Aziz, Khaled

Abstract Pancreatic adenocarcinoma remains one of the most lethal malignancies, primarily due to its robust resistance to genotoxic therapies, such as chemotherapy and radiotherapy. Understanding the mechanisms underlying this resistance is essential to improve clinical outcomes. In this study, we identified trimethylguanosine synthase 1 (TGS1), previously known for its role in RNA modification, as a critical mediator of homologous recombination (HR) repair that specifically contributes to resistance in pancreatic adenocarcinoma. TGS1 was significantly overexpressed in pancreatic adenocarcinoma tissues, correlating strongly with advanced disease stages, therapy resistance, and poor patient prognosis. Following DNA damage, ATM kinase phosphorylated TGS1 at serine residues S389 and S531, which mediated its direct interaction with BRCA1 and subsequent recruitment of BRCA1 to DNA damage sites. The phosphorylation-dependent interaction enhanced HR repair efficiency, enabling cancer cells to survive genotoxic stress. Depletion or pharmacologic inhibition of TGS1 induced HR deficiency and markedly enhanced sensitivity to DNA-damaging agents, particularly PARP inhibitors, in pancreatic adenocarcinoma cell lines in vitro and in both cell line– and patient-derived xenograft models in vivo. Collectively, these findings uncover an ATM–TGS1–BRCA1 signaling axis that promotes DNA repair and resistance to genotoxic therapies in pancreatic cancer, positioning TGS1 as a promising predictive biomarker and therapeutic target to enhance treatment efficacy. Significance: The ATM–TGS1–BRCA1 signaling axis is a critical regulator of DNA repair that can be targeted to overcome genotoxic therapy resistance, providing a promising therapeutic strategy that could transform pancreatic cancer treatment.

Metastatic castration-resistant prostate cancer (mCRPC) progresses aggressively and resists existing therapies. Although poly(ADP-ribose) polymerase inhibitors (PARPis) benefit a subset of patients with mCRPC and BRCA1/2 deficiencies, therapeutic options remain limited for those without such mutations. Here, we uncover a critical role for the ATM-TRMT10A-BRCA1 signaling axis in regulating homologous recombination (HR) repair and PARPi sensitivity. We demonstrate that ATM phosphorylates TRMT10A at serine-28 after DNA damage, promoting BRCA1 recruitment and efficient HR repair. TRMT10A deletion disrupts HR repair, sensitizing cells to PARPis. Moreover, TRMT10A is up-regulated in mCRPC through stabilization by USP10. Targeting USP10 with spautin-1 induces TRMT10A degradation and enhances tumor sensitivity to PARPis in cell-derived xenografts and patient-derived xenograft models. These findings identify TRMT10A as a therapeutic vulnerability in mCRPC and demonstrate that combined inhibition of PARP and USP10 offers a promising synthetic lethal strategy for a broader group of patients lacking classical BRCA mutations.

Abstract Background In breast cancer patients treated with pencil‐beam scanning proton therapy (PBS), the increased linear energy transfer (LET) near the end of the proton range can affect nearby ribs. This may associate with a higher risk of rib fractures. Purpose To study the effect of LET on rib fracture in breast cancer patients treated with PBS using a novel tool of dose‐LET volume histogram (DLVH). Methods From a prospective registry of patients treated with post‐mastectomy proton therapy to the chest wall and regional lymph nodes for breast cancer between 2015 and 2020, we retrospectively identified rib fracture cases detected after completing treatment. Contemporaneously treated control patients who did not develop rib fracture were matched to patients 2:1 considering prescription dose, boost location, reconstruction status, laterality, chest wall thickness, and treatment year. The DLVH index, V (d, l), defined as volume( V ) of the structure with at least dose(d) and dose‐averaged LET (l) (LETd), was calculated. DLVH plots between the fracture and control group were compared. Conditional logistic regression (CLR) model was used to establish the relation of V (d, l) and the observed fracture at each combination of d and l . The p ‐value derived from CLR model shows the statistical difference between fracture patients and the matched control group. Using the 2D p ‐value map derived from CLR model, the DLVH features associated with the patient outcomes were extracted. Results Seven rib fracture patients were identified, and fourteen matched patients were selected for the control group. The median time from the completion of proton therapy to rib fracture diagnosis was 12 months (range 5–14 months). Two patients had grade 2 symptomatic rib fracture while the remaining 5 were grade 1 incidentally detected on imaging. The derived p ‐value map demonstrated larger V (0–36 Gy[RBE], 4.0–5.0 keV/µm) in patients experiencing fracture ( p < 0.1). For example, the p ‐value for V (30 Gy[RBE], 4.0 keV/um) was 0.069. Conclusion In breast cancer patients receiving PBS, a larger volume of chest wall receiving moderate dose and high LETd may result in an increased risk of rib fracture.

Background Trastuzumab is life‐extending therapy for breast cancer patients overexpressing the human epidermal growth factor receptor 2 ( HER 2+), but has known cardiotoxic risk. We sought to determine if trastuzumab can be administered to patients with reduced baseline cardiac function at no higher cardiotoxicity risk than in those with normal cardiac function at baseline. Methods and Results We performed a retrospective study of women treated with trastuzumab for human epidermal growth factor receptor 2 breast cancer at Mayo Clinic Rochester between January 1, 2000 and August 31, 2015 with pre‐ and on‐therapy echocardiograms available for review. A left ventricular ejection fraction (LVEF) <53% was considered abnormal, and a ≥10% decline in LVEF as evidence of cardiotoxicity based on the criteria of the American Society of Echocardiography. A total of 428 women were identified; 408 had a normal cardiac function ( LVEF 63.4±5%) and 20 had an impaired cardiac function ( LVEF 45.4±7%) before trastuzumab. Seven women (35%) with reduced LVEF at baseline had a ≥10% reduction in LVEF , compared with 179 (43.9%) of those with normal LVEF before trastuzumab initiation ( P = NS ). Symptomatic heart failure developed more often in patients with reduced versus normal baseline LVEF (25% versus 4.2%, P <0.05). After adjusting for patient age and breast cancer disease stage, survival rates over 5 years from time of diagnosis were found to be lower for patients with reduced baseline LVEF compared with patients with normal baseline LVEF ( P <0.001); the adjusted proportion of patients surviving at 5 years for those with low LVEF at baseline was 79% and for those with normal LVEF was 93%. Conclusions Women undergoing trastuzumab therapy for breast cancer with impaired baseline cardiac function experience no higher risk of LVEF decline, but more frequently develop symptomatic heart failure. While trastuzumab could be considered, these patients should be co‐managed by a cardiologist.

e12522 Background: Trastuzumab is widely used in management of HER2+ breast cancer patients. A known adverse effect of trastuzumab use is cardiac dysfunction, which can often be reversed with cessation of therapy. Our objectives were to 1) assess if trastuzumab can be safely administered to breast cancer patients with reduced cardiac function and 2) identify patient characteristics that predict susceptibility to trastuzumab-induced cardiac dysfunction. Methods: A retrospective analysis was performed on female patients seen at Mayo Clinic for HER2+ breast cancer and treated with trastuzumab for localized or metastatic disease between January 1, 2000 and August 31, 2015. Eligibility criteria included documentation of and results from at least one echocardiogram prior to and at least one after trastuzumab initiation. Left ventricular (LV) ejection fraction (EF) of 53% or more was considered normal. Any LVEF reduction of 10% or more was considered significant. Among patients with normal EF, age strata of < 45, 45-60, and > 60 at time of trastuzumab initiation were used to assess risk factors for clinically diagnosed cardiac dysfunction (defined as EF < 53 or abnormal strain and physical symptoms of heart failure (HF)). Results: We identified 335 women (mean age 53.3, with 25.3% age < 45, 44.5% age 45-60, and 30.1% age > 60) who had normal LVEF (median EF 64, range: 53-75) and 23 women (mean age 53.4, with 30.4% age < 45, 43.5% age 45-60, and 26.1% age > 60) who had low LVEF at baseline (median EF 52, range: 25-52). Approximately a third (34.3%) of women with normal LVEF prior to initiation of therapy had at least one subsequent echocardiogram showing a drop of 10% or a low LVEF ( < 53). Approximately a quarter (26%) of women with low LVEF at baseline had a 10% drop in LVEF. HF incidence increased with age. Predictive factors for trastuzumab-induced cardiac dysfunction were obesity and history of coronary artery disease (CAD) across all age strata, and chest irradiation (IR) for those aged 45-60 only. Conclusions: Our results suggest that trastuzumab can be administered in women with reduced cardiac function at no greater risk than in those with preserved cardiac function. Some women with no obesity, history of CAD, or history of chest IR may not need echocardiograms during trastuzumab therapy.

Cellular effects of ionizing radiation (IR) are of great variety and level, but they are mainly damaging since radiation can perturb all important components of the cell, from the membrane to the nucleus, due to alteration of different biological molecules ranging from lipids to proteins or DNA. Regarding DNA damage, which is the main focus of this review, as well as its repair, all current knowledge indicates that IR-induced DNA damage is always more complex than the corresponding endogenous damage resulting from endogenous oxidative stress. Specifically, it is expected that IR will create clusters of damage comprised of a diversity of DNA lesions like double strand breaks (DSBs), single strand breaks (SSBs) and base lesions within a short DNA region of up to 15–20 bp. Recent data from our groups and others support two main notions, that these damaged clusters are: (1) repair resistant, increasing genomic instability (GI) and malignant transformation and (2) can be considered as persistent “danger” signals promoting chronic inflammation and immune response, causing detrimental effects to the organism (like radiation toxicity). Last but not least, the paradigm shift for the role of radiation-induced systemic effects is also incorporated in this picture of IR-effects and consequences of complex DNA damage induction and its erroneous repair.