Ataxia Telangiectasia Mutated Research Articles

Genotoxicity associated with retroviral CAR transduction of ATM-deficient T cells.

Somatic variants in DNA damage-response genes such as ATM are widespread in hematologic malignancies. ATM protein is essential for double-strand DNA break repair. Germline ATM-deficiencies underlie ataxia-telangiectasia (A-T), a disease manifested by radio-sensitivity, immunodeficiency and predisposition to lymphoid malignancies. A-T patients diagnosed with malignancies have poor tolerance to chemotherapy or radiation. We investigated chimeric-antigen receptor (CAR) T cells using primary T-cells from patients with A-T (ATM-/-), heterozygote donors (ATM+/-) and healthy donors. ATM-/- T-cells proliferate and can be successfully transduced with CARs, though functional impairment of ATM-/- CAR-T cells was observed. Retroviral transduction of the CAR in ATM-/- T-cells resulted in high rates of chromosomal lesions at CAR insertion sites, as confirmed by next-generation long-read sequencing. This work suggests that ATM is essential to preserve genome integrity of CAR-T cells during retroviral manufacturing, and its lack poses a risk of chromosomal translocations and potential leukemogenicity.

Microcephaly and Its Related Syndromes: Classification, Genetic, Clinical, and Rehabilitative Considerations

AbstractMicrocephaly, a form of cortical cortex malformation, results from abnormal cellular production and proliferation, identified when the occipital frontal head circumference (OFC) falls two or more standard deviations (SDs) below the expected average for age, gender, and population. Severity is classified based on SD: mild (OFC < 2 SD) or severe (OFC < 3 SD). While microcephaly can lead to developmental delay, intellectual disability, epilepsy, and cerebral palsy, not all cases exhibit these issues. Classified as primary/congenital or secondary/postnatal, microcephaly can stem from genetic or acquired factors in both types. Congenital microcephaly origins vary, while secondary microcephaly is characterized by normal OFC at birth, followed by a decrease within the first year, often associated with progressive cognitive and motor impairments. Primary hereditary microcephaly (MCPH), or microcephaly vera, is genetically diverse, with 28 related genes (MCPH1 to MCPH28) encoding proteins linked to centrosomes and progenitor cell mitosis in the brain ventricle's neuroepithelium. Defects in deoxyribonucleic acid (DNA) repair pathways (e.g., NBN, FANCA, ATR, ATM genes) can lead to microcephaly by impairing DNA repair. Enzyme deficiencies in metabolic pathways may also contribute, causing toxic metabolite accumulation or essential metabolite loss (microcephaly of metabolic origin). Acquired congenital microcephaly may result from ischemic or infectious processes, drugs, radiation, maternal diseases during pregnancy, with damage influenced by fetal genetics, environmental interactions, developmental stage, and exposure intensity/duration. Diagnostic workup includes electroencephalogram, ophthalmological, auditory, magnetic resonance imaging, metabolic, echocardiogram, and infection screening tests, alongside genetic evaluations like cytogenetic studies, fluorescence in situ hybridization, comparative genomic microarray-hybridization, single-nucleotide microarray-polymorphism, and exome sequencing. Symptomatic treatment is available, and genetic counseling is crucial for affected families.

A rare case of TFEB/6p21/VEGFA-amplified renal cell carcinoma diagnosed by whole-exome sequencing: clinicopathological and genetic feature report and literature review

BackgroundTFEB/6p21/VEGFA-amplified renal cell carcinoma (RCC) is rare and difficult to diagnose, with diverse histological patterns and immunohistochemical and poorly defined molecular genetic characteristics.Case presentationWe report a case of a 63-year-old male admitted in 2017 with complex histomorphology, three morphological features of clear cell, eosinophilic and papillary RCC and resembling areas of glomerular and tubular formation. The immunophenotype also showed a mixture of CD10 and P504s. RCC with a high suspicion of collision tumors was indicated according to the 2014 WHO classification system; no precise diagnosis was possible. The patient was diagnosed at a different hospital with poorly differentiated lung squamous cell carcinoma one year after RCC surgery. We exploited molecular technology advances to retrospectively investigate the patient’s molecular genetic alterations by whole-exome sequencing. The results revealed a 6p21 amplification in VEGFA and TFEB gene acquisition absent in other RCC subtypes. Clear cell, papillary, chromophobe, TFE3-translocation, eosinophilic solid and cystic RCC were excluded. Strong TFEB and Melan-A protein positivity prompted rediagnosis as TFEB/6p21/VEGFA-amplified RCC as per 2022 WHO classification. TMB-L (low tumor mutational load), CCND3 gene acquisition and MRE11A and ATM gene deletion mutations indicated sensitivity to PD-1/PD-L1 inhibitor combinations and the FDA-approved targeted agents Niraparib (Grade C), Olaparib (Grade C), Rucaparib (Grade C) and Talazoparib (Class C). GO (Gene Ontology) and KEGG enrichment analyses revealed major mutations and abnormal CNVs in genes involved in biological processes such as the TGF-β, Hippo, E-cadherin, lysosomal biogenesis and autophagy signaling pathways, biofilm synthesis cell adhesion substance metabolism regulation and others. We compared TFEB/6p21/VEGFA-amplified with TFEB-translocated RCC; significant differences in disease onset age, histological patterns, pathological stages, clinical prognoses, and genetic characteristics were revealed.ConclusionWe clarified the patient’s challenging diagnosis and discussed the clinicopathology, immunophenotype, differential diagnosis, and molecular genetic information regarding TFEB/6p21/VEGFA-amplified RCC via exome analysis and a literature review.

Clinico-genomic findings, molecular docking, and mutational spectrum in an understudied population with breast cancer patients from KP, Pakistan

In this study, we report the mutational profiles, pathogenicity, and their association with different clinicopathologic and sociogenetic factors in patients with Pashtun ethnicity for the first time. A total of 19 FFPE blocks of invasive ductal carcinoma (IDC) from the Breast Cancer (BC) tissue and 6 normal FFPE blocks were analyzed by whole-exome sequencing (WES). Various somatic and germline mutations were identified in cancer-related genes, i.e., ATM, CHEK2, PALB2, and XRCC2. Among a total of 18 mutations, 14 mutations were somatic and 4 were germline. The ATM gene exhibited the maximum number of mutations (11/18), followed by CHEK2 (3/18), PALB2 (3/18), and XRCC2 (1/18). Except one frameshift deletion, all other 17 mutations were nonsynonymous single-nucleotide variants (SNVs). SIFT prediction revealed 7/18 (38.8%) mutations as deleterious. PolyPhen-2 and MutationTaster identified 5/18 (27.7%) mutations as probably damaging and 10/18 (55.5%) mutations as disease-causing, respectively. Mutations like PALB2 p.Q559R (6/19; 31.5%), XRCC2 p.R188H (5/19; 26.31%), and ATM p.D1853N (4/19; 21.05%) were recurrent mutations and proposed to have a biomarker potential. The protein network prediction was performed using GeneMANIA and STRING. ISPRED-SEQ indicated three interaction site mutations which were further used for molecular dynamic simulation. An average increase in the radius of gyration was observed in all three mutated proteins revealing their perturbed folding behavior. Obtained SNVs were further correlated with various parameters related to the clinicopathological status of the tumors. Three mutation positions (ATMp. D1853N, CHEK2 p.M314I, and PALB2 p.T1029S) were found to be highly conserved. Finally, the wild- and mutant-type proteins were screened for two drugs: elagolix (DrugBank ID: DB11979) and LTS0102038 (a triterpenoid, isolated from the anticancer medicinal plant Fagonia indica). Comparatively, a higher number of interactions were noted for normal ATM with both compounds, as compared to mutants.

Abstract PO1-22-05: Radiation Therapy Toxicities and Survival Outcomes in Monoallelic ATM Variant Carriers with Non-Metastatic Breast Cancer: A Retrospective Analysis

Abstract Radiation Therapy Toxicities and Survival Outcomes in Monoallelic ATM Variant Carriers with Non-Metastatic Breast Cancer: A Retrospective Analysis Rayan Bensenane1 MD, Arnaud Beddok1,2,3 MD, Nadine Andrieu4 PhD, Fabienne Lesueur4 PhD, Eve Cavaciuti 4 MSc, Dorothee Le Gal4 MSc, Eon-Marchais Severine4 PhD, Dominique Stoppa Lyonnet 5MD PhD, Youlia Kirova1 MD 1. Institut Curie, PSL Research University, Radiation Oncology Department, Paris/Saint-Cloud/Orsay, France. 2. Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, 125 Nashua St., Boston, MA, 02114, USA 3. Institut Curie, PSL Research University, University Paris Saclay, Inserm LITO U1288 Orsay, France 4. Inserm, U900, Institut Curie, PSL Research University, Mines ParisTech, Paris, France Abstract (characters: 2952; max 3400 characters, not include spaces) Background: The Ataxia-Telangiectasia Mutated (ATM) gene, involved in the repair of DNA double-strand breaks, can contribute to radiosensitivity when a bi-allelic variant is present and lead to Ataxia-Telangiectasia syndrome. Moreover, monoallelic ATM pathologic variant (PV) carriers, especially women, has an estimated occurrence rate of 0.5-1% globally and face a 2 to 3-fold increased risk of developing breast cancer. Despite evidence of in vitro radiosensitivity in cells derived from monoallelic variant carriers, there is a dearth of patient studies examining the risk of radiation-induced toxicity. This study aims to explore radiation therapy (RT) toxicities in non-metastatic breast cancer women carrying a germline monoallelic ATM variant, compared to non-carriers. Methods: A retrospective study was conducted on patients treated at Institut Curie, Paris from 1999 to 2014 and participating to CoF-AT (a French national study) and GENESIS database. ATM variant screenings encompassed both PV and non-PV, with toxicities evaluated using CTCAE v.5. Variants were classified as pathogenic, variant of unknown significance (VUS), or benign. Follow-up started from age/date at breast cancer to acute, late toxicities, disease recurrence or last news. Survival and toxicity comparisons were made using Kaplan-Meier survival analysis and Chi-square tests, respectively, with a significance level of α set at 0.05. Results: Among 50 patients, nine were ATM variant carriers (3 PV/5 VUS/1 benign), and 41 were non-carriers. Most patients had no smoking history (68%), and invasive ductal carcinoma was the predominant diagnosis (82%). The majority underwent breast-conservative surgery (80%), and the dominant RT techniques were 3D-Conformational Radiation Therapy (70%) and Isocentric Lateral Decubitus (30%). The median RT dose was 50 Gy over an average period of 36.5 days. With a median follow-up of 12 years post-diagnosis, no significant difference in acute dermatitis, esophagitis, lymphedema, cutaneous fibrosis, telangiectasia, or heart disease was observed between the groups. Analysis of overall survival (OS) showed a 5-year OS of 98%, decreasing to 89% at 10 years. For ATM variant carriers, the OS at 5, 10, and 15 years was 100%, 89%, and 89%, respectively, similar to non-carriers. Kaplan-Meier analysis revealed no significant differences in 5, 10, and 15-year overall survival, progression-free survival, local failure-specific survival, and contralateral breast cancer rates between the groups. Conclusion: In non-metastatic breast cancer patients, monoallelic ATM variant carrier status does not significantly influence acute or late RT toxicities and survival outcomes. These findings, derived from a small cohort, highlight the need for prospective studies for further validation. Table: Acute and Late Toxicities Post-Radiation Therapy in Monoallelic ATM Variant Carriers vs Non-Carriers * Pearson/Chi2 test ; NS: non significant at α=0.05; ATM +/+: wild type for ATM; ATM +/- : ATM monoallelic germline variant carrier Citation Format: Rayan BENSENANE, Youlia Kirova, Arnaud BEDDOK, Andine ANDRIEU, Fabienne Lesueur, Eve CAVACIUTI, Dorothée Le GAL, Severine EON-MARCHAIS, Dominique STOPPA LYONNET. Radiation Therapy Toxicities and Survival Outcomes in Monoallelic ATM Variant Carriers with Non-Metastatic Breast Cancer: A Retrospective Analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-22-05.

Abstract PO1-22-03: Radiation Toxicity and Treatment Outcomes in Breast Cancer Patients with ATM Pathogenic and VUS Mutations: Implications for Personalized Therapy

Abstract Introduction: Previous studies have shown that ATM (ataxia-telangiectasia mutated) mutations may be associated with increased radiation sensitivity and altered treatment response. However, there is a limited understanding of the clinical implications and optimal management strategies for breast cancer patients with ATM mutations receiving radiotherapy (RT). The aim of our study is to assess the impact of ATM mutations on radiation response and treatment outcomes in breast cancer patients undergoing RT. Material and Methods: A total of 79 female patients diagnosed with breast cancer were included in the study, with 31 (39.3%) having pathogenic (P) and likely pathogenic (LP) variants (all of the variants were heterozygous) and 48 (60.8%) having VUS variants detected through whole ATM gene sequencing screening for patients in accordance with NCCN clinical practice guideline. Statistical analysis, including descriptive, graphical, and inferential methods, such as the Kolmogorov-Smirnov test, Mann-Whitney U Test, and Chi-square tests, was conducted using SPSS version 25.0 to evaluate the normal distribution of continuous variable scores and perform quantitative and qualitative comparisons between groups at a 95% confidence level (p < 0.05). Results: The median age of the patients was 44 years (range: 24-74), with 75% of them being 50 years old or younger .The rate of breast cancer in patients with VUS variants was significantly higher in those aged 50 and below compared to those with P/LP variants (83% vs. 61%, p=0.028). There was no statistically significant difference in clinical stage, tumour histological type, and molecular subtype classification based on ATM gene variant type (P/LP vs. VUS) among the patients (p>0.05), but the rate of high tumour grade was significantly higher in the VUS variant group (65% vs. 40%, p=0.034). The rate of patients who received RT was 87%, with 26 patients receiving radiation to the breast or chest wall and 43 patients receiving additional regional lymph node irradiation. There were no statistically significant differences in surgical and systemic treatment types and RT dose based on ATM gene variant type (P/LP vs. VUS) (p>0.05). Among the patients who received RT, 33 (48%) experienced early-stage skin reactions, and 15 (22%) experienced late-stage skin reactions according to Common Terminology Criteria for Adverse Events (CTCAE) v5. No Grade 3, 4 and 5 early and late toxicity were observed . The rate of early (83% vs. 23%; p< 0.001) and late (35% vs. 13%; p=0.029) skin reactions was significantly higher in the P/LP variant group compared to the VUS variant group. Grade I lymphedema was observed in 2 (2.5%) patients, 1 (3.2%) in the P/LP group and 1 (2.1%) in the VUS group (p>0.05). Among the 23 patients who underwent breast reconstruction, 1 (4%) had implant revision and 1 (4%) experienced implant loss, both of which were observed in the pathogenic variant group (p>0.05). Conclusion: Limited clinical data exists on RT toxicity in breast cancer patients with ATM gene mutations, and clear guidelines for decision-making are lacking. Our study revealed higher rates of acute and chronic skin reactions in the P/LP variant group, highlighting the need for further investigation into the impact of these variants on treatment outcomes and patient management. However, it is crucial to manage these reactions effectively and not allow them to hinder treatment. Additional research and interventions are warranted to better understand and address these reactions, aiming to enhance the overall treatment experience and outcomes for patients with ATM gene mutations. Citation Format: Evrim Tezcanli, Seda Eroz, Ugur Ozbek, Ahmet Yesilyurt, CIHAN URAS, Nuran Bese. Radiation Toxicity and Treatment Outcomes in Breast Cancer Patients with ATM Pathogenic and VUS Mutations: Implications for Personalized Therapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-22-03.

Abstract PO1-10-01: Racial/Ethnic Disparities in Rates of Pathological Complete Response and Survival in Patients with Inflammatory Breast Cancer

Abstract Radiation Therapy Toxicities and Survival Outcomes in Monoallelic ATM Variant Carriers with Non-Metastatic Breast Cancer: A Retrospective Analysis Rayan Bensenane1 MD, Arnaud Beddok1,2,3 MD, Nadine Andrieu4 PhD, Fabienne Lesueur4 PhD, Eve Cavaciuti 4 MSc, Dorothee Le Gal4 MSc, Eon-Marchais Severine4 PhD, Dominique Stoppa Lyonnet 5MD PhD, Youlia Kirova1 MD 1. Institut Curie, PSL Research University, Radiation Oncology Department, Paris/Saint-Cloud/Orsay, France. 2. Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, 125 Nashua St., Boston, MA, 02114, USA 3. Institut Curie, PSL Research University, University Paris Saclay, Inserm LITO U1288 Orsay, France 4. Inserm, U900, Institut Curie, PSL Research University, Mines ParisTech, Paris, France 5.Department of Genetics, Institut Curie; Inserm U830, Institut Curie; Paris-Cité University Abstract (characters: 2952; max 3400 characters, not include spaces) Background: The Ataxia-Telangiectasia Mutated (ATM) gene, involved in the repair of DNA double-strand breaks, can contribute to radiosensitivity when a bi-allelic variant is present and lead to Ataxia-Telangiectasia syndrome. Moreover, monoallelic ATM pathologic variant (PV) carriers, especially women, has an estimated occurrence rate of 0.5-1% globally and face a 2 to 3-fold increased risk of developing breast cancer. Despite evidence of in vitro radiosensitivity in cells derived from monoallelic variant carriers, there is a dearth of patient studies examining the risk of radiation-induced toxicity. This study aims to explore radiation therapy (RT) toxicities in non-metastatic breast cancer women carrying a germline monoallelic ATM variant, compared to non-carriers. Methods: A retrospective study was conducted on patients treated at Institut Curie, Paris from 1999 to 2014 and participating to CoF-AT (a French national study) and GENESIS database. ATM variant screenings encompassed both PV and non-PV, with toxicities evaluated using CTCAE v.5. Variants were classified as pathogenic, variant of unknown significance (VUS), or benign. Follow-up started from age/date at breast cancer to acute, late toxicities, disease recurrence or last news. Survival and toxicity comparisons were made using Kaplan-Meier survival analysis and Chi-square tests, respectively, with a significance level of α set at 0.05. Results: Among 50 patients, nine were ATM variant carriers (3 PV/5 VUS/1 benign), and 41 were non-carriers. Most patients had no smoking history (68%), and invasive ductal carcinoma was the predominant diagnosis (82%). The majority underwent breast-conservative surgery (80%), and the dominant RT techniques were 3D-Conformational Radiation Therapy (70%) and Isocentric Lateral Decubitus (30%). The median RT dose was 50 Gy over an average period of 36.5 days. With a median follow-up of 12 years post-diagnosis, no significant difference in acute dermatitis, esophagitis, lymphedema, cutaneous fibrosis, telangiectasia, or heart disease was observed between the groups. Analysis of overall survival (OS) showed a 5-year OS of 98%, decreasing to 89% at 10 years. For ATM variant carriers, the OS at 5, 10, and 15 years was 100%, 89%, and 89%, respectively, similar to non-carriers. Kaplan-Meier analysis revealed no significant differences in 5, 10, and 15-year overall survival, progression-free survival, local failure-specific survival, and contralateral breast cancer rates between the groups. Conclusion: In non-metastatic breast cancer patients, monoallelic ATM variant carrier status does not significantly influence acute or late RT toxicities and survival outcomes. These findings, derived from a small cohort, highlight the need for prospective studies for further validation. Table: Acute and Late Toxicities Post-Radiation Therapy in Monoallelic ATM Variant Carriers vs Non-Carriers Citation Format: Rebecca Zasloff, Samantha Thomas, Kendra Parrish, Astrid Botty van de Bruele, Gayle DiLalla, Maggie DiNome, Laura Rosenberger, Hannah Woriax, E Shelley Hwang, Jennifer Plichta, Akiko Chiba. Racial/Ethnic Disparities in Rates of Pathological Complete Response and Survival in Patients with Inflammatory Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-10-01.

Gastric cancer actionable genomic alterations across diverse populations worldwide and pharmacogenomics strategies based on precision oncology

Introduction: Gastric cancer is one of the most prevalent types of cancer worldwide. The World Health Organization (WHO), the International Agency for Research on Cancer (IARC), and the Global Cancer Statistics (GLOBOCAN) reported an age standardized global incidence rate of 9.2 per 100,000 individuals for gastric cancer in 2022, with a mortality rate of 6.1. Despite considerable progress in precision oncology through the efforts of international consortia, understanding the genomic features and their influence on the effectiveness of anti-cancer treatments across diverse ethnic groups remains essential.Methods: Our study aimed to address this need by conducting integrated in silico analyses to identify actionable genomic alterations in gastric cancer driver genes, assess their impact using deleteriousness scores, and determine allele frequencies across nine global populations: European Finnish, European non-Finnish, Latino, East Asian, South Asian, African, Middle Eastern, Ashkenazi Jewish, and Amish. Furthermore, our goal was to prioritize targeted therapeutic strategies based on pharmacogenomics clinical guidelines, in silico drug prescriptions, and clinical trial data.Results: Our comprehensive analysis examined 275,634 variants within 60 gastric cancer driver genes from 730,947 exome sequences and 76,215 whole-genome sequences from unrelated individuals, identifying 13,542 annotated and predicted oncogenic variants. We prioritized the most prevalent and deleterious oncogenic variants for subsequent pharmacogenomics testing. Additionally, we discovered actionable genomic alterations in the ARID1A, ATM, BCOR, ERBB2, ERBB3, CDKN2A, KIT, PIK3CA, PTEN, NTRK3, TP53, and CDKN2A genes that could enhance the efficacy of anti-cancer therapies, as suggested by in silico drug prescription analyses, reviews of current pharmacogenomics clinical guidelines, and evaluations of phase III and IV clinical trials targeting gastric cancer driver proteins.Discussion: These findings underline the urgency of consolidating efforts to devise effective prevention measures, invest in genomic profiling for underrepresented populations, and ensure the inclusion of ethnic minorities in future clinical trials and cancer research in developed countries.

Abstract PO4-09-01: Survival of patients harboring a germline ATM pathogenic/likely pathogenic variant and diagnosed with breast cancer: A case-control study

Abstract Introduction: Patients harboring a pathogenic/likely pathogenic variant (PV/LPV) in ATM present an increased lifetime risk of developing breast cancer (BC). The survival outcomes of these patients are not well-known. Methods: Retrospective, multicentric case-control study. Case group included patients with stage I-III breast cancer harboring a PV/LPV in ATM. Control group included patients with stage I-III breast cancer with a negative germline BC multigene panel testing including ATM gene analysis. Clinical outcomes defined as locoregional relapse-free survival (RFS), distant RFS and breast cancer specific survival were compared between cases and controls. Case group was obtained from five hereditary cancer units and control group was obtained from a sporadic clinic-based cohort. Cases and controls were matched 1:2 by stage, molecular subtype by immunohistochemistry, age at BC diagnosis and year of BC diagnosis. Baseline continuous variables were presented as mean and standard deviation and comparison was performed with Student´s t-test. Baseline categorical variables were presented with number and percentage and comparison were performed using chi-square test. Survival analyses were estimated by Kaplan-Meier curves, the comparison of survival was tested by stratified log-rank testing. Cox proportional hazards model was used to estimate the hazard ratio and confidence intervals. Results: We identified 64 patients (p) with an ATM PV/LPV and 120 controls. Median age at diagnosis was 47 years (28-84) and 46 years (25-88), respectively. The main tumoral characteristics in both groups were ductal (87.5% and 83.5%), luminal B-HER2 negative (37.5% and 45.8%) with histological grade II (54.7% and 58.5%) tumors. Majority of tumors in both groups were diagnosed at stage II (53.1% and 54.2%). Differences between groups were observed in first-degree BC family history (39p (61.9%) vs 51p (43.6%); p=0.02); frequency of multicentric/multifocal tumors (15p (25%) vs 13p (11.1%); p=0.018); contralateral breast cancer (16p (25%) vs 8p (6.7%); p=0.0004) and type of surgery (46.8% conservative surgery in cases and 69.2% in controls; p< 0.001). The result of the germline genetic study was not available for all patients before surgery. Baseline characteristics are summarized in Table 1. With a median follow-up of 6.7 years, we observed more locoregional recurrence and distant recurrence in the control group (ipsilateral local or lymphatic recurrence: 0p (0%) vs 15p (12.5%); p=0.078; metachronic contralateral breast cancer: 7p (12.7%) vs 3p (2.6%); p=0.02; distance recurrence 5p (7.8%) vs 24p (20%); p=0.03. No differences between groups were observed in BC-specific survival analysis, with a median BC-specific survival of 6.24y (4.67-12.1) in patients with ATM and 6.68y (6.12-7.94) in the control group (HR: 1.21 (0.88-1.65); p=0.24). Conclusions: Patients with BC harboring a germline ATM PV/LPV had more multifocal and multicentric disease at diagnosis; and more synchronous and metachronous contralateral BC compared to controls, with no differences in BC-specific survival. Further studies in a larger cohort are warranted to analyze sensitivity to systemic therapies. Table 1. Baseline characteristics of cases and control groups. ER (Estrogen Receptor) positive if > or equal to 1%; PR (Progesterone Receptor) positive if > or equal to 1%; HER2 (Human epidermal growth factor receptor-2); ChTh: Chemotherapy; SLNB: Sentinel Lymph Node Biopsy; AL: Axillar lymphadenectomy Citation Format: Mara Cruellas, Ariadna Roqué, Nuria Dueñas, Iris Teruel, Noemí Tuset Der-Abrain, Alejandra Rezqallah, Víctor Navarro, Laia Joval-Ramentol, Maite Torres, Cristina Saura, Joan Brunet, Judith Balmaña. Survival of patients harboring a germline ATM pathogenic/likely pathogenic variant and diagnosed with breast cancer: A case-control study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-09-01.

Identification of ATM Mutation as a Potential Prognostic Biomarker for Immune Checkpoint Inhibitors Therapy

Background: Ataxia telangiectasia mutated (ATM), an apical DNA damage response gene, is a commonly mutated gene in tumors, and its mutation could strengthen tumor immunogenicity and alter the expression of PD-L1, which potentially contributes to immune checkpoint inhibitors (ICIs) therapy. Methods: The characteristics of ATM mutation and its relationship with the ICIs-treated clinical prognosis have been analyzed comprehensively in this paper. The overall frequency of ATM mutations has been found to be 4% (554/10953) in the cancer genome atlas (TCGA) cohort. Results: Both the TMB and MSI levels in patients with ATM mutations were significantly higher than those in patients without mutations (P < 0.0001). The median TMB was positively correlated with the frequency of ATM mutations (r = 0.54, P = 0.003). In the TCGA cohort, patients with ATM mutations had better clinical benefits in terms of overall survival (OS, hazard ratio (HR) = 0.736, 95% CI = 0.623 - 0.869), progression-free survival (PFS, HR = 0.761, 95% CI = 0.652 - 0.889), and disease-free survival (DFS, HR = 0.686, 95% CI = 0.512 - 0.919)] than patients without ATM mutations. Subsequently, the verification results showed ATM mutations to be significantly correlated with longer OS in ICIs-treated patients (HR = 0.710, 95% CI = 0.544 - 0.928). Further exploration indicated ATM mutation to be significantly associated with regulated anti-tumor immunity (P < 0.05). Conclusion: Our findings highlight the value of ATM mutation as a promising biomarker to predict ICIs therapy in multiple tumors.

Predictive DNA damage signaling for low‑dose ionizing radiation.

Numerous studies have attempted to develop biological markers for the response to radiation for broad and straightforward application in the field of radiation. Based on a public database, the present study selected several molecules involved in the DNA damage repair response, cell cycle regulation and cytokine signaling as promising candidates for low‑dose radiation‑sensitive markers. The HuT 78 and IM‑9 cell lines were irradiated in a concentration‑dependent manner, and the expression of these molecules was analyzed using western blot analysis. Notably, the activation of ataxia telangiectasia mutated (ATM), checkpoint kinase 2 (CHK2), p53 and H2A histone family member X (H2AX) significantly increased in a concentration‑dependent manner, which was also observed in human peripheral blood mononuclear cells. To determine the radioprotective effects of cinobufagin, as an ATM and CHK2 activator, an in vivo model was employed using sub‑lethal and lethal doses in irradiated mice. Treatment with cinobufagin increased the number of bone marrow cells in sub‑lethal irradiated mice, and slightly elongated the survival of lethally irradiated mice, although the difference was not statistically significant. Therefore, KU60019, BML‑277, pifithrin‑α, and nutlin‑3a were evaluated for their ability to modulate radiation‑induced cell death. The use of BML‑277 led to a decrease in radiation‑induced p‑CHK2 and γH2AX levels and mitigated radiation‑induced apoptosis. On the whole, the present study provides a novel approach for developing drug candidates based on the profiling of biological radiation‑sensitive markers. These markers hold promise for predicting radiation exposure and assessing the associated human risk.

Uterine adenosarcoma: Clinical significance of histological classification and SNP array analysis

Mullerian adenosarcoma is a rare malignant biphasic tumor. The mesenchymal component may be low or high grade, with or without sarcomatous overgrowth (SO). Little is known about the molecular heterogeneity of these tumors. In this study, we aim to reclassify a large retrospective monocentric cohort of uterine adenosarcomas according to tumor grade and SO, to evaluate the clinical significance of pathological classification and to correlate with copy-number variations inferred from single nucleotide polymorphism array. Of the 67 uterine adenosarcomas, 18 (26.9%) were low grade without SO, 7 (10.4%) low grade with SO, 8 (11.9%) high grade without SO and 34 (50.7%) high grade with SO. SO, necrosis and RMS were more frequent in high grade than low grade adenosarcomas (p < 0.001). Low-rank test showed that recurrence-free survival was significantly shortened in high grade than low grade adenosarcomas (p = 0.035) and SO was associated with shortened overall and recurrence-free survival (p = 0.038 and p = 0.009, respectively). High-grade tumors displayed complex genomic profiles with multiple segmental losses including TP53, ATM and PTEN genes. The median genomic index was significantly higher in high grade than low grade tumors (27 [3–60] vs 5,3 [0–16], p < 0.0001) and was significantly higher in presence of SO in low grade tumors (12,8 [10–16] vs 2,6 [0–10], p = 0.0006). We propose to report sarcomatous overgrowth with the tumor grade for prognostication in adenosarcoma and representative sampling is crucial for evaluation of these histological criteria.

DNA Checkpoint Gene Mutation as a Biomarker for Immune Checkpoint Inhibitor Therapy in Advanced Biliary Tract Cancer.

The DNA checkpoint (DNACHK) pathway is engaged in signaling the need for cell cycle arrest. This pathway is being actively researched to assess its role in cancer immunotherapy. A total of 62 patients participated in this study. These patients were treated with immune checkpoint inhibitors (ICIs) for advanced biliary tract cancers (BTCs) from March 2020 to August 2022 at Samsung Medical Center. DNACHK mutated were defined as genomic alterations, such as single nucleotide variants, multi-nucleotide variants, and short insertion and deletions in seven genes; checkpoint kinase 1 (CHEK1), checkpoint kinase 2 (CHEK2), BRCA1, DNA repair-associated (BRCA1), the serine/threonine kinase ATM, the serine/threonine kinase ATR, mediator of DNA damage checkpoint 1 (MDC1) and tumor protein p53 binding protein 1 (TP53BP1). We analyzed the effect of DNACHK mutations on the efficacy of ICIs in advanced BTCs. Patient median age at diagnosis was 68.0 years. 10 patients (16.1%) had GB cancer; the remaining patients (n=52, 83.9%) were diagnosed with cholangiocarcinoma. Thirty-seven (59.7%) patients were categorized into the DNACHK wild-type (WT) group and 25 (40.3%) into the DNACHK mutated (MT) group. The most observed DNA checkpoint mutations were ATM mutations (n=14). Patients in the DNACHK MT group had better disease control rate (DCR) than patients in the DNACHK WT (60.0% vs. 48.6%, p=0.53). Median overall survival (OS) was 8.1 months (95% CI 5.1-22.8) in the MT group and 5.6 months (95%CI 3.1-11.0) in the WT group (p=0.33). The DNACHK pathway is expected to serve as a potential biomarker for ICI treatment.

Case report: Mutation evolution in a patient with TdT positive high grade B cell lymphoma with MYC and BCL2 rearrangements following the treatment of concurrent follicular lymphoma and diffuse large B-cell lymphoma

BackgroundConcurrent follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL)was reported in some studies, while the diagnosis of TdT (terminal deoxynucleotydil transferase) positive high grade B cell lymphoma (HGBL) with MYC and BCL2 rearrangements (“double hit”) transformed from FL/DLBCL has been rarely reported. Herein, we described the clinical features and mutation profiles of a case diagnosed with TdT positive “double hit” HGBL following the treatment of FL/DLBCL.Case presentationThis is a 43-year-old Chinese man who was diagnosed with low grade FL (account for 80%) combined with DLBCL (20%) at a stage of IVB. The patient presented with BCL2/IGH translocation without MYC rearrangement, as well as the expressions of CD20, CD19, CD10 and BCL2 at the initial diagnosis of FL/DLBCL. MYC rearrangement and TdT expression occurred after the treatment. The targeted sequencing revealed mutations in KMT2D, FOXO1, CREBBP, ATM, STAT6, BCL7A, DDX3X, MUC4, FGFR3, ARID5B, DDX11 and PRKCSH genes were the co-mutations shared by the FL/DLBCL and TdT positive “double hit” HGBL, while CCND3, BIRC6, ROBO1 and CHEK2 mutations specifically occurred after the treatment. The overall survival time was 37.8 and 17.8 months after the initial diagnosis of FL/DLBCL and TdT positive “double hit” HGBL, respectively.ConclusionThis study reports a rare case of TdT positive “double hit” HGBL following the treatment of concurrent FL/DLBCL and highlights the mutation characteristics. Collectively, this study will help enrich the knowledge of TdT positive “double hit” HGBL transformed from FL/DLBCL.

Rubella virus vaccine-induced granulomas: a case in children with ataxia-telangiectasia

Ataxia telangiectasia (AT) is a rare autosomal recessive primary immunodeficiency disorder (PID) resulting from a mutation in the ATM gene, which is involved in DNA repair. We describe the case of a young girl with cutaneous granulomas that developed after childhood vaccinations. Immunohistochemistry revealed granulomas induced by the rubella virus vaccine. This finding raises the question of live rubella vaccine strains safety in immunocompromised children.

Targeting SMAD3 Improves Response to Oxaliplatin in Esophageal Adenocarcinoma Models by Impeding DNA Repair.

TGFβ signaling is implicated in the progression of most cancers, including esophageal adenocarcinoma (EAC). Emerging evidence indicates that TGFβ signaling is a key factor in the development of resistance toward cancer therapy. In this study, we developed patient-derived organoids and patient-derived xenograft models of EAC and performed bioinformatics analysis combined with functional genetics to investigate the role of SMAD family member 3 (SMAD3) in EAC resistance to oxaliplatin. Chemotherapy nonresponding patients showed enrichment of SMAD3 gene expression when compared with responders. In a randomized patient-derived xenograft experiment, SMAD3 inhibition in combination with oxaliplatin effectively diminished tumor burden by impeding DNA repair. SMAD3 interacted directly with protein phosphatase 2A (PP2A), a key regulator of the DNA damage repair protein ataxia telangiectasia mutated (ATM). SMAD3 inhibition diminished ATM phosphorylation by enhancing the binding of PP2A to ATM, causing excessive levels of DNA damage. Our results identify SMAD3 as a promising therapeutic target for future combination strategies for the treatment of patients with EAC.

Abstract LB008: Integrative dynamic MultiOMICs analysis identifies cell cycle and DNA damage response phenotypes as downstream consequences of using the PRMT5 inhibitor AZD3470

Abstract Background: PRMT5 is an epigenetic enzyme that catalyzes symmetric di-methylation of arginine (SDMA) of multiple substrates that regulate biological processes including RNA splicing and cell cycle. The role of PRMT5 in controlling chromatin accessibility has been investigated in some cancer contexts, but its role in non-small cell lung cancer (NSCLC) global chromatin regulation is not known. AstraZeneca has developed an MTA-cooperative PRMT5 inhibitor (AZD3470) that selectively inhibits PRMT5 in MTAP-null tumors and currently is in Phase I clinical trial (NCT06130553, NCT06130553). Here we applied integrative dynamic MultiOMICs analysis upon AZD3470 treatment in six MTAP-null NSCLC cancer cell lines to inform on PRMT5’s function in maintaining tumor cell growth and survival. Methods: Utilizing an integrative approach, our study explored the effects of AZD3470 on human MTAP-deleted NSCLC cells. MultiOMICs analysis including SDMA post-translational modification (PTM) scans, ATAC-seq, RNA-seq, and mass spectrometry proteomics were employed to delineate the immediate effects and downstream phenotypes of AZD3470 PRMT5 inhibition. Results: AZD3470 induced significant SDMA modification of splicing factors consistent with known roles for PRMT5. PRMT5 inhibition by AZD3470 led to changes in global chromatin accessibility in NSCLC cells. Specific changes in genes involved in the cell cycle pathway were observed including CDK6. Integrative analysis of transcriptomics and proteomics data consistently showed alterations in cell cycle, DNA damage repair and splicing related pathways upon treatment, consistent with the established biological roles of PRMT5. Alternative splicing analysis showed that AZD3470 treatment induced a unique retained intron within the ATM gene and resulted in reduced ATM protein levels. Conclusion: Here we identify AZD3470-induced changes to protein post-translational modification, chromatin accessibility, gene expression and RNA splicing in MTAP-deficient NSCLC cancer cell lines. Different area of MultiOMICs data together pointed to changes in cell cycle and DNA repair pathways. Further, we identified alternative splicing of ATM as a consequence of AZD3470 PRMT5i treatment resulting in significant reduction of ATM protein expression. Keywords: AZD3470, NSCLC, PRMT5 Inhibition, Chromatin Accessibility, Alternative Splicing, DNA Repair, ATM Gene. Citation Format: Ted Hong, Steven Criscione, Andrew Jarnuczak, Jelena Urosevic, Stephanie Ashenden, Ghaith Hamza, Praveen Kumar, Nevena Cvetesic, Lauren Bradshaw, Shaun Moore, Daniel Karl, Tianhui Zhang, Abel Sousa, Jonathan Cairns, Anthony Iannetta, Andrew Zhang, Eric Miele, John Reicha, Chris Chambers, Ramy Elgendy, Julia Lindgren, Daniel Jachimowicz, Maryam Clausen, Graham Belfield, Tony Cheung, Michael Grondine, James T. Lynch, Ho Man Chan, Susan Critchlow, Emma Dean. Integrative dynamic MultiOMICs analysis identifies cell cycle and DNA damage response phenotypes as downstream consequences of using the PRMT5 inhibitor AZD3470 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB008.

Abstract LB181: First disclosure of XRD-0394, a novel dual ATM/DNA-PK inhibitor, that potently radiosensitizes and potentiates PARP and topoisomerase inhibitors

Abstract A majority of cancer patients receive radiation therapy (RT) as part of their treatment regimens, whether using external beam therapy or locally-delivered radioisotopes. While often effective, RT may not be efficacious for some tumors while exerting significant short-term and long-term toxicities. Thus, enhancing therapeutic effectiveness of radiation therapy remains an important goal. ATM (ataxia-telangiectasia, mutated) and DNA-PKcs (deoxyribonucleic acid [DNA]-dependent protein kinase, catalytic subunit) are related protein kinases and both are critical regulators of cellular responses to ionizing radiation. We report here the identification and initial characterization of XRD-0394, a potent, specific dual inhibitor of both ATM and DNA-PKcs, whose chemical structure will be disclosed. A dual ATM/DNA-PK inhibitor has practical and theoretical advantages over compounds which inhibit just one of these kinases: 1) blunting both DNA damage response (DDR) pathways enhances radiation-induced tumor cell kill compared to single target inhibition; and 2) simultaneous inhibition of two DDR pathways should overcome intrinsic or acquired resistance of tumor cells to either target alone. Notably, transient inhibition of both kinases by XRD-0394 has little adverse effects on cells in the absence of irradiation. XRD-0394 is orally bioavailable, with excellent pharmacological profiles, demonstrating significant in vitro and in vivo sensitizing activity in combination with ionizing radiation and in combination with immunotherapy and radiation. In addition, a CRISPR screen identified alterations in the Fanconi A/BRCA pathway as an opportunity for synthetic lethality in tumor cells exposed to XRD-0394, an insight that was validated in multiple tumor cell types. In vitro studies demonstrated synergy of XRD-0394 in combination with PARP inhibitors, particularly in BRCA-mutant cells. XRD-0394 also potentiates the effectiveness of topoisomerase inhibitors in vitro. Single doses of XRD-0394 were well-tolerated in combination with palliative RT in subjects with advanced cancer in a Phase Ia clinical trial (NCT05002140). No DLTs were observed. At a dose of 160 mg, plasma concentrations were well above the preclinical target plasma level of 530 ng/mL (1 µM) for up to 15 h and inhibition of ATM kinase activity was demonstrated by inhibition of radiation-induced pKAP1 in tumor tissue. Importantly, this concentration of drug is sufficient to induce potent radiosensitization in numerous preclinical models. The median tmax (2.3 h) and mean terminal t½ (11.1 h) at the 160 mg dose in subjects support coadministration of XRD-0394 and RT within a clinically feasible time frame. These results provide a rationale for future clinical trials with XRD-0394 in combination with RT, RT and immunotherapy, PARP inhibitors and targeted delivery of topoisomerase inhibitors. Citation Format: Tona M. Gilmer, Chun-Hsiang Lai, Kexiao Guo, Katherine Deland, Kathleen A. Ashcraft, Amy E. Stewart, Yaode Wang, Jianmin Fu, Kris C. Wood, Deborah A. Smith, Jonathan T. Yang, Christopher T. Chen, Michael F. Gensheimer, Paul B. Romesser, Steven H. Lin, David G. Kirsch, Michael B. Kastan. First disclosure of XRD-0394, a novel dual ATM/DNA-PK inhibitor, that potently radiosensitizes and potentiates PARP and topoisomerase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB181.

Safety of the Breast Cancer Adjuvant Radiotherapy in Ataxia-Telangiectasia Mutated Variant Carriers.

The Ataxia-Telangiectasia Mutated (ATM) gene is implicated in DNA double-strand break repair. Controversies in clinical radiosensitivity remain known for monoallelic carriers of the ATM pathogenic variant (PV). An evaluation of the single-nucleotide polymorphism (SNP) rs1801516 (G-A) showed different results regarding late subcutaneous fibrosis after breast radiation therapy (RT). The main objective of this study was to evaluate acute and late toxicities in carriers of a rare ATM PV or predicted PV and in carriers of minor allele A of rs1801516 facing breast RT. Fifty women with localized breast cancer treated with adjuvant RT between 2000 and 2014 at Institut Curie were selected. Acute and late toxicities in carriers of a rare PV or predicted PV (n= 9), in noncarriers (n = 41) and in carriers of SNP rs1801516 (G-A) (n = 8), were examined. The median age at diagnosis was 53 years old and 82% of patients had an invasive ductal carcinoma and 84% were at clinical stage I-IIB. With a median follow-up of 13 years, no significant difference between carriers and noncarriers was found for acute toxicities (p > 0.05). The same results were observed for late toxicities without an effect from the rs1801516 genotype on toxicities. No significant difference in acute or late toxicities was observed between rare ATM variant carriers and noncarriers after breast RT for localized breast cancer.

Abstract LB158: Synergistic cytotoxicity of histone deacetylase and poly-ADP ribose polymerase inhibitors and decitabine in pancreatic cancer cells: implications for novel therapy

Abstract Histone deacetylase inhibitors (HDACi) can modulate the acetylation status of proteins, influencing the genomic instability exhibited by cancer cells. Poly (ADP ribose) polymerase (PARP) inhibitors (PARPi) have a direct effect on protein poly (ADP-ribosyl)ation, which is important for DNA repair. Decitabine is a nucleoside cytidine analogue, which when phosphorylated gets incorporated into the growing DNA strand, inhibiting methylation and inducing DNA damage by inactivating and trapping DNA methyltransferase on the DNA, thereby activating transcriptionally silenced DNA loci. We explored various combinations of HDACi and PARPi +/- decitabine (hypomethylating agent) in pancreatic cancer cell lines BxPC-3 and PL45 (wild-type BRCA1 and BRCA2) and Capan-1 (mutated BRCA2). Colony formation and drug-mediated inhibition of cell proliferation in pancreatic cancer cell lines and comparison of the effects of each drug combination with the effect of the individual drugs are shown in Table. The combination of HDACi (panobinostat or vorinostat) with PARPi (talazoparib or olaparib) resulted in synergistic cytotoxicity in all cell lines tested. The addition of decitabine further increased the synergistic cytotoxicity noted with HDACi and PARPi, triggering apoptosis (evidenced by increased cleavage of caspase 3 and PARP1). The 3-drug combination treatments (vorinostat, talazoparib, and decitabine; vorinostat, olaparib, and decitabine; panobinostat, talazoparib, and decitabine; panobinostat, olaparib, and decitabine) induced more DNA damage (increased phosphorylation of histone 2AX) than the individual drugs and impaired the DNA repair pathways (decreased levels of ATM, BRCA1, and ATRX proteins). The 3-drug combinations also altered the epigenetic regulation of gene expression (NuRD complex subunits, reduced levels). This is the first study to demonstrate synergistic interactions between the aforementioned agents in pancreatic cancer cell lines and provides preclinical data to design individualized therapeutic approaches with the potential to improve pancreatic cancer treatment outcomes. Table. Colony formation and drug-mediated inhibition of cell proliferation in pancreatic cancer cell lines. Comparison of the effects of each drug combination with the effect of the individual drugs (Table shows the p-values for each comparison.) Colony formation BxPC-3 PL45 Capan-1 Pano SAHA TLZ Ola DAC Pano SAHA TLZ Ola DAC Pano SAHA TLZ Ola DAC Pano+TLZ 0.00048 0.0052 2.40E-06 2.70E-06 0.0051 0.021 Pano+Ola 0.0035 0.078 0.0011 0.00094 0.0016 0.022 SAHA+TLZ 1.80E-05 0.17 0.0029 0.012 0.0014 0.019 SAHA+Ola 0.00018 0.014 0.0016 0.0068 0.0066 0.029 Pano+TLZ+DAC 4.20E-05 0.00026 0.0015 1.70E-05 1.20E-05 2.70E-06 0.00052 0.00088 0.0064 Pano+Ola+DAC 3.40E-05 0.00049 0.0013 7.10E-07 1.70E-06 2.20E-06 0.00068 0.0028 0.0053 SAHA+TLZ+DAC 0.00016 0.00016 0.0011 1.90E-05 3.70E-06 9.30E-07 0.00018 0.00017 0.011 SAHA+Ola+DAC 4.90E-07 0.00035 0.001 0.00022 0.00026 0.00084 0.00016 0.0016 0.0035 Drug-mediated inhibition of cell proliferation Pano+TLZ+DAC 3.57E-05 3.89E-07 1.30E-07 2.91E-05 3.76E-06 1.80E-08 0.0239 ND 0.0092 Pano+Ola+DAC 7.76E-05 1.43E-07 2.52E-07 6.59E-07 1.03E-08 2.22E-07 0.0013 0.21 0.0034 SAHA+TLZ+DAC 3.04E-06 0.00034 1.17E-05 4.91E-08 4.45E-06 1.74E-07 0.0013 1.75E-01 0.007 SAHA+Ola+DAC 0.00012 0.0032 0.000068 9.64E-09 1.53E-08 9.35E-07 0.0007 0.18 0.0054 Abbreviations: DAC: decitabine; ND: not determined; Ola: olaparib; Pano: panobinostat; SAHA: vorinostat; TLZ: talazoparib P ≤ 0.05 is considered statistically significant. Citation Format: Apostolia M. Tsimberidou, Benigno C. Valdez, Bin Yuan, Yago Nieto, Mehmet Baysal, Abhijit Chakraborty, Borje S. Andersson. Synergistic cytotoxicity of histone deacetylase and poly-ADP ribose polymerase inhibitors and decitabine in pancreatic cancer cells: implications for novel therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB158.