tbuckley/cabot-search huggingface dataset:
Abstract A014: Mitochondrial dynamics in insulin-like growth factor binding protein 3-mediated radiosensitivity of oral squamous cell carcinoma cells
Authors: Ya-Wen Chen
Journal: Clinical Cancer Research (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 A002: Flash proton re-irradiation and hypofractionation alleviate radiation-induced toxicity of the head and neck tissues in mice
Authors: Priyanka Chowdhury, George Morcos, Michele Kim, Yuewei Lin, Ling Qin, James Metz, Alexander Lin, Costas Koumenis
Journal: Clinical Cancer Research (2025)

Abstract The effect of FLASH Proton Radiation therapy (F-PRT) in decreasing normal tissue toxicity while maintaining equal tumor control compared to Standard Proton Radiation therapy (S-PRT) has been previously investigated for head and neck tissues in mice using a single dose of either S-PRT/F-PRT. Here, we studied the effect of F-PRT following a hypo-fractionated regimen and in a re-irradiation setting. The head and neck area of C57Bl/6 mice was irradiated with a single dose of 12 Gy of F-PRT (128Gy/s) or S-PRT (0.95 Gy/s) and was followed with a hypo-fractionated re-irradiation scheme (6 Gy x 3). Mice with orthotopic tongue tumors were also irradiated with two different hypo-fractionated regimes of 8 Gy x 3 and 9 Gy x 3 respectively. Compared to the re-irradiation with S-PRT, F-PRT re-irradiated mice mitigate xerostomia by improving salivary flow. Histopathological analysis of the salivary gland showed increased acinar cell atrophy and individual cell death in the submandibular gland in mice re-irradiated with S-PRT compared to the ones re-irradiated with F-PRT. Re-irradiation with hypo-fractionated S-PRT showed a significant increase in the alveolar bone loss compared to F-PRT. Following irradiation with hypo-fractionated F-PRT mice with orthotopic tongue tumors significantly increases the overall survival compared to the ones irradiated with hypo-fractionated S-PRT. This study provides evidence of the sparing effect of F-PRT in minimizing radiation-induced head and neck tissue toxicity in a hypo-fractionated re-irradiation setting. The results support the efficacy of F-PRT for clinical application. Citation Format: Priyanka Chowdhury, George Morcos, Michele Kim, Yuewei Lin, Ling Qin, James Metz, Alexander Lin, Costas Koumenis. Flash proton re-irradiation and hypofractionation alleviate radiation-induced toxicity of the head and neck tissues in mice. [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 A002.
Abstract B013: Autoimmunity mechanisms in combined radiotherapy and immune-checkpoint inhibitor therapy-induced myocarditis
Authors: Shiguang Yu, Nhan T Vu, Tyler Verburg, Bo Lu
Journal: Clinical Cancer Research (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 &amp; 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 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: Samuel Ryu, Alexander Stessin, Charles Mikell, Agnieszka Kowalska, Roberta Seidman, Steven West, Kartik Mani
Journal: Clinical Cancer Research (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 B025: Identifying and exploiting a novel role of FTO in promoting cysteine metabolism for NSCLC therapy
Authors: Nishanth Kuganesan, Stavros Melemenidis, Edward E. Graves, Erinn B. Rankin
Journal: Clinical Cancer Research (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 A009: Targeting DNA damage responsive pathways in cancer therapy
Authors: Junjie Chen
Journal: Clinical Cancer Research (2025)

Abstract DNA double strand breaks (DSBs) result in activation of several key DNA damage response (DDR) kinases including ATM, ATR, and DNA-PK. These protein kinases not only promote DNA damage-induced checkpoint control, but also facilitate DSB repair in humans. Thus, these DDR kinases have become promising drug targets for cancer therapy. However, the benefits of targeting DDR kinases remain to be realized, in part due to the lack of predictive biomarkers. By undertaking CRISPR screens with inhibitors targeting key DDR kinases, we obtained a global and unbiased view of genetic interactions with DDR inhibition. Additionally, we compared the synergistic effects of combining different DDR inhibitors and found that ATM and PARP inhibitors showed remarkable synergy, which depends on the dominant negative function of ATM inhibition. Moreover, to provide comprehensive and unbiased perspective of DDR signaling pathways, we performed 30 fluorescence-activated cell sorting–based genome-wide CRISPR screens with antibodies recognizing distinct endogenous DNA damage–signaling proteins to identify new regulators involved in DNA damage response (DDR). We discovered that proteasome-mediated processing is an early and prerequisite event for cells to trigger camptothecin- and etoposide-induced DDR signaling. Furthermore, we identified PRMT1 and PRMT5 as new modulators that regulate ATM protein level. Additionally, we discovered that GNB1L is a master regulator of DDR signaling via its role as a co-chaperone for PIKK proteins. Collectively, these screens offer a rich resource for further investigation of DDR, which may provide insight into strategies of targeting these DDR pathways to improve therapeutic outcomes. More recently, we have adopted dTAG technology for the investigation of many essential DDR and replication proteins, which provide mechanistic insights into the roles of these essential proteins in genome maintenance. Additionally, we have expanded FACS-based screens for the studies of other cancer-associated pathways and explored key biological processes critical for cancer progression in vivo. These studies will facilitate the development of better therapies for cancer patients. Citation Format: Junjie Chen. Targeting DNA damage responsive pathways in cancer 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 A009.
Abstract IA07: Improving CAR T cell therapy efficacy in hematologic malignancies with low-dose total body irradiation
Authors: Monica L. Guzman
Journal: Clinical Cancer Research (2025)

Abstract Chimeric Antigen Receptor (CAR) T cell therapy represents a significant advance in the treatment of hematologic malignancies, as demonstrated by the high response rates and improved survival in diseases such as acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), Diffuse large cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL). The FDA has approved several CAR T cell therapies, including some approaches targeting CD19 (CART19) for adult and pediatric patients with B-cell malignancies. Response rates for CD19 CART therapy have been quite promising, reaching 80% overall response and 60% complete response; however, relapses are observed at an estimate of 30-40% within the first year. Thus, finding clinically translatable approaches to improve response rates for patients receiving CART19 therapies, such as the potential of LD-TBI, is critical. Multiple mechanisms of CAR T cell therapy resistance include limited persistence of the CAR T cell product upon infusion, CAR T cell exhaustion, and reduced or complete loss of target expression. Here, we will describe the significant role of radiation therapy, particularly low-dose total body irradiation (LD-TBI), in enhancing the long-term response of CAR T cell therapy. LD-TBI can modulate antigen stability, augment the expression of death receptors in tumor cells, and improve the persistence of CAR T cells. Moreover, LD-TBI also enhances lymphodepletion and the trafficking of CAR T cells to the tumor-infiltrated organs. As a result, LD-TBI significantly prolongs the survival of mice bearing lymphoma or B-ALL in combination with anti-CD19 CAR T cells, thereby improving patient outcomes and offering a promising future for cancer treatment. Citation Format: Monica L. Guzman. Improving CAR T cell therapy efficacy in hematologic malignancies with low-dose total body irradiation. [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 IA07
Abstract P010: Monitoring of cancer ferroptosis with [18F]hGTS13, a system xc- specific radiotracer
Authors: Abraham S. Moses, Rim Malek, Mustafa T. Kendirli, Pierre Cheung, Madeleine Landry, Marco Herrera-Barrera, Abbas Khojasteh, Syed Bukhari, Jody Hooper, Melanie Hayden-Gephart, Scott J. Dixon, Lawrence D. Recht, Corinne Beinat
Journal: Clinical Cancer Research (2025)

Abstract Ferroptosis has emerged as a significant process in cancer biology due to its ability to counteract mechanisms of tumor survival and drug resistance. Exploiting this vulnerability is an emerging therapeutic strategy in cancer treatment. System xc- plays a critical role in ferroptosis by regulating the availability of cysteine, a crucial precursor for glutathione synthesis, thereby influencing the cellular antioxidant defense system. We recently reported the development and validation of [18F]hGTS13, a radiolabeled glutamate derivative, as a novel radiopharmaceutical specific for system xc-. We characterized the sensitivity of various cell lines to pro-ferroptotic compounds and evaluated the ability of [18F]hGTS13 to distinguish between sensitive and resistant cell lines and monitor changes in response to ferroptosis-inducing drugs. We then correlated changes in tracer uptake with cellular glutathione content. Furthermore, we performed PET/CT imaging of C6 glioma-bearing rats with [18F]hGTS13, revealing high, sustained uptake within the intracranial glioma, and demonstrated effective blocking of system xc- in vivo using imidazole ketone erastin. In summary, [18F]hGTS13 represents a promising tool for distinguishing cell types that demonstrate sensitivity or resistance to ferroptotic therapies, and monitoring of ferroptosis-inducing drug engagement. Its successful application in preclinical models make it a valuable asset for advancing our understanding of glioma biology and evaluating the efficacy of emerging ferroptosis-targeted therapies. As synergistic ferroptosis/radionuclide therapies are currently under investigation, [18F]hGTS13 represents a valuable tool for identifying patients who would benefit from combinatorial therapy, and monitoring treatment response in glioma and other cancers. Citation Format: Abraham S. Moses, Rim Malek, Mustafa T. Kendirli, Pierre Cheung, Madeleine Landry, Marco Herrera-Barrera, Abbas Khojasteh, Syed Bukhari, Jody Hooper, Melanie Hayden-Gephart, Scott J. Dixon, Lawrence D. Recht, Corinne Beinat.Monitoring of cancer ferroptosis with [18F]hGTS13, a system xc- specific radiotracer.[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 P010
Abstract B033: Long-Term quality of life and hearing preservation after stereotactic radiosurgery for vestibular schwannoma
Authors: Shayzal Siddiqui, Joseph S. Lee, Julia Abbo, Jessica Cummings, Avi Desai, Inga S. Grills, Peter Y. Chen, Jeffrey Jacob, Kuei C. Lee
Journal: Clinical Cancer Research (2025)

Abstract Purpose/Objective(s): The aim of this study is to evaluate the long-term quality of life (QOL) and hearing preservation outcomes following definitive single-fraction Gamma Knife stereotactic radiosurgery (GKSRS) for vestibular schwannoma (VS). Materials/Methods: Baseline and follow-up QOL and audiogram data were collected from our prospectively maintained institutional database of VS patients treated with single-fraction GKSRS from 2006 to 2023. QOL metrics included the Hearing Handicap Inventory (HHI), Dizziness Handicap Inventory (DHI), Tinnitus Handicap Inventory (THI), and the 36-Item Short-Form Survey (SF-36). Serviceable hearing preservation was classified according to the Gardner-Robertson scale using pure-tone average (PTA) and speech discrimination (SD). Linear mixed-effects models were constructed for each QOL metric over time. Results: A total of 388 patients (median age 61 years) were included with a median follow-up of 48 months. Median tumor size was 1.6 cm (interquartile range [IQR] 1.1-2.1 cm), with a median tumor volume of 0.6 cc (IQR 0.2-1.6 cc). Most patients received a prescription marginal dose of 12.5 Gy with a median cochlear mean dose of 2.7 Gy (IQR 1.9-3.8 Gy). Baseline median HHI, DHI, THI, and SF-36 scores were 28, 12, 12, and 73 respectively. Linear mixed-effects analyses indicated no statistically significant decline in any of these QOL metrics up to 7 years after GKSRS. Of patients with serviceable hearing at baseline, hearing preservation was maintained in 79% at 12 months, 67% at 2 years, and 68% at 3 years. Conclusion: GKSRS preserves long-term patient quality of life and serviceable hearing in the definitive management of VS. Citation Format: Shayzal Siddiqui, Joseph S. Lee, Julia Abbo, Jessica Cummings, Avi Desai, Inga S. Grills, Peter Y. Chen, Jeffrey Jacob, Kuei C. Lee. Long-Term quality of life and hearing preservation after stereotactic radiosurgery for vestibular schwannoma. [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 B033.
Abstract IA05: Toward multi-modal foundation AI for precision oncology
Authors: Ruijiang Li
Journal: Clinical Cancer Research (2025)

Abstract Clinical decision-making is a complex process that involves information obtained from multiple data modalities. Artificial intelligence (AI) approaches that can effectively integrate multi-modal data hold significant promise to advance clinical care. Two areas of success are imaging and digital pathology, where AI has shown great potential to improve cancer diagnosis and treatment. This talk will provide an overview on how AI can be used to extract information from imaging and pathology and identify prognostic and predictive biomarkers for personalized cancer treatment. In particular, I will present our recent work on building multi-modal foundation models for precision oncology. Citation Format: Ruijiang Li. Toward multi-modal foundation AI for precision oncology. [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 IA05