bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A014: Mitochondrial dynamics in insulin-like growth factor binding protein 3-mediated radiosensitivity of oral squamous cell carcinoma cells
Authors: Chen Ya-Wen 
Published: January 2025

Abstract
Radiation therapy, a common adjuvant therapy for oral squamous cell carcinoma (OSCC) patients either received operation or not, efficiently reduces the tumor infiltration area and growth. Insulin-like growth factor binding protein 3 (IGFBP3) is a member of a secretary glycoprotein family. We previously found that IGFBP3 promotes cell migration and lymph node metastasis of OSCC cells. However, OSCC patients with high IGFBP3 expression had a better prognostic outcome than those with low IGFBP3 expression. Moreover, we verified that ectopic expression of IGFBP3 augmented the radiosensitivity, while IGFBP3 knockdown diminished the radio-resistance of OSCC cells. We observed changes in mitochondrial morphology in IGFBP3-expressing OSCC cells after ionizing radiation (IR) treatment; however, the roles of IGFBP3 in mitochondrial dynamics remain unclear. The analyses of cell survival, reactive oxygen species production, and loss of mitochondrial membrane potential were used to verify the IGFBP3-mediated radiosensitivity. Using mitochondria by 3D cell explorer and quantification of mitochondria dynamics by immunofluorescence staining, the fission and fusion mitochondria in irradiated IGFBP3-expressing cells and IGFBP3 knockdown cells were increased, respectively. By western blot, we found phosphorylated dynamin-related protein 1 (DRP1) positively associated with IGFBP3 levels in irradiated cells. By transiently expressing DRP1 in IGFBP3-expressing cells, we found that IGFBP3-mediated radiosensitivity and mitochondrial fission were flattened by DRP1 inhibition, suggesting the role of DRP1 in IGFBP3-mediated mitochondrial fission. Our study is to elucidate the mechanism of IGFBP3-mediated radiosensitivity and hope to provide different strategies to sensitize radiotherapy and enhance the synergy between radiotherapy and immunotherapy.
Citation Format: Ya-Wen Chen. Mitochondrial dynamics in insulin-like growth factor binding protein 3-mediated radiosensitivity of oral squamous cell carcinoma cells. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr A014
Abstract B002: Pre-vaccine radiation and CTLA-4 blockade increase adjuvant effects of SARS-COV-2 mRNA vaccines
Authors: Grippin Adam , Copling Sage , Kim Andrew , Young Elliana , Kim Betty , Heymach John , Jiang Wen , Lin Steven H 
Published: January 2025

Abstract
Background: We recently reported that SARS-CoV-2 mRNA vaccines stimulate massive production of interferon-⍺ (IFN-⍺) (Grippin, et al., SITC, 2024) that drives a near-doubling of median OS and three-year overall survival (OS) in patients with non-small cell lung cancer (NSCLC) and metastatic melanoma (p&lt;0.003) (Grippin, et al., ESMO, 2024). However, design of prospective clinical trials to validate this effect is limited by insufficient understanding of the interaction of mRNA vaccines, ICIs, and local therapies. We therefore analyzed our clinical dataset to understand whether radiation and specific ICIs augment the adjuvant effects of mRNA vaccines. Methods: We utilized institutional databases to identify and extract clinical data for patients with Stage III and Stage IV non-small cell lung cancer (NSCLC) (n=2406) and metastatic melanoma (n=756) with biopsy specimens between August 2019 and August 2023. Differences in survival between groups were assessed with Gehan-Breslow-Wilcoxon tests. Results: After controlling for 34 covariates including performance status, clinical stage, steroid use, tumor proportion score (TPS) of PDL1, disease burden at presentation, cycle of therapy, mutation status, concurrent therapies, and comorbidities with multivariate Cox-proportional hazards regression, we found that receipt of a COVID mRNA vaccine within 100 days of initiation of treatment with ICI was associated with substantial survival advantage in patients with Stage III (HR 0.46, 05% CI 0.31-0.70) and Stage IV NSCLC (HR 0.46, 95% CI 0.36-0.59). Moreover, patients with Stage III disease treated with chemoradiation followed by durvalumab experienced the greatest benefits of vaccination (HR 0.17, 95% CI 0.06-0.49). Since dual agent immunotherapy was uncommon in patients with NSCLC, we then reviewed data from patients with Stage IV melanoma treated with different ICI regimens. We found that adjuvant effects of mRNA vaccines were magnified in patients who received combination therapy with dual inhibition of CTLA-4 and PD-1 (HR 0.32, 95% CI 0.17-0.60) compared to single-agent PD-1 blockade (HR 0.63, 95% CI 0.33-1.3). Conclusions: Together, this data suggests that pre-vaccine radiation therapy and combination therapy with CTLA-4 blockade enhance the adjuvant effects of mRNA vaccines. Future work will include validation of these findings in preclinical models and prospective clinical trials.
Citation Format: Adam Grippin, Sage Copling, Andrew Kim, Elliana Young, Betty Kim, John Heymach, Wen Jiang, Steven H Lin. Pre-vaccine radiation and CTLA-4 blockade increase adjuvant effects of SARS-COV-2 mRNA vaccines. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B002.
Abstract B006: Targeting REV-ERB/RORα/IRF3 axis to enhance radiation-induced immune response in cancer radiotherapy
Authors: LI Nan , Bruan Chen , Lin Steven Hsesheng 
Published: January 2025

Abstract
Radiotherapy is an important component of the therapeutics for cancer. Although the primary objective of RT is the local control of tumors, RT-mediated antitumor adaptive immunity is emerging as a promising tool in cancer treatment. Increasing evidence indicates that RT enhances adaptive anti-tumor immunity by augmenting the innate immune sensing of tumors in a type I IFN-dependent matter. Both retinoic acid-related orphan receptor α (RORα) and nuclear heme receptor Rev-erbα, are core components of the circadian rhythm, all have critical roles in inflammation and immune process. Our preliminary data showed that both RORα inverse agonist (antagonist) SR1001 and Rev-erbα agonist GSK4112 significantly enhanced radiation-induced type I IFN activation. We also found that both RORα and Rev-erbα could associate with IRF3 and regulate IRF3 phosphorylation, which enhance radiation-induced type I IFN activation. Furthermore, our data indicated that radiation induced Type I IFN production may depend on circadian cycle, and SR1001 treatment contribute to antitumor immunity of radiation. These results usher the hypothesis that RORα/Rev-erbα work together to regulate radiation-induced type I IFN response, and contribute to antitumor immunity of RT. Specifically, our data shown the critical role of RORα/Rev-erbα/IRF3 axis in regulating radiation-induced type I IFN activation and targeting RORα/Rev-erbα will synergize with radiotherapy. Altogether, the preliminary data generated from this proposal opens additional avenues of research, both preclinically and clinically, to help better understand the relationship of the circadian rhythm proteins on the RT-immune response.
Citation Format: Nan LI, Chen Bruan, Steven Hsesheng Lin. Targeting REV-ERB/RORα/IRF3 axis to enhance radiation-induced immune response in cancer radiotherapy. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B006.
Abstract B010: Interim report of Phase I study of window-of-opportunity fractionated stereotactic radiotherapy combined with checkpoint blockade prior to surgical resection for newly diagnosed glioblastoma
Authors: Ryu Samuel , Stessin Alexander , Mikell Charles , Kowalska Agnieszka , Seidman Roberta , West Steven , Mani Kartik 
Published: January 2025

Abstract
Background: Preclinical studies with transplanted GL261 glioma in mouse brain treated with radiosurgery and checkpoint blockade showed dramatic improvement of tumor cure and prolonged survival, associated with activated macrophage infiltration in the tumor site. We perform phase I study in patients with glioblastoma to assess safety and local tumor response by combined radiosurgery and checkpoint inhibitor given during window-of-opportunity prior to surgical resection, and progression-free survival and overall survival. Method and Procedure: Biopsy-proven WHO grade 4 glioblastoma patients were enrolled to the study (NCT05423210). Patients were treated with two doses of intravenous Atezolizumab at the beginning and at the end of the two-week period, concomitantly with fractionated radiosurgery (8 Gy x 4 to the grossly enhancing tumor) over 4 days during the course of 2 weeks. Maximal safe surgical resection was subsequently performed within 2 weeks from completion of radiosurgery. Adjuvant radiation 50 Gy over 5 weeks and Temozolomide were given as per standard treatment of GBM along with continuation of Atezolizumab until unacceptable toxicity or tumor progression. The initial biopsy specimen and surgical specimen were collected for laboratory examination of immune profiles. Results: The study plans to enroll total 12 histologically confirmed CNS WHO Grade 4 GBM patients also planned for surgical resection. Six patients were enrolled after consenting so far. There was no grade 3 or 4 toxicity from the window-of-opportunity combination treatment, all 6 patients successfully completing the treatment. Three patients reported fatigue and two patients had skin rash. There was one patient experiencing metallic taste. At present, five patients survive progression-free at 25, 18, 16 and 6 months since the treatment. An unanticipated finding is that there was significantly less intraoperative bleeding in the surgical field than usual brain tumor surgery. Conclusion: Preoperative fractionated radiosurgery and Atezolizumab was well tolerated so far, and appear to improve tumor control. We continue enroll the patients. Lab study of immune cell profile is underway.
Citation Format: Samuel Ryu, Alexander Stessin, Charles Mikell, Agnieszka Kowalska, Roberta Seidman, Steven West, Kartik Mani. Interim report of Phase I study of window-of-opportunity fractionated stereotactic radiotherapy combined with checkpoint blockade prior to surgical resection for newly diagnosed glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B010.
Abstract B013: Autoimmunity mechanisms in combined radiotherapy and immune-checkpoint inhibitor therapy-induced myocarditis
Authors: Yu Shiguang , Vu Nhan T , Verburg Tyler , Lu Bo 
Published: January 2025

Abstract
Immuno-checkpoint inhibitors (ICI) are frequently used as a major cancer therapy, frequently combined with radiotherapy, particularly among patients with lung cancer. There is an increasing awareness of potential cardiotoxicities from either therapy, thus raising concerns when both therapies are combined. It is likely that radiation-induced cardiac inflammation becomes unchecked when ICIs are administered, contributing to myocarditis although the underlying specific mechanisms have not been characterized. We developed a mouse model of ICI and cardiac irradiation-induced myocarditis through an image-guided small animal irradiator in the A/J mice, which is prone to ICI-induced myocarditis. Our results showed that 20 % of ICI treated mice developed mild myocarditis, whereas 40 to 50% of mice with ICI plus irradiation treatment showed severe myocarditis, characterized by lots of infiltration of CD4+ T cells, CD8+ T cells, B cells and macrophages in hearts. Flow cytometry analysis showed that the number of infiltrated CD4+ T cells is 2 to 3 folds of CD8+ T cells in the heart tissue with disease. Severe fibrosis in hearts was associated with severe myocarditis. The levels of cardiomyocyte-specific protein troponin I in serum was correlated well with the severity of myocarditis, implicating that ICI and irradiation caused many cardiomyocyte damages. ELISA assay showed that serum IL-17 was dramatically increased in mice treated with ICI alone or ICI plus radiation, implying Th17 cells may play a pathogenic role in ICI & irradiation-induced myocarditis. In addition, we compared the myocarditis induced by ICI and irradiation in less susceptible prone of C57 mice with the more susceptible strain of A/J mice. The incidence of myocarditis was significantly lower in C57 mice compared with A/J Mice. Overall, our study indicates that irradiation promotes the pathogenesis of ICI-induced myocarditis, and individuals with autoimmune tendency have a high risk to develop severe myocarditis after administration of combined ICIs and irradiation. (This work is supported by NIH grant R01)
Citation Format: Shiguang Yu, Nhan T Vu, Tyler Verburg, Bo Lu. Autoimmunity mechanisms in combined radiotherapy and immune-checkpoint inhibitor therapy-induced myocarditis. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B013.
Abstract B015: PLK4 inhibition as a strategy to enhance non-small cell lung cancer radiosensitivity
Authors: Dominguez-Vigil Irma G. , Banik Kishore , Baro Marta John , Contessa Joseph N. , Hayman Thomas J. 
Published: January 2025

Abstract
Lung cancer is the leading cause of cancer-related mortality worldwide. Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer and comprises 85% of cases. Despite treatment advances, local control after curative-intent chemoradiation for NSCLC remains suboptimal. Polo-like kinase 4 (PLK4) is a serine-threonine kinase that plays a critical role in the regulation of centrosome duplication and cell cycle progression and is overexpressed in NSCLC, thus, making it a potential therapeutic target. CFI-400945 is an orally available PLK4 inhibitor currently undergoing clinical trial evaluation. As radiation causes cell death primarily by mitotic catastrophe, a process enhanced by alterations in centrosome amplification, we hypothesized that disruption of the mitotic machinery by inhibition of PLK4 would enhance the effects of radiation in NSCLC. PLK4 inhibition by CFI-400945 resulted in radiosensitization of NSCLC cell lines. In contrast, CFI-400945 had no effect on the radiosensitivity of normal lung fibroblasts. PLK4 inhibition did not affect cell-cycle phase distribution prior to radiation, but rather the combination of CFI-400945 and radiation resulted in increased G2/M cell cycle arrest, increased centrosome amplification, and a concomitant increase in cell death through mitotic catastrophe. Lastly, CFI-400945 treatment enhanced the radiation-induced tumor growth delay of NSCLC tumor xenografts. These data indicate that targeting PLK4 is a novel approach to enhance the radiation sensitivity of NSCLC in vitro and in vivo through potentiation of centrosome amplification and cell death through mitotic catastrophe.
Citation Format: Irma G. Dominguez-Vigil, Kishore Banik, Marta John Baro, Joseph N. Contessa, Thomas J. Hayman. PLK4 inhibition as a strategy to enhance non-small cell lung cancer radiosensitivity. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B015.
Abstract B021: FTO inhibition enhances the therapeutic index of radiation therapy in head and neck cancer
Authors: Ji Lu , Pu Leighton , Cao Hongbin , Melemenidis Stavros , Sinha Subarna , Guan Li , Laseinde Eyiwunmi E. , Richter Sara , Eyben Rie , Casey Kerriann M. , Kong Christina , Graves Edward , Le Quynh-Thu , Rankin Erinn 
Published: January 2025

Abstract
Despite the use of intensive combined modality therapy such as chemoradiation or surgery and radiation, the overall survival rate for patients with HPV-negative head and neck squamous cell carcinoma (HNSCC) remains poor. This underscores the unmet clinical need for the development of more effective drug-radiotherapy combinations to enhance the therapeutic index of radiation therapy (RT). The RNA demethylase enzyme FTO has emerged as a promising target for cancer therapy. However, its role as a radiosensitizer in HNSCC remains unknown. Here, we investigated the potential of targeting FTO to augment the effectiveness of RT in HPV-negative HNSCC. We found that genetic and pharmacologic inhibition of FTO enhanced the efficacy of RT in both human and mouse HNSCC tumor xenografts. Importantly, FTO inhibition did not increase radiation-induced oral mucositis. Mechanistically, FTO inhibition radiosensitizes HPV-negative HNSCC cells through amplifying DNA damage while reducing RAD51 foci formation, providing a molecular rationale for exploiting FTO inhibitors as radiation sensitizers in HNSCC. Collectively, our results suggest that therapeutic targeting of FTO may be an effective strategy to enhance the therapeutic index of RT for the treatment of HNSCC.
Citation Format: Lu Ji, Leighton Pu, Hongbin Cao, Stavros Melemenidis, Subarna Sinha, Li Guan, Eyiwunmi E. Laseinde, Sara Richter, Rie Eyben, Kerriann M. Casey, Christina Kong, Edward Graves, Quynh-Thu Le, Erinn Rankin. FTO inhibition enhances the therapeutic index of radiation therapy in head and neck cancer. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B021.
Abstract B025: Identifying and exploiting a novel role of FTO in promoting cysteine metabolism for NSCLC therapy
Authors: Kuganesan Nishanth , Melemenidis Stavros , Graves Edward E. , Rankin Erinn B. 
Published: January 2025

Abstract
The RNA demethylase enzyme FTO is emerging as an important oncogenic factor and therapeutic target in a variety of solid tumors. However, its effect on cancer metabolism remains largely unknown. Here we show that FTO promotes cysteine metabolism, a hallmark of metabolic rewiring in non-small cell lung cancer (NSCLC) cells. Mechanistically, FTO inhibition reduces the expression of multiple targets in the cysteine metabolism pathway including the cystine transporter SLC7A11 involved in exogenous cystine uptake as well as two key enzymes cystathionine β-synthetase (CBS) and cystathionine γ-lyase (CTH) involved in de novo cysteine synthesis. Functionally, FTO inhibition reduces cystine uptake and NSCLC growth and survival in a homocysteine-dependent manner. As cysteine plays a crucial role in glutathione biosynthesis and maintenance of cellular redox homeostasis, FTO inhibition decreased glutathione levels and increased reactive oxygen species (ROS) levels in NSCLC cells. To therapeutically exploit the increased oxidative stress in NSCLC cells treated with FTO inhibitors, we combined FTO inhibition with radiation therapy. FTO inhibition enhanced the radiosensitivity of NSCLC cells. Our findings reveal a novel role for FTO in NSCLC cysteine metabolism and oxidative stress, highlighting the therapeutic potential of FTO inhibition as a strategy to enhance the efficacy of radiation therapy for the treatment of NSCLC.
Citation Format: Nishanth Kuganesan, Stavros Melemenidis, Edward E. Graves, Erinn B. Rankin. Identifying and exploiting a novel role of FTO in promoting cysteine metabolism for NSCLC therapy. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B025.
Abstract IA03: Tumor draining lymph nodes: Friends or foes
Authors: Le Quynh-Thu 
Published: January 2025

Abstract
Nodal metastasis is the most common pattern of spread in head and neck squamous cell carcinoma (HNSCC). Nodal involvement has been linked to tumor aggressiveness and poor prognosis as reflected in the staging system. It also leads to the current surgical and radiation managements of HNSCC that include elective nodal treatment in addition to addressing gross disease. Yet, elective nodal treatment (either with surgery or radiation) has been linked to immune suppression since the tumor-draining lymph nodes (TDLN) are crucial for the development of a tumor-directed adaptive immune response, particularly in T-cell priming. Here I will touch on some recent work showing: (1) how nodal metastasis can influence tumor distant spread; (2) potential role of B cells in the TDLNs in driving anti-tumor T cell immunity through the recognition of extracellular vesicle-linked antigens, (3) potential treatment approaches of HNSCC that can mitigate the negative consequences of targeting TDLN.
Citation Format: Quynh-Thu Le. Tumor draining lymph nodes: Friends or foes. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr IA03