tbuckley/cabot-search huggingface dataset:
Abstract IA12: Enhancing radiation-induced anti-tumoral immune responses with PARP inhibitors in PDAC and DIPG
Authors: Meredith M. Morgan
Journal: Clinical Cancer Research (2025)

Abstract Inhibitors of PARP sensitize cancers to radiation through mechanisms involving DNA damage, replication stress, and PARP trapping. These mechanisms may also activate innate immune signaling leading to Type I Interferon (T1IFN) production. The overall goal of this talk is to explore the hypothesis that PARP inhibitors potentiate radiation-induced T1IFN to activate an anti-tumoral immune response in pancreatic cancer (PDAC) and H3K27 altered-diffuse midline glioma (DMG). Preclinical data supporting this hypothesis will be described including the effects PARP1/2 inhibition (olaparib) as well as PARP1 selective inhibition (AZD5305, AZD4974) in combination with radiation on T1IFN production, modulation of the tumor microenvironment, and the contributions of CD8+ T and NK cells to anti-tumor immune responses in PDAC and DMG, respectively. Furthermore, the translation of these preclinical studies to early phase clinical trials will be discussed. Citation Format: Meredith M. Morgan. Enhancing radiation-induced anti-tumoral immune responses with PARP inhibitors in PDAC and DIPG. [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 IA12
Abstract B021: FTO inhibition enhances the therapeutic index of radiation therapy in head and neck cancer
Authors: 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
Journal: Clinical Cancer Research (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 IA10: Immune side effects in ferroptosis-targeted therapy
Authors: Daolin Tang
Journal: Clinical Cancer Research (2025)

Abstract Ferroptosis, a regulated form of cell death driven by lipid peroxidation, has emerged as a promising strategy in cancer therapy, complementing established modalities such as chemotherapy, immunotherapy, and radiotherapy. While the mechanisms of ferroptosis are highly context-dependent, the classical approach to inducing ferroptosis involves targeting the GPX4 (glutathione peroxidase 4) pathway. GPX4 is a critical enzyme that detoxifies lipid hydroperoxides (L-OOH) by reducing them to non-toxic lipid alcohols (L-OH) using glutathione (GSH) as a cofactor, thereby preventing lipid peroxidation and ferroptotic cell death. Although targeting GPX4 effectively induces ferroptosis in cancer cells, its widespread expression in both tumor and normal cells presents challenges. Direct inhibition of GPX4 can lead to unintended immune cell death, potentially impairing antitumor immunity by reducing the activity of cytotoxic T cells and other immune effectors essential for robust immune responses. This immunosuppressive effect could undermine the therapeutic benefits of ferroptosis-targeted therapies. To overcome this limitation, alternative strategies have been explored. For instance, non-direct targeting of GPX4, such as inducing TRIM25-mediated degradation of GPX4, has shown promise in selectively killing cancer cells while sparing normal tissues and preserving immune function. This approach minimizes toxicity and maintains the activity of key immune cells, including cytotoxic T cells, enhancing the overall efficacy of ferroptosis-based treatments. Understanding the potential risks and immune-related side effects of ferroptosis-targeted therapies is critical for their successful clinical translation. Citation Format: Daolin Tang. Immune side effects in ferroptosis-targeted 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 IA10
Abstract B002: Pre-vaccine radiation and CTLA-4 blockade increase adjuvant effects of SARS-COV-2 mRNA vaccines
Authors: Adam Grippin, Sage Copling, Andrew Kim, Elliana Young, Betty Kim, John Heymach, Wen Jiang, Steven H Lin
Journal: Clinical Cancer Research (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&amp;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 IA09: Radiotherapy immunotherapy interactions: What determines success or failure?
Authors: Ralph R. Weichselbaum
Journal: Clinical Cancer Research (2025)

Abstract Radiation therapy (RT) can both stimulate antitumor immunity and induce immunosuppressive responses, complicating its therapeutic efficacy. Data indicate that certain patient subsets—such as those undergoing combination treatment with radiation and immune-oncology drugs and/or targeted therapies may benefit from strategies that target immunosuppression or metastasis-promoting factors. One of the key challenges is the heterogeneous and context-dependent nature of myeloid suppressive states in the tumor microenvironment, which often leads to resistance to RT and immunotherapy. RT has been shown to skew myeloid plasticity towards immune suppression by expanding myeloid-derived suppressor cell (MDSC) populations, increasing their trafficking into tumor tissues, and promoting the development of suppressive macrophage subsets. Targeting myeloid cell plasticity post-RT presents a promising therapeutic strategy. Interventions that block the systemic induction of immunosuppressive myeloid cells to inhibit their trafficking to tumors, or those that promote the conversion of suppressive myeloid cells into anti-tumor populations could enhance the effectiveness of RT. Additionally, radiation-induced proteins that can be inhibited or amplified may provide a potential avenue to overcome the limitations of RT alone, and in combination with immunotherapy. Citation Format: Ralph R. Weichselbaum. Radiotherapy immunotherapy interactions: What determines success or failure?. [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 IA09
Abstract IA11: FLASH – Where are we and where are we going in the clinical trial future space
Authors: Jeffrey Buchsbaum
Journal: Clinical Cancer Research (2025)

Abstract FLASH is one of the most promising findings in radiation therapy in the last decade. If the FLASH effect takes place, it is thought that normal tissue is spared while tumor tissue is not spared. The biology of FLASH is not fully understood. Exactly when the FLASH effect occurs, if it occurs with every fraction delivered in the same way if it occurs at all, and how to test it in a clinical trial are the real questions that need to be addressed. All of these are complex issues that will be hard to study across OAR’s, populations, and technologies. The first part of the talk will review the published data on clinical trial needs including the quality assurance and other processes needed to open a trial with focus on the NCTN. IROC data and other data will be presented. The second part of the talk will be a review of the clinical data, and pre-clinical data, currently being collected and evaluated. Two P01 grants will be reviewed and discussed (their public components). The talk will conclude with some models for trials that have been proposed as well as a possible thought experiment looking at next steps and moving forward. Citation Format: Jeffrey Buchsbaum. FLASH – Where are we and where are we going in the clinical trial future space. [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 IA11
Abstract B018: GSK3β inhibition synergizes with radiation therapy to stimulate type-I interferon and anti-tumor effects in lung cancer
Authors: Chen Braun, Nan Li, Steven H. Lin
Journal: Clinical Cancer Research (2025)

Abstract Radiation therapy (RT) is widely used to treat various tumor types to minimize the risk of recurrence. However, only a subset of patients experiences significant responses to RT, primarily due to inadequate immune responses within lung tumors. Therefore, there is a pressing need to develop innovative strategies to overcome tumor immunosuppression following RT. In this study, we investigated alternative mediators that could mitigate the effects of immunosuppression in lung cancer cells. We screened over 700 pharmacological inhibitors using an interferon beta-1(IFNβ1)-luciferase reporter system, identifying a group of glycogen synthase kinase 3 beta inhibitors (GSK3βi) that enhanced IFNβ1 expression. Notably, one GSK3βi agent, Kenpaullone, significantly induced IFNβ1 in multiple lung cancer cell lines. Compared to other GSK3β inhibitors, it exhibited superior synergy (over 20-fold) without inducing cellular cytotoxicity, even at high doses (30 µM). Furthermore, our syngeneic mouse models showed that GSK3βi and RT reduced tumor size more effectively than monotherapy and enhanced immunologic response in these tumors. This pharmacological-RT combination approach holds promise for improving the immunologic response to RT in lung cancer patients, potentially reducing tumor burden in those that already exhausted standard of care treatment options. Citation Format: Chen Braun Nan Li, Steven H. Lin. GSK3β inhibition synergizes with radiation therapy to stimulate type-I interferon and anti-tumor effects in lung 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 B018
Abstract B009: Abscopal effect in metastatic melanoma: generating clinical insights from radiation-induced immune response
Authors: Baovy N. Phan
Journal: Clinical Cancer Research (2025)

Abstract Despite modern advancements in systemic therapies, melanoma remains a highly malignant cancer, with persistent resistance to therapies such as checkpoint inhibitors and inhibitors of mutated BRAF V600E. Current therapy for targeting metastatic melanoma remains palliative radiation therapy, particularly directly at symptomatic sites. Extraordinarily, few case studies have reported locally targeted radiation resulting in regression of distal non-targeted lesions. This rare phenomenon was coined as the abscopal effect and presents with increasing frequency due to the advancement of systemic therapy. This narrative review attempts to understand the underlying mechanisms behind the abscopal effect through clinical data from 21 melanoma patients reported in 19 case studies. Case identification focused on patients who had progressed on systemic therapy before receiving radiation. Our study observed a mean total Gy of 34 (median total 30 Gy) and mean fractionation Gy of 8 (median fractionation 7.5 Gy) with increased frequency of reported abscopal effects with incorporation of modern systemic immunotherapies. The reviewed cases suggest that combining radiation with immunotherapy may enhance systemic tumor control, though further research is required to better understand the underlying mechanisms and improve treatment outcomes. Citation Format: Baovy N. Phan. Abscopal effect in metastatic melanoma: generating clinical insights from radiation-induced immune response. [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 B009.
Abstract B015: PLK4 inhibition as a strategy to enhance non-small cell lung cancer radiosensitivity
Authors: Irma G. Dominguez-Vigil, Kishore Banik, Marta John Baro, Joseph N. Contessa, Thomas J. Hayman
Journal: Clinical Cancer Research (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 A013: Shikonin, a strong inhibitor of Phosphoinositide 3-Kinase (PI3K) and Mitogen-Activated Protein (MAP) Kinase pathways, induces cell death in UV-B irradiated B16F10 melanoma cells
Authors: Aalim Maqsood Bhat, Sheikh Tasduq Abdullah
Journal: Clinical Cancer Research (2025)

Abstract Ultraviolet (UV) radiation-induced skin damage plays a pivotal role in the pathogenesis of melanoma, a highly aggressive and fatal form of skin cancer. Shikonin, naturally occurring nathoquinone , is well-known for its inhibitory effects on phosphoinositide 3-kinase (PI3K) and mitogen-activated protein (MAP) kinase signaling pathways. It has previously been demonstrated to exert effects against various non-melanoma skin cancers. In this study, we investigated the effects of Shikonin treatment on UVB-irradiated B16F10 melanoma cells, revealing a dose-dependent reduction in cell viability and an enhancement of apoptosis. Invitro findings indicate that the pro-apoptotic effects of shikonin in UVB-exposed B16F10 cells are mediated by several mechanisms, including the generation of reactive oxygen species (ROS), modulation of the antioxidant defense response, and mitochondrial membrane potential (ΔΨM) depolarization. Further supporting the apoptotic role of Shikonin, we observed DNA fragmentation, caspase activation, poly(ADP-ribose) polymerase (PARP) cleavage, and an increase in sub-G2 cell populations. Shikonin treatment also significantly attenuated MEK-ERK signaling, influenced the PI3K/Akt pathway, and potentially inhibited UVB-induced nuclear translocation of NF-κB. Additionally, co-treatment with UVB and Shikonin led to a decrease in the Bcl-2/Bax ratio and upregulated the expression of pro-apoptotic proteins Bax and caspases. Collectively, these data suggest that Shikonin may act as a potential therapeutic agent for melanoma when combined with UVB exposure, providing a novel avenue for future treatment strategies. Citation Format: Aalim Maqsood Bhat, Sheikh Tasduq Abdullah. Shikonin, a strong inhibitor of Phosphoinositide 3-Kinase (PI3K) and Mitogen-Activated Protein (MAP) Kinase pathways, induces cell death in UV-B irradiated B16F10 melanoma 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 A013.
Abstract B006: Targeting REV-ERB/RORα/IRF3 axis to enhance radiation-induced immune response in cancer radiotherapy
Authors: Nan LI, Chen Bruan, Steven Hsesheng Lin
Journal: Clinical Cancer Research (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.