Aldehyde dehydrogenases are versatile enzymes that serve a range of biochemical functions.  Although traditionally considered metabolic housekeeping enzymes because of their ability to detoxify reactive aldehydes, like those generated from lipid peroxidation damage, the contributions of these enzymes to other biological processes are widespread.  For example, the plant pathogen Pseudomonas syringae strain PtoDC3000 uses an indole-3-acetaldehyde dehydrogenase to synthesize the phytohormone indole-3-acetic acid to elude host responses. Here we investigate the biochemical function of AldC from PtoDC3000.  Analysis of the substrate profile of AldC suggests that this enzyme functions as a long-chain aliphatic aldehyde dehydrogenase.  The 2.5 Å resolution x-ray crystal of the AldC C291A mutant in a dead-end complex with octanal and NAD+ reveals an apolar binding site primed for aliphatic aldehyde substrate recognition.  Functional characterization of site-directed mutants targeting the substrate and NAD(H) binding sites identify key residues in the active site for ligand interactions, including those in the 'aromatic box' that define the aldehyde binding site.  Overall, this study provides molecular insight for understanding the evolution of the prokaryotic aldehyde dehydrogenase superfamily and their diversity of function.

OBJECTIVE Immune checkpoint inhibitors (ICIs) and epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs) are commonly used in the systemic management of non–small cell lung cancer (NSCLC) brain metastases (BMs). However, optimizing control of NSCLC BM with stereotactic radiosurgery (SRS) and various systemic therapies remains an area of investigation. METHODS Between 2016 and 2019, the authors identified 171 NSCLC BM patients with 646 BMs treated with single-fraction SRS within 3 months of receiving treatment with ICIs (n = 56; 33%), EGFR-TKI (n = 30; 18%), chemotherapy and ICIs (n = 23; 14%), or standard chemotherapy alone (n = 62; 36%). Time-to-event analysis was conducted, and outcomes included distant intracranial control (DIC), local control (LC), and overall survival from SRS. RESULTS The median follow-up from BM diagnosis was 8.9 months (range 0.3–127 months). The 12-month Kaplan-Meier DIC rates were 37%, 53%, 41%, and 21% (p = 0.047) for the ICI, EGFR-TKI, ICI and chemotherapy, and chemotherapy-alone groups, respectively. On multivariate analysis, DIC was improved with EGFR-TKI (HR 0.4, 95% CI 0.3–0.8, p = 0.005) compared with conventional chemotherapy and treatment with SRS before systemic therapy (HR 0.5, 95% CI 0.3–0.9, p = 0.03) compared with after; and LC was improved with SRS before (HR 0.4, 95% CI 0.2–0.9, p = 0.03) or concurrently (HR 0.3, 95% CI 0.1–0.6, p = 0.003) compared with after. No differences in radionecrosis were noted by timing or type of systemic therapy. CONCLUSIONS The authors’ analysis showed significant differences in DIC based on receipt of systemic therapy and treatment with SRS before systemic therapy improved DIC. Prospective evaluation of the potential synergism between systemic therapy and SRS in NSCLC BM management is warranted.

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Background: Advances in imaging and systemic therapy have improved the survival for patients with breast cancer brain metastases (BCBM). However, an improved understanding of patients with long-term survival after stereotactic radiation (SRT) for BCBM is warranted and could allow for better prognostication and personalized treatment. Methods: This is a single institution retrospective review of 188 patients who underwent SRT sessions to 685 BCBM from August 2004 to June 2020. Patients who were lost to follow up within 2 years after SRT were excluded. Patients were stratified into 2 groups: those with overall survival (OS) from SRT less than 2 years (short-term survival, STS) and those with OS from SRT of at least 2 years (long-term survival, LTS). Patient, tumor, and treatment characteristics were compared between the 2 groups via the student t-test and Chi-square testing as appropriate. The Kaplan-Meier (KM) method was used to calculate OS, local control (LC), and distant intracranial control (DIC) from the date of SRT. The reverse KM method was used to estimate follow-up from SRT. Results: The median follow up from BCBM diagnosis was 52.8 months (95% CI: 40.5-75.2 months). Of the 685 treated BCBMs, 552 (81%) received stereotactic radiosurgery (SRS) to a median dose of 21 Gy (12-24 Gy) and 133 received fractionated stereotactic radiation therapy (FSRT) to a median dose of 25 Gy (20-35 Gy) in 3-5 fractions. The 2-year LC, DIC, and OS was 78.4%, 26.5%, and 38.3%, respectively. The 5-year OS was 19%. There were 72 patients (38%) in the LTS group and 116 patients (62%) in the STS group. The LTS group had lower rates of invasive lobular carcinoma (0% vs 6%, p=0.001) and higher rate of HER2+ disease (61% vs 30%, p< 0.001). The LTS group had lower rates of concurrent extracranial metastasis (74% vs 89%, p=0.008) and lung metastasis (33% vs 53%, p=0.009), though there were no differences in the rates of bone or liver metastasis. The LTS group had less BCBM at the time of SRT (mean 1.9 vs 2.5, p=0.013) and more often received SRT to a single BCBM (65% vs 42%, p=0.002). There were no significant differences in age or performance status between the groups. Conclusion: Prognosis for patients with BCBM is heterogeneous, as a minority of patients have prolonged OS after SRT. These patients more often have limited BCBM, HER2+ disease, and a lower extracranial disease burden. Citation Format: Joseph D. Tang, Matthew N. Mills, Chetna Thawani, Daniel E. Oliver, Aixa Soyano, Arnold Etame, Hsiang-Hsuan Michael Yu, Nam Tran, Michael A. Vogelbaum, Peter A. Forsyth, Brian J. Czerniecki, Hatem H. Soliman, Hyo S. Han, Kamran A. Ahmed. Characteristics of Long-Term Survival in Breast Cancer Brain Metastasis after Stereotactic Radiation [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD7-06.