Given the recent renewed interest in NK-cell-mediated immunotherapy response, SIRT2 could present a new opportunity to mediate immunotherapy response and resistance.
Citation Format: Fen Xia. Sirt2: A tumor suppressor or promotor? [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-024.
Abstract IA-025: Exploiting Redox Biology for Selectively Targeting Cancer Cells
Authors: Spitz Douglas R 
Published: April 2021

Abstract
Relative to normal cells, cancer cells have been shown to demonstrate fundamental alterations in oxidative metabolism leading to increased steady-state levels of superoxide, hydrogen peroxide, and labile iron pools. Alterations in cancer cell oxidative metabolism in turn lead to disruptions in many redox sensitive signaling and gene expression pathways that impact cell growth, differentiation, genomic instability, and cancer progression. Cancer cells adapt to this altered metabolic state by activating many signaling and gene expression pathways that allow them to survive and continue to progress to malignancy. The current talk will discuss how pharmacological ascorbate and superoxide dismutase mimics can be used to target the oxidative metabolic frailties of cancer versus normal cells to enhance therapeutic outcomes to radio-chemo-therapies both in pre-clinical and clinical trials. The long-term goal is to utilize a detailed mechanistic understanding of alterations in cancer versus normal cell oxidative metabolism and redox biology to develop rapidly implementable new strategies that can enhance tumor responses while protecting normal tissues during standard radio-chemo-therapy protocols. (Supported by P01 CA217797, R01 CA182804, T32 CA078586).
Citation Format: Douglas R Spitz. Exploiting Redox Biology for Selectively Targeting Cancer Cells [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-025.
Abstract PO-003: Mitotic enrichment as an efficient radiosensitization strategy
Authors: de Gooijer Mark C. , Slangen Paul L.G. , Çolakoğlu Hilal , Çitirikkaya Ceren H. , El Ouazani Amal , Shah Ronak , Borst Gerben R. , van Tellingen Olaf 
Published: April 2021

Abstract
Radiotherapy remains one of the most effective modalities for anticancer treatment. Boosting the efficacy of radiotherapy is therefore a logical avenue to improve patient survival. We have developed a radiosensitization strategy called ‘induction of mitotic enrichment’. It has long been known that the radiosensitivity of a cell depends to a large extent on the phase of the cell cycle and that especially mitotic cells are especially vulnerable. Enriching the tumor for mitotic cells by arresting them during division prior to each radiotherapy fraction should therefore render the tumor population more sensitive to irradiation. Ideally, induction of mitotic enrichment should be reversible and non-cytotoxic to prevent healthy tissue toxicity and be compatible with clinically applied fractionated radiotherapy regimens. We have now identified an orally available targeted tubulin polymerization inhibitor that can achieve repeated and reversible mitotic enrichment for up to 10 hours prior to radiotherapy, without causing cytotoxicity in vitro or healthy tissue toxicity in vivo. Most importantly, this tubulin inhibitor efficiently radiosensitizes a range of preclinical glioblastoma models in vitro and in vivo and significantly improves survival, but only in a mitotic enrichment setup when given several hours prior to radiotherapy to allow accumulation in mitosis. We have initiated development of mitotic enrichment for GBM, the most common primary malignant brain tumor. Their location and highly aggressive nature renders GBM among the most deadly and devastating of human malignancies. Despite extensive treatment involving surgery and adjuvant chemo-radiotherapy, prognosis is still dismal and novel treatment strategies are urgently needed. Of all available adjuvant therapies, radiotherapy contributes most to extending overall survival. Increasing the efficacy of existing radiotherapeutic regimens therefore offers a logical rationale to improve the survival of GBM patients. We are currently also expanding our preclinical development of mitotic enrichment as a radiosensitization strategy to other mitotic targets and different cancers for which radiotherapy is a mainstay treatment and have thus far achieved promising results in vitro. In parallel, we are preparing a phase 0 trial to demonstrate induction of mitotic enrichment in human GBM.
Citation Format: Mark C. de Gooijer, Paul L.G. Slangen, Hilal Çolakoğlu, Ceren H. Çitirikkaya, Amal El Ouazani, Ronak Shah, Gerben R. Borst, Olaf van Tellingen. Mitotic enrichment as an efficient radiosensitization strategy [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-003.
Abstract PO-019: Radiotherapy in cancer is associated with a deletion signature that contributes to poor patient outcomes
Authors: Kocakavuk Emre , Anderson Kevin J. , Varn Frederick S. , Johnson Kevin C. , Amin Samirkumar B. , Sulman Erik. P. , Lolkema Martijn , Barthel Floris P. , Verhaak Roel G.W. 
Published: April 2021

Abstract
Diffuse gliomas are highly aggressive brain tumors that invariably relapse despite treatment with chemo- and radiotherapy. Treatment with alkylating chemotherapy can drive tumors to develop a hypermutator phenotype. In contrast, the genomic effects of radiation therapy (RT) remain unknown. We analyzed the mutational spectra following treatment with ionizing radiation in sequencing data from 190 paired primary-recurrent gliomas from the Glioma Longitudinal Analysis (GLASS) dataset and 3693 post-treatment metastatic tumors from the Hartwig Medical Foundation (HMF). We identified a significant increase in the burden of small deletions following radiation therapy that was independent of other factors. These novel deletions demonstrated distinct characteristics when compared to pre-existing deletions present prior to RT-treatment and deletions in RT-untreated tumors. Radiation therapy-acquired deletions were characterized by a larger deletion size (GLASS and metastatic cohort, P=1.2e-02 and P=8e-11, respectively; Mann-Whitney U test), an increased distance to repetitive DNA elements (P&lt;2.2e-16, Kolmogorov-Smirnov test) and a reduction in microhomology at breakpoints (P=3.2e-02, paired Wilcoxon signed-rank test). These observations suggested that canonical non-homologous end joining (c-NHEJ) was the preferred pathway for DNA double strand break repair of RT-induced DNA damage. Furthermore, radiotherapy resulted in frequent chromosomal deletions and significantly increased frequencies of CDKN2A homozygous deletions. Finally, a high burden of RT-associated deletions was associated with worse clinical outcomes (GLASS and metastatic cohort, P &lt; 1e-04 and P = 2.6e-02, respectively; Wald test). Our results suggest that effective repair of RT-induced DNA damage is detrimental to patient survival and that inhibiting c-NHEJ may be a viable strategy for improving the cancer-killing effect of radiotherapy. Taken together, the identified genomic scars as a result of radiation therapy reflect a more aggressive tumor with increased levels of resistance to follow up treatments.
Citation Format: Emre Kocakavuk, Kevin J. Anderson, Frederick S. Varn, Kevin C. Johnson, Samirkumar B. Amin, Erik. P. Sulman, Martijn Lolkema, Floris P. Barthel, Roel G.W. Verhaak. Radiotherapy in cancer is associated with a deletion signature that contributes to poor patient outcomes [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-019.
Abstract PO-035: Understanding the role of hypoxia and PTEN loss in driving prostate cancer progression
Authors: Suvac Alexandru , Rebello Richard , Lyons Stephen , Bristow Robert G. 
Published: April 2021

Abstract
Prostate cancer is the most commonly diagnosed cancer in the UK. Increased levels of prostate hypoxia have been shown to drive tumor aggression as an adverse prognostic factor following surgery or radiotherapy, especially when combined with tumor genetic instability. Our recent collaborative bioinformatic studies (Bhandari et al, Nat. Genetics 2019; Nat. Communications 2020) have shown various copy number changes to be enriched in hypoxic tumors, with mono- or bi-allelic loss of the PTEN being the most significant. To delineate a direct relationship between hypoxia and PTEN loss, we interrogated the impact of chronic hypoxia (1% O2, 0.2% O2; 72 h) on PTEN oncogenic signaling and asked whether this translates to improved fitness and survival in non-transformed and transformed PTEN isogenic cell lines. Despite increased oncogenic signaling (increased phospho-AKT) of PTEN-null 22Rv1 cells and hTERT-immortalized prostate epithelial cells (GHM) under chronic hypoxic gassing conditions, this did not lead to increased adaption and tumor clone survival. Differential survival for the PTEN isogenic cell lines following prostate cancer therapies (i.e. IR, PARPi, cDDP, taxols) under oxia and hypoxia are underway to further this work and determine a potential translational importance to clinical treatment. Independent evidence also points to hypoxia/PTEN loss in deregulating centrosome biology as a potential mechanism for genetic instability under hypoxia. Hence, we also hypothesized that the relationship between PTEN and hypoxia might be unearthed if aberrant unstable mitoses following deregulation of spindle poles under hypoxia selectively adapt and have a survival advantage. Quantitative immunofluorescence of centrosome aberrations, using antibodies to phospho-Histone H3 and Centrin-1, show significant increases in centriole numbers (p &lt; 0.05) in mitotic cells under chronic hypoxic conditions and an increase in the incidence of micronuclei (p &lt; 0.005), specifically in chronic hypoxic cells with PTEN loss, supporting our hypothesis. Current studies are investigating in situ staining of centrosomes as a readout of chromosomal instability (CIN) in primary prostate cancer tissues with variable PTEN status as a new biomarker for aggressiveness to link hypoxia-associated genetic instability with novel clinical trial development. (Funded by Cancer Research UK as a core grant to RGB).
Citation Format: Alexandru Suvac, Richard Rebello, Stephen Lyons, Robert G. Bristow. Understanding the role of hypoxia and PTEN loss in driving prostate cancer progression [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-035.
Abstract PO-053: Targeting focal adhesions to limit radiation-induced glioblastoma cell invasion
Authors: Decotret Lisa R. , Shi Rocky , Bennewith Kevin L. 
Published: April 2021

Abstract
Introduction: Glioblastoma multiforme (GBM) is a grade IV brain tumor that is considered incurable with a median overall survival of 15 months. This low survival rate is partially attributed to the highly infiltrative nature of GBM cells. A key component of GBM cell invasion is the degradation of extracellular matrix (ECM), which is facilitated by the formation of invadosomes: focal adhesions (FAs) and invadopodia. The majority of GBM patients will receive a conventional radiation schedule of 2 Gy in 30 fractions, while a subset of patients will receive a hypofractioned radiation schedule of ~3 Gy in 15 fractions. Recent pre-clinical reports indicate the population of GBM cells that survive ionizing radiation (IR) exhibit increased invasiveness, suggesting IR may regulate FA and invadopodia function. Understanding how IR affects invadosome biology may lead to new therapeutic strategies to halt the invasion of GBM cells and increase overall survival of patients treated with radiation. Results: We found that irradiated GBM cells were significantly more invasive in vitro. GBM cells irradiated with 0-4 Gy and plated onto fluorescently-tagged gelatin to analyze ECM degradation. Cells exposed to 0-2 Gy IR produced small dot-like patterns of degradation resembling active invadopodia. However, cells exposed to 3-4 Gy IR produced oblong-shaped patterns of degradation at the periphery of the cell resembling active FAs. Using immunofluorescent markers of invadopodia (TKS5/actin) and FAs (vinculin), we found total focal adhesion and invadopodia formation remained unchanged. Rather, we found that exposing cells to 3 Gy IR increased pFAK-397 in FA structures suggesting IR increases ECM degradation by promoting FA activity. Conclusions: These data suggest higher IR doses promote FA-mediated ECM degradation and GBM cell invasion. We are currently investigating the impact of IR on FAs, ECM degradation, and GBM cell invasion in murine brain slices ex vivo.
Citation Format: Lisa R. Decotret, Rocky Shi, Kevin L. Bennewith. Targeting focal adhesions to limit radiation-induced glioblastoma cell invasion [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-053.
Abstract PO-054: Correlation of hematological toxicity with the bone marrow radiation dose and volume during concurrent chemo radiation in patients with cervical cancer
Authors: Madabhavi Irappa , Sagar Ragavendra , Patel Apurva , Sarkar Malay 
Published: April 2021

Abstract
Aims & Objective: Hematological toxicity is common in patients with cervical cancer treated with concurrent chemo radiotherapy (CT-RT), so the purpose is to assess this hematological toxicity and correlate the toxicity with the dose and volume of bone marrow included in the field of radiation. Materials & Methods: Twenty-five patients with histologically proven cervical cancer attending to our cancer center from July 2008-August 2009 were the subjects of this study. Patients were treated on 6 MV linear accelerator with a radical intent with concurrent chemotherapy using cisplatin 50 mg weekly. The planning CT was done for all the patients before the treatment and contouring of the pelvic bone marrow apart from other organs at risk was done. Hematological toxicity was assessed using RTOG common toxicity criteria weekly during and at 2 weeks after the completion of the treatment. Results: A total of 25 patients on CT-RT treatment were assessed. Sixteen patients were in locally advanced stage. The variation in HB, TLC, Platelets, and ANC counts from the baseline to 2 weeks after chemo radiotherapy were assessed. Grade II anemia was observed in 12 and Grade III in 2 patients. There were no toxicity as far as WBC and platelets were considered. There was also no correlation between the volume of bone marrow included in the field of irradiation and appearance of anemia. Conclusion: CT-RT for cervical cancer is safe and is associated with minimal hematological toxicity in the form of anemia. The toxicity is same for different volumes of bone marrow included in the field of irradiation with both conventional as well as 3DCRT technique. The toxicity observed is probably contributed by Cisplatin.
Citation Format: Irappa Madabhavi, Ragavendra Sagar, Apurva Patel, Malay Sarkar. Correlation of hematological toxicity with the bone marrow radiation dose and volume during concurrent chemo radiation in patients with cervical cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-054.