bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A018: Targeting STAT3 for bladder cancer prevention – in vitro studies using spheroid and organoid models
Authors: Singh Surya P , Pathuri Gopal , Asch Adam , Cholewa Brian , Shoemaker Robert , Rao Chinthalapally V. , Madka Venkateshwar 
Published: December 2022

Abstract
Signal Transducer and Activator of Transcription 3 (STAT3) is tightly regulated in normal cells to maintain a transiently active state. In contrast, persistent STAT3 activation is frequently observed in bladder cancer (BC) and is associated with poor prognosis and chemoresistance. Hence, developing small molecule inhibitors targeting STAT3 may be helpful for preventing BC progression and improving the survival rate of patients with metastatic BC. Recently, the use of three-dimensional in vitro models in drug development has gained popularity as they closely resemble, to an extent, the in vivo environment in heterogeneity and physiological conditions.
Here we established spheroid and organoid models for bladder cancer and evaluated STAT3 inhibitors (C188-9 and SH5-07) for their anticancer activity in vitro.
Initially, we optimized the spheroid growth from human, rat, and mouse BC cell lines (J82, NBT-II, MB49, respectively) and tumoroid growth from the BBN-rat bladder cancer model. The anticancer efficacy of C188-9 and SH5-07 was evaluated in vitro at various doses (0-50 µM) in the 3D models of BC. Assays were performed to determine spheroid viability (calcein AM (CA) and EtBr staining), ATP and ROS production (MitoSOX™). Protein isolated from control and drug treated spheroids/tumoroids was used to evaluate pharmacodynamic biomarkers of cell proliferation, apoptosis, and STAT3 signaling. We demonstrate that treatment with C188-9 and SH5-07 significantly decreased the spheroids size (39-45% smaller compared to untreated, p&lt;0.0001) along with decreased ATP (20%-40%, p&lt;0.05), and pSTAT3 protein expression in spheroids derived from BC cell lines and rat BC organoids. Further, MitoSOX™ staining showed that STAT3 inhibitor treatment induced mitochondrial mediated ROS generation in BC spheroids. CA and EtBr staining showed that C188-9 and SH5-07 treatment induced cell death in BC spheroids that was also associated with caspase-3 cleavage.
These findings indicate that C188-9 and SH5-07 could suppress the activation of the STAT3 pathway and inhibit the bladder cancer spheroid growth by inducing ROS production and thus warrants further evaluation in vivo. Furthermore, our study provided valuable spheroid and organoid models for evaluating therapeutic candidates in an in vivo-mimic microenvironment, thereby providing great potential for drug testing. (Partly supported by P30CA225520 and Kerley-Cade Endowed Chair)
Citation Format: Surya P Singh, Gopal Pathuri, Adam Asch, Brian Cholewa, Robert Shoemaker, Chinthalapally V. Rao, Venkateshwar Madka. Targeting STAT3 for bladder cancer prevention – in vitro studies using spheroid and organoid models [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A018.
Abstract A019: Targeting STAT3 for lung cancer prevention
Authors: Siegfried Jill M. , Soloff Adam C. , Davis Autumn Gaither , Powers Amy A. , Eisenberg Seth H. , Stabile Laura P. 
Published: December 2022

Abstract
Former smokers have an elevated risk of lung cancer and account for a large proportion of newly diagnosed lung cancer. Former smokers with airway dysplasia have received modest benefit in randomized chemoprevention trials, while active smokers have not. More effective chemoprevention agents for former smokers at risk for lung cancer are needed. We previously reported that a cyclic double-stranded DNA oligonucleotide STAT3 decoy (CS3D) administered intravenously (IV) had strong anti-tumor effects in lung cancer xenograft models and was also effective as a chemoprevention agent using a tobacco carcinogen (NNK)-induced lung cancer mouse model that mimics “ex-smokers”. CS3D prevents the binding of activated STAT3 dimers to the promoter of target genes and induces p-STAT3 degradation. Our goal was to develop a clinically applicable direct delivery method of CS3D to the lungs. Using fluorescently tagged CS3D, we evaluated the feasibility and determined the optimal dosing schedule of CS3D administered intratracheally (IT, a mimic of human inhalation) compared to IV in mice. IT delivery 3 times/week provided a high initial drug level that was cleared from the lungs within a few hours, while IV dosing provided lower initial drug levels but persisted up to 8 hrs, with CS3D accumulation over time in the lungs. While the pharmacodynamic effect was also greater with systemic dosing, IT delivery produced inhibition of the STAT3 pathway. Phosphorylated STAT3, VEGF, IL6 and Ki67 expression in NNK-induced lung preneoplasias was down-modulated by IT CS3D delivery after 4 weeks of treatment compared to the mutant oligonucleotide (CS3M), confirming our previous findings with IV delivery. We also demonstrated that CS3D delivered IT altered the pulmonary environment by promoting a pro-inflammatory, anti-tumor response in myeloid cells of the lung directly, or by acting on tumor and stromal components to establish an immune-reactive tumor-microenvironment. No toxicities were found during IT or IV treatment and no organ abnormalities were detected by either regimen. A long-term chemoprevention study of CS3D delivered IT in the ex-smoker lung cancer murine model is underway. Our findings suggest that blocking STAT3 may be a useful strategy for lung cancer prevention, and may involve both inhibition of oncogenic signaling and enhanced anti-tumor immunity.
Citation Format: Jill M. Siegfried, Adam C. Soloff, Autumn Gaither Davis, Amy A. Powers, Seth H. Eisenberg, Laura P. Stabile. Targeting STAT3 for lung cancer prevention [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A019.
Abstract IA002: Combination of naproxen and a novel chemically-stable eicosapentaenoic acid analogue provide synergistic tumor protection in Pirc rats
Authors: Beach Ryan , Hatano Yuichiro , Qiao Yong , Grady James , Sei Shizuko , Mohammed Altaf , Rosenberg Daniel W. 
Published: December 2022

Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Patients with the genetic disorder Familial Adenomatous Polyposis (FAP) develop hundreds to thousands of polyps that unless removed by prophylactic colectomy will progress to CRC at an early age. Non-steroidal anti-inflammatory drugs (NSAIDs) and ω-3 marine fish oils, such as eicosapentaenoic acid (EPA), have been evaluated for their chemopreventive potential in delaying the onset of CRC in high-risk patients. In this study, we determined whether the NSAID, naproxen, alone or in combination with a chemically-stable form of EPA (TP-252), affects tumor formation in the ApcPirc rat model. Rats fed a combination of naproxen and TP-252 exhibited a 95% reduction in tumor formation and a 98% reduction in tumor volume, respectively. To elucidate potential mechanisms of tumor protection, a comprehensive lipidomic analysis was performed on colonic mucosa to determine changes in eicosanoid metabolism. Animals receiving TP-252 alone or in combination with naproxen had significantly reduced mucosal levels of pro-inflammatory ω-6 eicosanoids (PGE2, 5-HETE, and 14,15-DiHETrE), along with a simultaneous increase in anti-inflammatory EPA-derived ω-3 eicosanoids. Our colonic mucosal lipidomic analysis also uncovered several potential pharmacodynamic (PD) lipid biomarkers, including resolvin E2, 9-HEPE, 12-HEPE and 18-HEPE, that were increased in both the tissue and plasma of rats receiving TP-252 and were significantly correlated with tumor protection. Further studies with this drug combination should be focused on dose optimization and the role of EPA-derived lipid mediators in CRC initiation and progression.
Citation Format: Ryan Beach, Yuichiro Hatano, Yong Qiao, James Grady, Shizuko Sei, Altaf Mohammed, Daniel W. Rosenberg. Combination of naproxen and a novel chemically-stable eicosapentaenoic acid analogue provide synergistic tumor protection in Pirc rats [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr IA002.
Abstract IA005: Discovery and development of LFA-9 for CRC prevention
Authors: Rao Chinthalapally V. 
Published: December 2022

Abstract
Colorectal Cancer (CRC) is a major public health issue with an estimated 980,000 deaths annually, worldwide. Current trends show an increase of CRC incidence and mortality worldwide. Colonic adenomas are very common in ages 50 and over. Though, nonsteroidal antiinflammatory agents like Aspirin, Naproxen and COX-2 inhibitor and Celecoxib are useful to prevent the polyp progression and reducing CRC burden, continuous/chronic usage of these drugs are limited by GI toxicity and unwanted side effects. Thus, the rationale to establish safer anti-inflammatory agents for CRC prevention is important. Mechanistic studies suggest that up-regulation of 15-PGDH, sparing COX-1/2 and prostaglandin (PG)I2 synthase and/or selectively targeting mPGES-1 and 5-LOX would reduce the cardiovascular side effects and may improve the chemopreventive efficacy. There are limited to no studies on targeting mPGES-1/5LOX and it is one of the unexplored areas in colorectal cancer chemoprevention towards safer drug development. To design and develop selective inhibitors of dual mPGES-1/5-LOX, we used in-silico small molecular docking simulation approaches, and identified LFA-9 as a novel duel mPGES-1/5-LOX inhibitor among &gt;35 analogs. Azoxymethane (AOM)-induced rat colonic tumors were utilized as ex-vivo to assess pharmacodynamic inhibitory effects of LFA-9 on mPGES-1 and 5-LOX by Radio-HPLC. In a series of animal experiments, we established the dose-range of toxicity and optimal doses of LFA-9. Potential preventive efficacy of LFA-9 was assessed AOM-rat colon carcinogenesis (Aberrant Crypt Foci, (ACF) as surrogate marker in male F344 rats and intestinal tumor inhibition in APCMin/+ mice. Furthermore, we have shown the efficacy of LFA-9 administered in the diet at the adenoma stage significantly suppressed colonic adenocarcinoma formation in AOM-induced colon cancer (sporadic CRC model) and PIRC rat model (FAP model). Overall, the above results show that LFA-9, a novel dual mPGES-1/5-LOX inhibitor, is a safer agent and has potential for prevention of CRC in high-risk patients. {This work was supported by NCI-PREVENT Cancer Program, R01 CA213987 and VA Merit Awards}
Citation Format: Chinthalapally V. Rao. Discovery and development of LFA-9 for CRC prevention [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr IA005.
Abstract IA006: Reverse-engineering discovery of targets, involved cell types, and compounds for liver cancer chemoprevention
Authors: Hoshida Yujin 
Published: December 2022

Abstract
Hepatocellular carcinoma (HCC) is a cancer type with clinically unequivocal and well-defined predisposing conditions, namely chronic fibrotic liver diseases caused by viral hepatitis and metabolic disorders. By following up the at-risk patient cohort, natural history of HCC development can be captured over the timeframe of one to two decades. Archived biospecimens are often available from the time of initial liver disease diagnosis, and unbiased molecular profiling of the specimens provides unique opportunities to interrogate molecular dysregulations confidently correlated with the real long-term clinical outcome, i.e., HCC development from early-stage liver diseases. This “reverse-engineering” strategy helps increase the likelihood of identifying clinically relevant therapeutic targets without solely relying on data from experimental preclinical models. This is particularly useful in cancer chemoprevention target discovery given the the requirement of overwhelmingly lengthy and costly clinical validation of experimentally derived candidate targets, which is often practically infeasible. Utilizing this strategy, we could successfully identify HCC chemoprevention targets (e.g., cellular signaling such as EGFR pathway, circulating bioactive lipids), involved cell types (e.g., hepatic myofibroblasts, conventional dendritic cells), and compounds (e.g., small molecular signaling pathway inhibitors, generic agents), streamline the process of their clinical validation, and facilitate translation of promising chemoprevention agents to the care of liver disease patients.
Citation Format: Yujin Hoshida. Reverse-engineering discovery of targets, involved cell types, and compounds for liver cancer chemoprevention [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr IA006.
Abstract IA008: How to move a preventative agent from design into approval
Authors: Krol Danielle 
Published: December 2022

Abstract
Cancer prevention is a global public health challenge that requires a multidisciplinary approach including biology, epidemiology, medicine, nutrition, education, clinical trials and public policy. An intent-to-treat analysis of a randomized controlled trial differs from that in the observational setting, therefore, it is important to understand the underlying disease process and aspects of the intervention through research. The genetic heterogeneity of some cancers strongly support an enhanced focus on prevention as a strategy in high-risk individuals. Important factors when developing preventative cancer agents include the time course of the intervention, dose and duration of exposure needed to effect risk reduction, trial endpoints, durability of the impact of intervention, and methodological problems in implementing and interpreting randomized trials to evaluate prevention strategies. The clinical development of cancer prevention therapeutics has many challenges, including the long duration necessary to conduct trials, the lack of adherence to therapy, and unanswered questions on the best endpoint remain. The government, whether it be local, state or national, plays a vital role in regulation and education. The history of chemoprevention regulatory approvals has taught us that these programs are important in the fight against cancer. The Food and Drug Administration has identified barriers to clinical trial participation and challenges in surrogate endpoints, although with a multidisciplinary approach including communication with industry, are extremely positive about the future direction of chemoprevention research.
Citation Format: Danielle Krol. How to move a preventative agent from design into approval [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr IA008.
Abstract IA009: National Cancer Institute Small Business Innovation Research Development Center NCI SBIR & STTR resources for commercializing innovative cancer prevention
Authors: Franca-Koh Jonathan 
Published: December 2022

Abstract
The Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) Programs at the National Institutes of Health (NIH) serve as one of the largest sources of early-stage capital for technology commercialization in the United States (US). In FY2021, the National Cancer Institute (NCI) SBIR and STTR Programs provided approximately $182M in non-dilutive funding to US small businesses and managed over 400 different projects. By supporting startups and other small businesses in the cancer space, the NCI SBIR and STTR Programs act as catalysts of innovation for novel technologies and products to achieve NCI’s mission to prevent, diagnose, and treat cancer. Staffed by a dedicated team of scientists with wide-ranging technology and industry experience, the NCI SBIR Development Center provides both funding and non-funding resources to US small businesses all aimed at translating technologies to the clinic to help cancer patients and providers.
During the past 5 years, NCI has provided SBIR/STTR funding to approximately 25 companies who are developing novel cancer prevention agents. Companies focused on prevention of several indications such as colorectal cancer, oral squamous cell carcinomas, and human papillomavirus-related cancers. Award sizes ranged from $200k-$2M and included support for companies with technologies in the preclinical and clinical stages of development. NCI provided opportunities for non-funding support as well, including entrepreneurial training programs such as I-Corps™ at NIH and programs to facilitate connections between innovators and potential investors. Whether a technology is in the preclinical or clinical stage of development, NCI can help small businesses translate their innovative research to the marketplace so they become available to healthcare providers and their patients.
Citation Format: Jonathan Franca-Koh. National Cancer Institute Small Business Innovation Research Development Center NCI SBIR & STTR resources for commercializing innovative cancer prevention [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr IA009.
Abstract IA010: NCATS Collaborative Translational Research/Drug Development Resources
Authors: Simeonov Anton 
Published: December 2022

Abstract
The mission of the National Center for Advancing Translational Sciences (NCATS) is to catalyze the generation of innovative methods and technologies that will enhance the development, testing, and implementation of interventions across a wide range of human diseases and conditions. NCATS is directly addressing this problem by discovering new technologies and other approaches that could greatly accelerate the process of developing and deploying therapeutic solutions. An introduction of the Center’s internal research operations will be presented, focusing on the use of advanced assay and chemistry technologies to address the wide range of needs associated with early discovery space. Further, an overview of collaborative opportunities for joint projects will be provided.
Citation Format: Anton Simeonov. NCATS Collaborative Translational Research/Drug Development Resources [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr IA010.
Abstract IA011: Modulation of tumor associated macrophages in breast cancer
Authors: Guerriero Jennifer L. 
Published: December 2022

Abstract
Macrophages are an innate immune cell that play a critical role in host defense and maintaining tissue homeostasis, however their infiltration into tumors has been associated with disease progression and resistance to therapy. Tumor associated macrophages (TAMs) represent a significant proportion of solid tumors, including breast cancer. TAMs play a major role in tumorigenesis as they can enhance tumor cell growth, angiogenesis and metastasis. In addition, TAMs can inhibit anti-tumor responses of T cells. Our recent work has shown that removal or conversion of TAMs to an anti-tumor phenotype enhances chemo- and immuno-therapy establishing TAMs as targets for anti-cancer therapy. We recently revealed that a Class II HDAC inhibitor can polarize TAMs to an anti-tumor phenotype to facilitate reduction in primary and metastatic tumor burden. In addition, we have found that some types of therapy such as poly(ADP-ribose) polymerase (PARP) inhibition (PARPi) can drive development of highly suppressive TAMs, restricting anti-tumor T cell function and survival. Murine models demonstrate that in the absence of TAMs, PARPi induce a robust recruitment of cytotoxic T cells and durable antitumor responses. Therefore, targeting TAMs is a promising strategy for improving PARPi treatment efficacy. However, while there is an urgent need to target TAMs during tumorigenesis and cancer therapy, to date, failure to fully characterize TAM biology and classify multiple subsets has hindered advancement in therapeutic targeting. Deep analysis of TAMs in solid tumors has revealed the complexity of TAMs and revealed major gaps in our knowledge of the functional and phenotypic characterization of TAM subsets associated with cancer, before and after treatment. Here we will discuss the complexity of TAMs in solid tumors including characterizing TAM subsets, location, and crosstalk with neighboring cells, as well as novel TAM-modulating strategies and combinations that are likely to enhance current therapies and overcome chemo- and immuno-therapy resistance.
Citation Format: Jennifer L. Guerriero. Modulation of tumor associated macrophages in breast cancer [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr IA011.
Abstract IA012: Sulindac modulates the response of proficient MMR colorectal cancer to immune checkpoint inhibitors
Authors: Xi Yaguang 
Published: December 2022

Abstract
Immune checkpoint inhibitors (ICIs) therapy has been widely used to treat different human cancers, particularly advanced solid tumors. However, clinical studies have reported that ICI immunotherapy benefits only ~15% of colorectal cancer (CRC) patients, specifically those with tumors characterized by microsatellite instability (MSI), a molecular marker of defective DNA mismatch repair (dMMR). For the majority of CRC patients who carry proficient MMR (pMMR), ICIs have shown little clinical benefit. In this study, we examined the efficacy of sulindac to enhance the response of pMMR CRC to anti-PD-L1 immunotherapy. We first utilized CT26 and CMT93 syngeneic mouse tumor models to compare the inhibitory effects of PD-L1 antibody (Ab), sulindac, and their combination on pMMR CRC tumor growth. We found that mice treated with combination therapy showed a significant reduction in tumor volume, along with increased infiltration of CD8+ T lymphocytes in the tumor tissues. We also demonstrated that sulindac could downregulate PD-L1 by blocking NF-κB signaling, which in turn led to a decrease in exosomal PD-L1. Notably, PD-L1 Ab can be bound and consumed by exosomal PD-L1 in the blood circulation. Therefore, in combination therapy, sulindac downregulating PD-L1 leads to increased availability of PD-L1 Ab, which potentially improves the overall efficacy of anti-PD-L1 therapy. We validated all these results using humanized Patient-Derived Xenografts (PDX) animal models. Moreover, we demonstrated the safety of low-dose sulindac as it did not have a systemic inhibitory effect on prostaglandin E2 (PGE2). In conclusion, our findings provide unique insights into the mechanism of action and efficacy for sulindac as an immunomodulatory agent for the ICI therapy and immunoprevention of pMMR CRC.
Citation Format: Yaguang Xi. Sulindac modulates the response of proficient MMR colorectal cancer to immune checkpoint inhibitors [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr IA012.