SACM - United States of America
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Item Restricted SYNTHESIS AND EVALUATION OF NOVOBIOCIN ANALOGUES AS POTENTIAL INHIBITORS OF POLYMERASE THETA POLΘ IN DNA DAMAGE AND REPAIR(University of Arkansas at Little Rock, 2025) Albuhluli, Mohammed; Anindya, Ghosh; Darin, JonesKilling tumors while leaving normal cells unharmed is the goal of precision cancer therapy, a challenging feat that is enabled by targeting tumor-specific vulnerabilities [1]. Targeting Polθ potentiates PARP inhibitors (PARPi) in specifically killing homology-directed repair (HDR)-deficient tumor cells and re-sensitize PARPi resistant tumor cells [1]. The induced essentiality between Polθ and HDR-deficiency underscores the value of Polθ as a therapeutic target in the context of tumors with HDR genetic mutations [1]. The helicase-like domain (HLD) is a super family 2 (SF2)-type domain with DNA-dependent ATPase activity [1]. We previously discovered that the antibiotic NVB acts as an inhibitor of N-terminal HLD of Polθ [1]. Consequently, a Phase I clinical trial of Novobiocin (NVB) is currently underway in patients with tumors that harbor aberrant DNA repair genes [1]. To inform enigmatic theta-mediated end joining (TMEJ) and support ongoing preclinical and clinical studies, we therefore investigated the mechanism of action of NVB-mediated inhibition of Polθ ATPase activity [1]. By combining hydrogen deuterium exchange-mass spectrometry (HX-MS), biochemical assays, microscale thermophoresis (MST), cellular assays and computational modelling, we determined that NVB is a non-ATP competitive inhibitor that binds to an allosteric site near the ssDNA binding channel in the ATPase core [1]. This is contrary to the current view of NVB as an ATP competitive inhibitor of DNA gyrase [1]. This NVB binding mode blocks ssDNA binding and inhibits ssDNA-mediated stimulation of Polθ ATPase activity [1]. Importantly, we find that NVB blocks Polθ binding to ssDNA both in vitro and in cells [1]. Using novobiocic acid (the aglycone of NVB), we investigated the orientation of NVB binding and established the contribution of the sugar group in enhancing the potency of NVB [1]. Our study identified the NVB binding pocket and provides a path for optimization and investigation of the importance of ssDNA binding for Polθ biological functions at double-strand breaks (DSBs) and stalled replication forks [1].20 0Item Restricted Field Cancerization and Microbiome Effects on Lung Cancer: A Source of Early Detection Biomarkers to Improve Patients’ Outcome(George Mason University, 2024-08-16) Alhammad, Rayan; Luchini, AlessandraLung cancer results in more deaths than any other cancer in the United States and worldwide, with non-small cell lung cancer (NSCLC) accounting for most cases. Diagnosis typically involves chest imaging, molecular testing, and biopsy. However, most patients are diagnosed at advanced stages, with only a 6% chance of a 5-year survival rate. In contrast, early-stage diagnosis and treatment can result in a favorable prognosis, with a high 5-year survival rate of 70-90%. The concept of tumor field cancerization describes a phenomenon where exposure to carcinogens can cause histologic changes in large areas of tissue, creating a field of pre-malignant cells that can eventually develop into tumors. Additionally, microbiota dysbiosis might influence tumor development. Studies have identified several commensal bacteria present in the lower airway tracts, such as Streptococcus, Prevotella, and Veillonella. The high mortality rate of lung cancer is often attributed to i) its late-stage diagnosis, ii) aggressive nature given its ability to metastasize early in the disease process complicating treatment and reducing survival rates, and iii) significant therapeutic challenges despite current treatments such as surgery, chemotherapy, radiation therapy, targeted therapy and immunotherapy. Despite advancements, the survival rate for advanced lung cancer remains low. To address this challenge, our research focuses on identifying risk protein biomarkers that are associated with the earliest molecular changes indicative of an ongoing tumorigenic process, thus offering significant potential for early intervention. Our study investigates the phenotypic molecular changes in the bronchial tree of NSCLC patients in light of the field cancerization theory and correlates these findings with blood biomarkers to support the future development of a non-invasive risk assessment test. Using enhanced liquid chromatography tandem mass spectrometry (LC-MS/MS) proteomic analysis and two independent cohorts of lung cancer patients (N=18, and N=263) with matched plasma and bronchial tree tissue specimens, we identified a set of 6 and 13 candidate risk plasma biomarkers with tissue origin. Additionally, we explored the microbiome proteome composition in NSCLC patient tissue and plasma to support future characterization of its potential role in cancer development. Risk biomarkers will enable the evaluation of individuals at high risk, guiding necessary lifestyle adjustments and facilitating the development of personalized prevention plans and therapies.52 0Item Restricted THE TOBACCO CEMBRANOID (+)-β-CEMBRENEDIOL AND THE PHYTOCANNABINOID (-)-CANNABIDIOL SUPPRESS CANCER PROGRESSION AND RECURRENCE VIA MODULATING TRYPTOPHAN CATABOLISM(University of Louisiana Monroe, 2024-05-22) Mudhish, Ethar; Elsayed, KhalidProstate cancer (PC) and lung cancer (LC) are among the top leading causes of death in United States. Despite completing a therapeutic treatment regimen, including chemotherapies, targeted therapies, surgical excision and/or radiation, patients with PC and LC have a high incidence of recurrence. Recurred tumors usually have a high resistant and aggressive profile and usually lead to high mortality. Unfortunately, there are currently no formally FDA-approved drugs that can prevent cancers recurrence. Therefore, it is crucial to discover and validate safe and effective recurrence suppressors for PC and LC survivors. Studies have shown that the enzyme indoleamine-2,3-dioxygenase (IDO1), usually driving the cellular tryptophan catabolism, plays a critical role in the progression, survival, and motility of PC and LC. IDO1 catabolizes (-)-tryptophan to (-)-kynurenine (Kyn) through the catalytic oxidative cleavage of the indole ring ∆2,3 system. Kyn binding to the aryl hydrocarbon receptor (AhR) lead to the activation lead of several mitogenic downstream pathways, which promote cancer progression and survival. Recently, numerous publications have shed lights on the contribution of tryptophan catabolism in cancer and defined the active and important role of the IDO1-Kyn-AhR axis in promoting oncogenesis. Thus, IDO1-Kyn-AhR validated as a viable molecular target for cancer control. The tobacco cembranoids (+)-(1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol (β-CBT) and its C-4 epimer α-CBT are critical flavor components that exist naturally in fresh unfermented tobacco leaves. During the commercial tobacco fermentation, a significant portion of tobacco cembranoids, >60%, is intentionally degraded to provide fermented tobacco flavor terpene ingredients with smaller molecular weights. Previous investigations have demonstrated that β-CBT inhibited the invasion of the androgen-independent metastatic PC cell line PC-3M cells and induced tighter intercellular barriers. Further comprehensive studies indicating that β-CBT has in vitro anti-migratory and anti-clonogenicity effects against various human PC cell lines. Additionally, in vivo β-CBT daily treatments significantly suppressed the PC-3M cell locoregional and distant tumor recurrences after primary tumor surgical excision in male nude mice. β-CBT treatments also suppressed the levels of IDO1, TDO2, and Kyn expression levels in PC-3M cells, as well as the systemic levels of the PC biochemical recurrence marker PSA and Kyn in treated animals. These results validated the β-CBT tryptophan catabolism as the main molecular target and highlighted its potential as a novel PC recurrence suppressive lead with high safety and efficacy profiles. IDO1 and AhR are sporadically dysregulated in some PC phenotypes, including metastatic castration-resistance prostate cancer mCRPC. (-)-Cannabidiol (CBD) is a non-psychoactive phenolic secondary metabolite occurring in the leaves and flowers of Cannabis sativa and is assumed a prominent constituent in medical marijuana. CBD formulations approved by the US Food and Drug Administration (FDA) in 2018 and 2019 for treatments of rare epilepsies and tuberous sclerosis complex. These approvals uniquely made CBD exceeds the nutraceutical level and proved its candidacy as a novel drug entity. In vitro studies have demonstrated that CBD exhibited anticancer activities against a variety of malignancies, including human neuroblastoma, medulloblastoma, and lymphocytic leukemia cells, as well as breast, colon, lung, pancreatic, bladder, cervical, endometrial, and prostate cancers. The potential of CBD in cancer therapy has generated considerable interest in recent years, and further research in this area is warranted to establish its clinical efficacy and safety as anticancer drug. This study aimed to comprehensively explore the potential of CBD as a suppressive entity for the progression and recurrence of PC. In vitro experiments revealed that CBD exerted a potent dose-dependent reduction in the viability and colony formation ability of several PC cell lines. Exploring the expression levels of IDO1 and AhR in PC cell lines indicated their dysregulation in metastatic castration-resistant PC (mCRPC) cells. CBD notably suppressed the IDO1 and AhR expression in mCRPC cells. In vivo experiments involving male athymic nude mice xenografted with the mCRPC CWR-R1ca-Luc cells showed that a daily oral dose of CBD effectively suppressed the progression, the locoregional and distant recurrences. Moreover, CBD-treated mice showed a significant reduction in serum Kyn levels, the final product of the IDO1-catalyzed tryptophan catabolism. Knockdown of IDO1 in the mCRPC CWR-R1ca cells resulted in a significant loss of colony formation ability compared to mock-type cells, highlighting the crucial role of IDO1 in mCRPC motility. The catabolism of tryptophan plays a significant role in the pathogenesis of non-small cell lung cancer (NSCLC), a leading cause of cancer-related deaths worldwide. CBD has been found to exhibit anti-proliferative effects on NSCLC cell lines and significantly altered their colony formation abilities. A panel of NSCLC cells has been shown to exhibit dysregulated levels of IDO1 and AhR, both of which are implicated in survival and progression. CBD has been shown to reduce the levels of IDO1 and AhR significantly, thereby providing a promising avenue for curtailing the growth of NSCLC. In light of the presented results, it can be concluded that the modulation of tryptophan catabolism including the IDO1-Kyn-AhR axis is a viable molecular target to control malignancies. The fresh tobacco cembranoid β-CBT presents itself as a promising nutraceutical entity appropriate for use by PC patients to suppress-prevent their disease relapse. Additionally, this study provides support for the notion that CBD serves as a viable natural product lead for regulating the IDO1-Kyn-AhR axis in the context of controlling the progression and recurrence of both PC and NSCLC. β-CBT and CBD are novel anticancer natural products with high translational potential for novel use as prospective cancer recurrence preventing entities.5 0Item Restricted Ultrasound Nano-Scale Phase Change Contrast Agent for Hepatocellular Carcinoma Radiosensitization(Saudi Digital Library, 2023-08-05) Falatah, Hebah; Eisenbrey, John; Wheatley, MargaretThe purpose of this study was to develop and characterize nano-scale phase change droplets less than 200 nm from commercially available ultrasound contrast agents and demonstrate their ability to enhance hepatocellular carcinoma (HCC) radiosensitization, which is critically needed to enhance the poor outcomes (two years survival < 50%) of current HCC radiotherapy treatments. Primary liver cancer is the third cause of cancer death worldwide with 906,000 new cases and 830,000 deaths annually. Of these, 75-85% of patients present with hepatocellular carcinoma (HCC), while the remaining 15-25% are intrahepatic cholangiocarcinoma and other types. Due to the late clinical presentation of the disease and treatment limitations of chemotherapy and immunotherapies, HCC has a poor prognosis. Localized radiotherapy in the early and mid-stages of HCC has shown some success in treatment response 25-50%. In such therapy, the hepatic artery supplying blood to the cancer is injected with radioisotope yttrium-90 (Y90), a beta particle emitter that provides localized radiation therapy. Another therapeutic option is external beam radiation (XRT) with MRI or CT guidance. XRT has been used cautiously in HCC treatment due to the radiosensitivity of liver tissue and technological limitations. Fractionated approaches are used to overcome the toxicity to the liver or radiation-induced liver diseases caused by high doses of radiation. The result of these limitations is that the overall five years survival for HCC patients in the United States is 20%, and the two years survival is less than 50%.Therefore, developing more effective HCC treatments is essential to improve patient outcomes. In recent years, researchers have been exploring a variety of radiosensitizers as a means of overcoming radiotherapy resistance. One promising radiotherapy enhancement mechanism is ultrasound-mediated microbubble destruction, which has been shown to sensitize solid tumors to radiotherapy through endothelial cell disruption in tumors. Ultrasound microbubbles have a diameter between 1 to 8 (micrometers) μm and consist of a high molecular weight gas encapsulated by a lipid, protein, or polymer shell. However, the relatively large size of the bubbles prevents them from passing into extravascular spaces, and as a result researchers have developed phase-change contrast agents (PCCAs). PCCAs contain a low boiling point such as -37oC liquid in place of the usual gas and can transition from the liquid to the gaseous state under external stimuli. This technology has been widely used in ultrasound medical imaging, vascular occlusion, and cavitation activity enhancement. The small diameters < 400 nm of these PCCAs allow them to diffuse and accumulate in solid tumors via the enhanced permeability and retention effect before the phase transition. Using ultrasound as an acoustic stimulus can provide local vaporization as well as cavitation of the resultant microbubble, thereby generating local force in tumor tissues. The development and characterization of sub-micrometer (< 200 nm diameter) phase change droplets from commercial ultrasound contrast agents, including their ability to decrease tumor vascularity and enhance cell apoptosis are described in addition to their ability to enhance HCC tumor radiosensitization.18 0