Efficacy In Clinical Trials Research Articles

The case for neuregulin-1 as a clinical treatment for stroke.

Ischemic stroke is the leading cause of serious long-term disability and the 5th leading cause of death in the United States. Revascularization of the occluded cerebral artery, either by thrombolysis or endovascular thrombectomy, is the only effective, clinically-approved stroke therapy. Several potentially neuroprotective agents, including glutamate antagonists, anti-inflammatory compounds and free radical scavenging agents were shown to be effective neuroprotectants in preclinical animal models of brain ischemia. However, these compounds did not demonstrate efficacy in clinical trials with human patients following stroke. Proposed reasons for the translational failure include an insufficient understanding on the cellular and molecular pathophysiology of ischemic stroke, lack of alignment between preclinical and clinical studies and inappropriate design of clinical trials based on the preclinical findings. Therefore, novel neuroprotective treatments must be developed based on a clearer understanding of the complex spatiotemporal mechanisms of ischemic stroke and with proper clinical trial design based on the preclinical findings from specific animal models of stroke. We and others have demonstrated the clinical potential for neuregulin-1 (NRG-1) in preclinical stroke studies. NRG-1 significantly reduced ischemia-induced neuronal death, neuroinflammation and oxidative stress in rodent stroke models with a therapeutic window of >13 h. Clinically, NRG-1 was shown to be safe in human patients and improved cardiac function in multisite phase II studies for heart failure. This review summarizes previous stroke clinical candidates and provides evidence that NRG-1 represents a novel, safe, neuroprotective strategy that has potential therapeutic value in treating individuals after acute ischemic stroke.

Multi-Drug Resistant Gonorrhea: An Emerging Global Threat

<i>Neisseria gonorrhoeae</i> is the bacterial culprit behind gonorrhea, a highly prevalent sexually transmitted infection (STI) found worldwide. Despite over 1 million daily cases, many infections are asymptomatic, contributing to its widespread transmission. The emergence of multidrug-resistant strains poses a significant challenge to public health, limiting treatment options and increasing the risk of complications. Key aspects covered include the bacterium's transmission dynamics, pathogenesis, clinical manifestations, laboratory diagnosis methods, and epidemiology. Transmission primarily occurs through sexual contact, with the bacterium thriving on mucous membranes in various parts of the body. Clinical presentations range from urethritis and cervicitis to more severe complications such as pelvic inflammatory disease and disseminated gonococcal infection. Laboratory diagnosis relies on culture, nucleic acid amplification tests (NAATs), and Gram staining, with NAATs offering high sensitivity. However, antimicrobial susceptibility testing is essential to guide treatment decisions, given the rapid emergence of resistance. Gonorrhea's epidemiology varies globally, with higher prevalence rates in low- and middle-income countries. Surveillance programs play a crucial role in monitoring antimicrobial resistance trends and informing treatment guidelines. The economic burden of gonorrhea is substantial, with potential increases in medical expenses and the challenge of managing outbreaks. Despite these challenges, there is hope for the development of new treatments and vaccines. Promising candidates such as zoliflodacin and solithromycin have shown efficacy in clinical trials, while vaccine development faces obstacles due to the bacterium's antigenic variation. The paper provides a comprehensive overview of <i>N. gonorrhoeae,</i> covering its basic features, transmission, pathogenesis, clinical presentation, laboratory diagnosis, epidemiology, challenges of drug-resistant gonorrhea, and prospects for the development of new treatments and vaccines. The paper underscores the urgent need for continued research, surveillance, and development of effective strategies to combat drug-resistant gonorrhea. Investment in new treatments and vaccines is crucial to mitigate the spread of the infection and its associated complications.

PD-L1 Immunohistochemical Expression in Endometrial Carcinoma: Egyptian Cross-Sectional Study.

Endometrial carcinoma (EC) is the most common cancer of the female genital tract. According to the recently evolved strategies of cancer immunotherapy, immune checkpoints inhibitors are one of the most crucial strategies. Programmed Death Ligand 1 (PD-L1) is an important immune checkpoint regulator. PD-L1 antibodies have shown efficacy in clinical trials of some malignancies. Some of these antibodies have been approved for clinical usage by the Food and Drug Administration (FDA). This retrospective study included a total of 100 ECs, collected from archived, formalin-fixed, paraffin-embedded tissue blocks of hysterectomy specimens of Egyptian females. The samples were immunohistochemically analyzed for PD-L1 expression (in both tumor cells; TCs and tumor infiltrating leucocytes; TILs) by a semiquantitative score (0 to 4), with cutoff points of (0: <1% of the cells, 1: 1% to 4%, 2: 5% to 9%, 3: 10% to 49%, and 4: ≥ 50%). Membranous staining only was considered positive. PD-L1 was highly expressed in ECs (67% TCs+ and 61% TILs+), with statistically significant relationships with age, lympho-vascular space invasion (LVSI) and TILs score (P = 0.006, 0.016 and <0.005 respectively). However, no statistically significant relationships were detected between PD-L1 expression and the following parameters: histological type, histological grade, pathological stage (pT) or FIGO stage, myometrial, cervical, adnexal/serosal, parametrial involvements and nodal metastasis, as well as ESMO risk stratification system. Moreover, statistically significant relationships were achieved when correlating TILs score with tumor grade and LVSI (P = 0.034 and 0.012 respectively). Also, comparing endometrial hyperplasia (EH) PD-L1 and TCs PDL1 median scores achieved statistically significant relationship (P = 0.001). Our results concluded that PD-L1 expression was greater in both TCs and TILs in a subgroup of patients that have advanced age, LVSI and are TILs-rich, identifying them as potential candidates for anti-PD-1/PD-L1 immunotherapy.

Reducing Inequity in the Use of Automated Insulin Delivery Systems by Adults With Type 1 Diabetes: Key Learnings From a Safety Net Diabetes Clinic Program

BackgroundRecent advancements in diabetes technology have significantly improved Type 1 diabetes (T1D) management, but disparities persist, particularly in the adoption of automated insulin delivery (AID) systems within minoritized communities. We aimed to improve patient access to AID system training and overcome clinical inertia to referral. MethodsWe report on a transformative program implemented at Boston Medical Center, the largest safety-net hospital in New England, aimed at reducing disparities in AID system utilization. We employed a multidisciplinary team and quality improvement principles to identify barriers and develop solutions. Strategies included increasing access to diabetes educators, creating a referral system, and developing telemedicine education classes. We also made efforts to raise clinician awareness and confidence in recommending AID therapy. ResultsAt baseline, 13.5% of our clinic T1D population was using an insulin pump. The population referred included 97 people with T1D (49% female, mean A1c 8.7%, 68% public insurance beneficiaries, 25% Hispanic and 25% non-Hispanic Black). Results from the first year showed a 166% increase in AID system use rates, with 64% of referred patients starting on AID. Notably, 78% of patients with A1c >8.5% adopted AID systems, addressing a gap in representation observed in clinical efficacy trials. The initiative successfully narrowed disparities in AID use among minoritized populations. ConclusionsThe program's success among minoritized patients underscores the significance of tailored, collaborative, team-based care and targeted educational initiatives. Our experience provides a foundation for future efforts to ensure equitable access to diabetes technologies, emphasizing the potential of local quality improvement interventions.

Mapping knowledge landscapes and emerging trends of Marburg virus: A text-mining study

BackgroundMarburg virus (MARV), a close relative of Ebola virus, could induce hemorrhagic fevers in humans with high mortality rate. In recent years, increasing attention has been paid to this highly lethal virus due to sporadic outbreaks observed in various African nations. This bibliometric analysis endeavors to elucidate the trends, dynamics, and focal points of knowledge that have delineated the landscape of research concerning MARV. MethodsRelevant literature on MARV from 1968 to 2023 was extracted from the Web of Science Core Collection database. Following this, the data underwent bibliometric analysis and visualization procedures utilizing online analysis platform, CiteSpace 6.2R6, and VOSviewer 1.6.20. Three different types of bibliometric indicators including quantitative indicator, qualitative indicators, and structural indicators were used to gauge a researcher's productivity, assess the quality of their work, and analyze publication relationships, respectively. ResultsMARV is mainly prevalent in Africa. And approximately 643 confirmed cases have been described in the literature to date, and mortality observed was 81.2 % in overall patients. A total of 1014 papers comprising 869 articles and 145 reviews were included. The annual publications showed an increasing growth pattern from 1968 to 2023 (R2 = 0.8838). The United States stands at the forefront of this discipline, having dedicated substantial financial and human resources to scientific inquiry. However, co-authorship analysis showed the international research collaboration needs to be further strengthened. Based on reference and keywords analysis, contemporary MARV research encompasses pivotal areas: primarily, prioritizing the creation of prophylactic vaccines to impede viral spread, and secondarily, exploring targeted antiviral strategies, including small-molecule antivirals or MARV-specific monoclonal antibodies. Additionally, a comprehensive grasp of viral transmission, transcription, and replication mechanisms remains a central focus in ongoing investigations. And future MARV studies are expected to focus on evaluating clinical trial safety and efficacy, developing inhibitors to contain viral spread, exploring vaccine immunogenicity, virus-host association studies, and elucidating the role of neutralizing antibodies in MARV treatment. ConclusionThe present study offered comprehensive insights into the contemporary status and trajectories of MARV over the past decades. This enables researchers to discern novel collaborative prospects, institutional partnerships, emerging topics, and research forefronts within this domain.

A Core Outcome Set for Efficacy of Acute Treatment of Hereditary Angioedema

BackgroundClinical trials investigating drugs for acute treatment of hereditary angioedema attacks have assessed many different outcomes. This heterogeneity limits comparability of trial results and may lead to selective outcome reporting bias and a high burden on trial participants. ObjectiveTo achieve consensus on a Core Outcome Set comprising key outcomes that should ideally be utilized in all clinical efficacy trials involving acute treatment of hereditary angioedema attacks. MethodsA Delphi consensus study was conducted involving all relevant parties: hereditary angioedema patients, hereditary angioedema expert clinicians and clinical researchers, pharmaceutical companies, and regulatory bodies. Two internet-based survey rounds were conducted. In round 1, panelists indicated the importance of individual outcomes used in clinical trials on a 9-point Likert scale. Based on these results, a core outcome set was developed and voted on by panelists in round 2. ResultsFifty-eight worldwide panelists completed both rounds. The first round demonstrated high importance scores and substantial agreement among the panelists. In the second round, a consensus of ≥90% was achieved on a core outcome set consisting of five key outcomes: change in overall symptom severity at one predetermined time point between 15 minutes and 4 hours after treatment, time to end of progression of all symptoms, need for rescue medication during the entire attack, impairment of daily activities, and treatment satisfaction. ConclusionThis international study obtained a high level of consensus on a core outcome set for acute treatment of hereditary angioedema attacks consisting of five key outcomes.

Interplay of cytokines in the pathophysiology of atopic dermatitis: insights from Murin models and human.

The pathogenesis of atopic dermatitis (AD) is understood to be crucially influenced by three main factors: dysregulation of the immune response, barrier dysfunction, and pruritus. In the lesional skin of AD, various innate immune cells, including Th2 cells, type 2 innate lymphoid cells (ILC2s), and basophils, produce Th2 cytokines [interleukin (IL)-4, IL-5, IL-13, IL-31]. Alarmins such as TSLP, IL-25, and IL-33 are also produced by epidermal keratinocytes, amplifying type 2 inflammation. In the chronic phase, not only Th2 cells but also Th22 and Th17 cells increase in number, leading to suppression of filaggrin expression by IL-4, IL-13, and IL-22, which further deteriorates the epidermal barrier function. Dupilumab, which targets IL-4 and IL-13, has shown efficacy in treating moderate to severe AD. Nemolizumab, targeting IL-31RA, effectively reduces pruritus in AD patients. In addition, clinical trials with fezakinumab, targeting IL-22, have demonstrated promising results, particularly in severe AD cases. Conversely, in murine models of AD, several cytokines, initially regarded as promising therapeutic targets, have not demonstrated sufficient efficacy in clinical trials. IL-33 has been identified as a potent activator of immune cells, exacerbating AD in murine models and correlating with disease severity in human patients. However, treatments targeting IL-33 have not shown sufficient efficacy in clinical trials. Similarly, thymic stromal lymphopoietin (TSLP), integral to type 2 immune responses, induces dermatitis in animal models and is elevated in human AD, yet clinical treatments like tezepelumab exhibit limited efficacy. Therapies targeting IL-1α, IL-5, and IL-17 also failed to achieve sufficient efficacy in clinical trials. It has become clear that for treating AD, IL-4, IL-13, and IL-31 are relevant therapeutic targets during the acute phase, while IL-22 emerges as a target in more severe cases. This delineation underscores the necessity of considering distinct pathophysiological aspects and therapeutic targets in AD between mouse models and humans. Consequently, this review delineates the distinct roles of cytokines in the pathogenesis of AD, juxtaposing their significance in human AD from clinical trials against insights gleaned from AD mouse models. This approach will improve our understanding of interspecies variation and facilitate a deeper insight into the pathogenesis of AD in humans.

Abstract 2386: Meta-analysis of efficacy and safety in early-phase clinical trials for refractory colorectal cancer

Abstract Introduction: Despite a decade of metastatic colorectal cancer (mCRC) therapeutic innovations, a comprehensive synthesis of patient outcome and risk-benefit assessment of phase 1/2 trials, extending beyond single-center studies, is missing. The aim of this meta-analysis is to assess efficacy, safety, and trends over time for phase 1 and 2 mCRC trials by examining clinical benefit rate (CBR), overall response rate (ORR), grade 3 or higher adverse events (AE), and discontinuation due to AE. Methods: The protocol and search were preregistered on PROSPERO. We searched PubMed and Embase for publications of phase 1/2 trials between 2010-2022. Reports were screened for inclusion criteria, followed by data-extraction by two researchers. Trials reporting on non-standard therapies for treatment-refractory mCRC or trials reporting specific mCRC efficacy data were included. CBR was defined as the proportion of patients with complete/partial response or stable disease ≥14 weeks. We used logit transformations for pooled effect analysis via a random-effects model, assigning study weights by the inverse variance method. Subgroup analyses were performed for publication year, preselection on molecular traits, and drug class: antiangiogenics, chemotherapy, immunomodulator, targeted therapy, or vaccine. Data are presented with 95% confidence intervals (CI); reported differences had non-overlapping CIs. Results: The search strategy yielded 4175 unique reports, from which we extracted data for 279 trials. Most trials were phase 1 (63%). ORR was limited to 6% [6-7] in both phase 1 and 2, CBR was higher in phase 2 than in phase 1 trials (36% vs 27%). Trials testing antiangiogenic drugs had the highest CBR (47%) and immunomodulators the highest ORR (8%). Trials with patients preselected on molecular traits had higher CBR compared to other trials (38% vs 28%). We observed an increase in efficacy, especially in phase 2 trials, with a CBR rising from 22% to 42% between trials published in 2010-2012 and 2019-2021. Compared with 2010-2012, trials in 2019-2021 were more often testing immunomodulators (23% vs 4%), performed on molecular preselected populations (38% vs 4%), and including younger patients (median age &amp;lt;60 in 66% vs 44%). The occurrence of grade 3+ AE was 33% [28-38] in both phase 1 and 2. AE led to discontinuation in 12% of phase 1 trial patients, and 7% of phase 2 patients. Grade 3+ AE occurred in 4% of vaccine trial patients, in contrast to 41% in trials on targeted therapies. Occurrence of grade 3+ AE did not change over time. Conclusion: We found limited ORR and CBR in early phase trials conducted in 2010-2021 for mCRC patients, while noting severe AEs in many patients. However, during this period, clinical benefit rate increased for phase 2 trials, possibly due to evolving study strategies that entail testing new treatment types in a younger, fitter, and stricter preselected study population based on molecular traits. Citation Format: Maarten A. Huismans, Lidwien P. Smabers, Niels N. van Nieuwenhuijzen, Monique C. Minnema, Miriam Koopman, Hugo J. Snippert, Anne M. May, Jeanine M. Roodhart. Meta-analysis of efficacy and safety in early-phase clinical trials for refractory colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2386.

Abstract 3821: Real world outcomes among patients with newly diagnosed acute myeloid leukemia

Abstract Introduction: Treatment options for patients with acute myeloid leukemia (AML) have expanded in recent years. Although new treatments have demonstrated efficacy in clinical trials, less is known about their effect on outcomes in routine clinical practice. We examined outcomes for patients with newly-diagnosed AML (ND-AML) using real world data (RWD). Methods: This retrospective observational study was conducted using the COTA real-world (rw) database, a de-identified source of longitudinal electronic health record data pertaining to the diagnosis, management, and outcomes of patients with cancer. Adult patients with ND-AML, diagnosed January 1, 2013 to March 20, 2023 were included. First-line treatment regimens were grouped into therapeutic categories and outcomes were summarized. The index date was defined as date of initiation of first-line therapy. Results: Among 2516 patients with ND-AML included (Table), the most common regimens used were intensive chemotherapy with cytarabine (IC w/ara-C), hypomethylating agents with venetoclax (HMA+ven), and HMA alone. Complete response rate was highest in patients treated with IC w/ara-C or investigational regimen(s). Median overall survival (OS) was 16 mo overall, with highest median OS seen in patients treated with IC w/ara-C and investigational regimen(s). Median OS for patients treated with HMA+ven was 13.5 mo. Thirty-day mortality was lowest in patients treated with IC w/ara-C, CPX-351 (liposomal daunorubicin + cytarabine), and HMA+ven. Conclusions: Results suggest that IC w/ara-C remains the standard of care for most patients with ND-AML and this regimen has a higher CR rate and median OS. Variation of patient demographics and clinical characteristics across treatment groups did not permit cross-treatment comparisons, though future analyses evaluating these subgroups may provide further insight into effectiveness and safety of AML regimens in routine care for populations underrepresented in clinical trials. rwCR rate Median rwOS 30-day mortality N % (95% CI) Months (95% CI) % (95% CI) Overall 2516 45.3 (43.2, 47.3) 16.0 (14.9, 17.3) 5.9 (5.0, 6.8) IC w/ara-C 1171 60.6 (57.8, 63.4) 36.4 (31.0, 46.0) 1.6 (0.9, 2.3) HMA+ ven 300 33.7 (28.3, 39.3) 13.5 (11.4, 15.5) 3 (1.1, 4.9) Decitabine 242 12.8 (8.9, 17.7) 8.4 (6.7, 9.9) 10.4 (6.5, 14.2) Azacitidine 206 7.8 (4.5, 12.3) 7.2 (5.3, 9.6) 10.7 (6.4, 14.8) Investigational 206 61.6 (54.6, 68.3) 21.3 (15.2, 27.8) 3.4 (0.9, 5.9) Lower dose cytarabine 62 12.9 (5.7, 23.9) 8.7 (5.4, 16.1) 14.9 (5.4, 23.4) CPX-351 based 61 55.7 (42.4, 68.5) 9.3 (7.3, 15.1) 0.0 No treatment 188 NA 1.9 (1.5, 2.8) 30 (22.7, 36.6) Citation Format: Elizabeth D. Pulte, Laura L. Fernandes, Joseph Wynne, Eric Hansen, Andrew J. Belli, Anna Barcellos, Christina M. Zettler, Rebecca Bystrom, Jonathon Vallejo, Wenjuan Gu, Catherine Lerro, Kelly Norsworthy, Angelo DeClaro, Marc R. Theoret, Donna Rivera, Ching-Kun Wang. Real world outcomes among patients with newly diagnosed acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3821.

Abstract 347: Tumor necrosis factor related apoptosis inducing ligand (TRAIL)-induced cytokine production in TNBC promotes neutrophil chemotaxis and immune suppression

Abstract Background: TRAIL induces apoptosis in many preclinical cancer models including breast cancers and has been extensively studied as a potential cancer therapeutic. However, its efficacy in clinical trials is limited, suggesting an unknown modulatory mechanism responsible for lack of TRAIL activity in vivo. Here, we describe that TRAIL treatment elicits transcriptional changes in TNBC cells that alter the immune milieu. Method: We performed RNAseq of MDA-MB-231 cells treated with TRAIL for different time points, followed by validation with RT-PCR in various TNBC cells. RNAi, silencing key differentially regulated genes, along with RT-PCR, ELISA and CHIP assays, were used to validate RNAseq findings. Elucidation of the functional relevance of the outcome was supported both in vitro and in vivo by chemotaxis assay, cytotoxicity assay, RNAseq analysis of donor isolated neutrophils and intravital microscopy, CODEX analysis in TNBC xenografts from mice treated with the TRAIL respectively. Results: TRAIL treatment of the TNBC significantly induced expression of several cytokines, such as CXCLs 1, 2, 3, 8,11 and IL6, both in vitro and in vivo which are known to affect neutrophil function. Mechanistically, induction of these cytokines was predominantly mediated by death receptor 5 and caspase-8 protein, but not caspase-8 enzymatic activity. GSEA of the RNAseq data indicated that NFKB pathway was significantly enriched. Concordantly, we confirmed that both canonical NFKB1 and non-canonical NFKB2 pathways were activated by TRAIL in vitro and in vivo. However, the induction of the cytokine mRNAs was primarily dependent on the NFKB2 pathway. Neutrophils isolated from healthy human donors incubated with supernatants from TNBC cells in vitro indicated that TRAIL-induced CXCLs and IL6 significantly increased neutrophil chemotaxis. Additionally, CODEX analysis as well as intravital imaging confirmed that TRAIL treatment increases the number of neutrophils in the tumor. Preincubation of neutrophils with supernatants from TRAIL-treated TNBC significantly inhibited their cytotoxic effect against TNBCs. Further, transcriptome analysis of neutrophils incubated with either TRAIL or supernatant of TRAIL treated TNBC revealed significant enrichment of expression of inflammatory cytokine genes, immune modulating and immune checkpoint genes like PDL1. Functional studies with these neutrophils confirmed their suppressive effect on T cell function as well as the effect of TRAIL on decreased neutrophil apoptosis. Conclusion: Collectively, our study suggests the novel role of TRAIL-induced NFKB2-dependent cytokine production promoting neutrophil chemotaxis and immune suppression. This study implies that alterations in the innate immune system may modulate the effects of TRAIL on TNBC tumors. Citation Format: Manjari Kundu, Yoshimi Endo Greer, Lisa Ann Ridnour, David A Wink, Yeap S. Ng, Roberto Weigert, Stan Lipkowitz. Tumor necrosis factor related apoptosis inducing ligand (TRAIL)-induced cytokine production in TNBC promotes neutrophil chemotaxis and immune suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 347.

Abstract 6358: Arming tumor-associated macrophages to inhibit cancer progression

Abstract Integrin αvβ3 is a marker of cancer progression in a range of epithelial cancers. In the 1990s, a humanized anti-αvβ3 antibody (Etaracizumab) was developed to target αvβ3+ cancer cells via NK cell-mediated cytotoxicity. While it demonstrated safety and some efficacy in clinical trials, our recent study of the immune microenvironment in αvβ3+ human epithelial tumors revealed increased tumor-associated macrophages (TAMs) but minimal NK cell accumulation. Accordingly, we re-engineered Etaracizumab to favor TAM engagement over NK cells and compared the efficacy of this antibody (ABT101) to that of Etaracizumab in various αvβ3+ epithelial cancer models. While ABT101 and Etaracizumab exhibited identical affinity for αvβ3, ABT 101 showed superior anti-tumor activity in vivo. Notably, depleting NK cells in mice had no impact on ABT101’s effectiveness, while macrophage depletion completely abolished its anti-tumor activity. Interestingly, tumors in mice treated with ABT101 displayed a significant increase in TAMs. Here we define an “antigen-effector cell matching” strategy that allows for maximal anti-tumor activity for various drug resistant epithelial cancers. ABT101 will enter clinical trials for patients with drug resistant lung cancer in the first quarter of 2024. Citation Format: Joshua P. Reddy, Ziqi Yu, Ryan M. Shepard, Tami Von Schalscha, Stephen J. McCormack, Sara M. Weis, David A. Cheresh, Hiromi I. Wettersten. Arming tumor-associated macrophages to inhibit cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6358.

Combination of EZH2 and ATM inhibition in BAP1-deficient mesothelioma.

More than half of mesothelioma tumours show alterations in the tumour suppressor gene BAP1. BAP1-deficient mesothelioma is shown to be sensitive to EZH2 inhibition in preclinical settings but only showed modest efficacy in clinical trial. Adding a second inhibitor could potentially elevate EZH2i treatment efficacy while preventing acquired resistance at the same time. A focused drug synergy screen consisting of 20 drugs was performed by combining EZH2 inhibition with a panel of anti-cancer compounds in mesothelioma cell lines. The compounds used are under preclinical investigation or already used in the clinic. The synergistic potential of the combinations was assessed by using the Bliss model. To validate our findings, in vivo xenograft experiments were performed. Combining EZH2i with ATMi was found to have synergistic potential against BAP1-deficient mesothelioma in our drug screen, which was validated in clonogenicity assays. Tumour growth inhibition potential was significantly increased in BAP1-deficient xenografts. In addition, we observe lower ATM levels upon depletion of BAP1 and hypothesise that this might be mediated by E2F1. We demonstrated the efficacy of the combination of ATM and EZH2 inhibition against BAP1-deficient mesothelioma in preclinical models, indicating the potential of this combination as a novel treatment modality using BAP1 as a biomarker.

Abstract 4942: Unraveling a prognostic and predictive 8-gene signature related to cuproplasia in pan-cancer

Abstract This study aims at identifying a cuproplasia-related gene signature to predict outcome for cancer patients based on gene regulatory networks. Copper is a vital micronutrient involved in many biological processes. Copper influences tumor growth through a process called cuproplasia, defined as abnormal copper-dependent cell-growth and proliferation. Copper-chelation therapy targeting this process has demonstrated efficacy in several clinical trials against cancer. While the molecular pathways associated with cuproplasia are partially known, genetic heterogeneity across different cancer types has limited the understanding of how cuproplasia impacts patient survival. We proposed a novel framework based on gene regulatory networks to identify critical cuproplasia-related genes (CCGs) across different cancer types. Utilizing RNA-sequencing data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) datasets, we generated gene regulatory networks for 23 different cancer types. We applied a network control method to discover critical genes in these networks and combined with copper metabolism related genes to identify CCGs across 23 cancer types. We then performed a comprehensive analysis on the identified CCGs to better understand their potential roles and associations with cancer patient survival. We discovered 30 CCGs which were enriched in pathways related to a wide range of biological processes supporting cancer progression and immune evasion processes. The specific processes related to the identified CCGs include autophagy, cell cycle regulation, cell proliferation, kinase signaling pathways, immune infiltration, and immune checkpoint regulation. From this, we identified a novel 8-CCG signature significantly associated with survival pan-cancer, including CDK1, AP1S1, CASP3, MAP1LC3A, SNCA, TMPRSS6, MAPT, and GSK3B. Although some of these genes are known for their important roles in various malignancies and are associated with poor survival, this is the first study defining their connection with high copper levels in cancer cells. Furthermore, in keeping with previous studies that have used metal regulatory genes to predict outcomes in a specific cancer type, we specifically used low grade glioma (LGG), a cancer type highly impacted by intracellular copper level, as an example to explore the role of CCGs in a specific cancer type. Through our proposed gene regulatory network methodology, we identified a 3-gene signature that overlapped with a 6-gene prognostic risk score model for LGG patients. These 6 genes included ALB, CASP3, CDK1, CP, CYP1A1, and MT-CO1. To our knowledge, this is the first pan-cancer analysis for genes related to cuproplasia. The findings from our study highlight the use of gene regulatory networks to identify CCGs which could be used to develop novel targeted therapeutic strategies. Citation Format: Vu Viet Hoang Pham, Toni Jue, Jessica Bell, Fabio Luciani, Filip Michniewicz, Giuseppe Cirillo, Linda Vahdat, Chelsea Mayoh, Orazio Vittorio. Unraveling a prognostic and predictive 8-gene signature related to cuproplasia in pan-cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4942.

Abstract 4073: Decoy-resistant IL-18 enhances checkpoint inhibitor combinations beyond anti-PD-1 in vitro and in vivo

Abstract Background: Interleukin-18 (IL18) is a proinflammatory cytokine that modulates both innate and adaptive immune responses. Historically, wild-type recombinant IL-18 has shown limited anti-tumor efficacy in preclinical models and clinical trials, likely due to upregulation of IL-18 binding protein (IL-18BP), a negative regulator of the IL-18 signaling axis. Accordingly, an engineered IL-18 cytokine capable of interacting with the IL-18 receptor, but resistant to IL-18BP interactions (i.e., “Decoy-Resistant IL-18”, DR-18), has demonstrated enhanced therapeutic potential in mouse tumor models, both as a single agent and in combination with anti-PD-1 [1, 2]. Here we evaluated murine DR-18 in combination with additional checkpoint inhibitors beyond anti-PD-1 in a set of mouse tumor models, and tested human DR-18 activity in vitro/ex vivo for activation of human immune cells and anti-tumor activity. Results: Treatment with mDR-18 elicited strong efficacy as a single agent and combination activity with immune checkpoint inhibitors (ICIs) across diverse syngeneic mouse models of solid tumors. As a single agent, mDR-18 demonstrated robust single agent activity in tumor growth inhibition for MC38 (&amp;gt;80%), CT26 (&amp;gt;60%) and B16-F10 (&amp;gt;55%). Combination treatment of mDR-18 with anti-PD-1, anti-CTLA-4, or anti-LAG-3 increased the efficacy for the MC38 (&amp;gt;85-95%), CT26 models (&amp;gt;80-85%), while the B16-F10 (&amp;gt;60%) showed smaller efficacy enhancement with the combinations. In vitro assays revealed human DR-18 (ST-067) activated immune cells and enhanced A549 tumor cell killing over 72hrs. Furthermore, ex vivo studies of 3D patient-derived tumor spheroids demonstrated that ST-067 impaired growth and increased immune cell infiltration, highlighting the potential of hDR-18 to enhance immune activity within the human tumor microenvironment. Conclusion: These studies expand the breadth of IL-18/checkpoint synergism beyond anti-PD-1 and confirm enhanced human immune response in vitro with the clinical candidate ST-067. Taken together, these findings strengthen the rationale for clinical combination of ST-067 with ICI agents in patients with solid tumors. 1.Zhou T, Damsky W, Weizman OE, et al. IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy. Nature. 2020;583(7817):609-614. doi:10.1038/s41586-020-2422-62.Minnie SA, Waltner OG, Ensbey KS, et al. Depletion of exhausted alloreactive T cells enables targeting of stem-like memory T cells to generate tumor-specific immunity. Sci Immunol. 2022;7(76):eabo3420. doi:10.1126/sciimmunol.abo3420 Citation Format: Jeffrey N. Lindquist, Kai Qin, Aaron M. Ring, Hirdesh Uppal. Decoy-resistant IL-18 enhances checkpoint inhibitor combinations beyond anti-PD-1 in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4073.

State of the Art in 3D Culture Models Applied to Thyroid Cancer.

Thyroid cancer (TC) is the prevalent endocrine tumor with a rising incidence, particularly in higher-income countries, leading to an increased interest in its management and treatment. While overall, survival rates for TC are usually favorable, advanced cases, especially with metastasis and specific histotypes, pose challenges with poorer outcomes, advocating the need of systemic treatments. Targeted therapies have shown efficacy in both preclinical models and clinical trials but face issues of resistance, since they usually induce partial and transient response. These resistance phenomena are currently only partially addressed by traditional preclinical models. This review explores the limitations of traditional preclinical models and emphasizes the potential of three-dimensional (3D) models, such as transwell assays, spheroids, organoids, and organ-on-chip technology in providing a more comprehensive understanding of TC pathogenesis and treatment responses. We reviewed their use in the TC field, highlighting how they can produce new interesting insights. Finally, the advent of organ-on-chip technology is currently revolutionizing preclinical research, offering dynamic, multi-cellular systems that replicate the complexity of human organs and cancer-host interactions.

Abstract 2815: Immunotherapy development landscape for bone metastasis - need of predictive preclinical efficacy evaluation for de-risking clinical development

Abstract Most cancer deaths are due to metastases, and bone metastases are challenge especially in breast and prostate cancer, being developed in 70-90% of advanced-stage patients. Bone metastases remain incurable causing high mortality, skeletal-related effects and decreased quality of life. Currently used immunotherapies are ineffective in bone metastases. This creates a need to improve understanding immune microenvironment in bone metastases, namely interactions between tumor, immune and bone cells according to the osteoimmuno-oncology (OIO) concept, and ultimately to develop immunotherapies that primarily target bone metastases. We used 1stOncology database, a cancer drug development resource to identify novel immunotherapies in development for breast and prostate cancer bone metastasis. Twenty-four immunotherapies that included evaluation of effects on bone metastasis were identified. Efficacy of only three of the identified therapies had been evaluated in preclinical bone metastasis models, one reason being that such models have not been commonly available. The use of clinically relevant and predictive preclinical bone metastasis models would significantly de-risk decision making when moving to clinical development in bone metastasizing cancers. To support predictive preclinical evaluation of immunotherapies for bone metastatic cancers, we describe a preclinical bone metastasis technology platform for evaluating efficacy of immunotherapies. The platform utilizes tumors growing in bone microenvironment, mimicking growth of bone metastases in patients, and generates tumor-induced bone effects in a cancer-type specific manner. Syngeneic and/or humanized mouse models with tumor and immune cells of the same species are needed for development of immunotherapies, allowing interactions of tumor and immune cells in the bone metastatic microenvironment to support mode-of-action studies. The platform is clinically predictive, as demonstrated with observed effects that align with clinical findings. As an example, anti-PD-1 antibody had no effects on breast and prostate cancer bone metastases, predicting recent clinical findings that demonstrate lack of efficacy in clinical prostate cancer trials. We conclude that tumor microenvironment in bone metastases has unique characteristics and is understudied as a potential primary cause of lack of efficacy of many immunotherapies, especially in breast and prostate cancer. It is prime time to focus on bone metastases by increasing understanding of the immune landscape in the bone tumor microenvironment according to the OIO concept. The biologically relevant and clinically predictive preclinical bone metastasis technology platform should be routinely used to study the mechanism-of-action and efficacy of therapies before entering clinical development in bone metastasizing cancers. Citation Format: Tiina E. Kähkönen, Jussi M. Halleen, Gary MacRitchie, Ronnie M. Andersson, Jenni Bernoulli. Immunotherapy development landscape for bone metastasis - need of predictive preclinical efficacy evaluation for de-risking clinical development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2815.

Longitudinal data of serum creatine kinase levels and motor, pulmonary, and cardiac functions in 337 patients with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) presents with skeletal muscle weakness, followed by cardiorespiratory involvement. The need for longitudinal data regarding DMD that could serve as a control for determining treatment efficacy in clinical trials has increased notably. The present study examined the longitudinal data of Japanese DMD patients collectively and assessed individual patients with pathogenic variants eligible for exon-skipping therapy. Patients with DMD who visited Kobe University Hospital between March 1991 and March 2019 were enrolled. Data between the patients' first visit until age 20 years were examined. Three hundred thirty-seven patients were included. Serum creatine kinase levels showed extremely high values until the age of 6 years and a rapid decline from ages 7-12 years. Both the median 10-m run/walk velocity and rise-from-floor velocity peaked at the age of 4 years and declined with age. The values for respiratory function declined from the age of 11 years. The median left ventricular ejection fraction was >60% until the age of 12 years and rapidly declined from ages 13-15 years. Examination of the relationship between pathogenic variants eligible for exon-skipping therapy and longitudinal data revealed no characteristic findings. We found that creatine kinase levels and motor, respiratory, and cardiac functions each exhibited various changes over time. These findings provide useful information about the longitudinal data of several outcome measures for patients with DMD not receiving corticosteroids. These data may serve as historical controls in comparing the natural history of DMD patients not on regular steroid use in appropriate clinical trials.

MASH clinical trials and drugs pipeline: An impending tsunami.

Metabolic dysfunction-associated steatotic liver disease, formerly known as NAFLD, has ascended to prominence as the predominant chronic liver disease in Western countries and now stands as a leading cause of liver transplantations. In the more advanced stage, metabolic dysfunction-associated steatohepatitis (MASH) may lead to fibrosis, a gateway to cirrhosis, liver cancer, and liver failure. Despite extensive research and exploration of various drug mechanisms, the anticipation for the inaugural approved drug to materialize by 2024 is palpable, marking a significant milestone. Numerous pathways have been investigated for MASH treatment, exploring thyroid hormone receptors, glucagon-like peptides 1, peroxisome proliferator-activated receptors, and agents influencing hepatic steatosis synthesis, inflammatory pathways, genetic components, fibrosis mechanisms, and an array of other avenues. Over time, key regulatory directions have crystallized, now manifesting in 2 primary endpoints under investigation: resolution of steatohepatitis without worsening fibrosis and/or improvement of fibrosis stage without worsening of steatohepatitis, especially used in phase 3 clinical trials, while alternative noninvasive endpoints are explored in phase 2 trials. The prospect of proving efficacy in clinical trials opens doors to combination therapies, evaluating the ideal combination of drugs to yield comprehensive benefits, extending beyond the liver to other organs. Certain combination drug trials are already underway. In this review, we discuss the forefront of MASH drug research as of 2023/2024, illuminating mechanisms, outcomes, and future trajectories. Furthermore, we tackle the challenges confronting MASH trials and propose potential strategies for surmounting them.

Efficacy of dupilumab in real-life settings: a STROBE study.

Dupilumab, a monoclonal antibody targeting IL-4 and IL-13, has demonstrated its efficacy in several clinical trials. However, to date, real-life data remains limited. The aim of our study was to assess the real-life impact of dupilumab on patients with severe and uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP) quality of life. This was a retrospective, monocentric, observational, real-life study, conducted in accordance with the STROBE guidelines. The following parameters were collected before treatment and at 1, 4, and 12 months: Sino-Nasal Outcome Test-22 (SNOT-22), nasal polyp score (NPS), Sniffin' Sticks-16 (SST-16), visual analog scale (VAS) for loss of smell, nasal congestion score (NCS), gustatory VAS, asthma control, oral corticosteroid usage, surgery rates, and occurrence of side effects. The study included 47 patients. SNOT-22 scores decreased from 52.4 ± 24.3 to 12.7 ± 10.5 at 12 months (p < 0.001). NPS decreased from 6.15 ± 1.71 to 1.57 ± 1.40 at 12 months (p < 0.001). SST-16 scores increased from 1.6 ± 2.83 to 9.1 ± 5.4 at 12 months (p < 0.001). NCS decreased from 2.45 ± 0.72 to 0.38 ± 0.63 at 12 months (p < 0.001). Prior to treatment, 72.3% were using oral corticosteroids, compared to 17.0% at 12 months (p < 0.01). Two patients required additional surgery, and 17% reported completely uncontrolled asthma, compared to 0% at 12 months (p < 0.01). Our real-life results confirm the efficacy of Dupilumab in the treatment of severe and uncontrolled CRSwNP.

Pharmacological Activities, Therapeutic Effects, and Mechanistic Actions of Trigonelline.

Trigonelline (TRG) is a natural polar hydrophilic alkaloid that is found in many plants such as green coffee beans and fenugreek seeds. TRG potentially acts on multiple molecular targets, including nuclear factor erythroid 2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor γ, glycogen synthase kinase, tyrosinase, nerve growth factor, estrogen receptor, amyloid-β peptide, and several neurotransmitter receptors. In this review, we systematically summarize the pharmacological activities, medicinal properties, and mechanistic actions of TRG as a potential therapeutic agent. Mechanistically, TRG can facilitate the maintenance and restoration of the metabolic homeostasis of glucose and lipids. It can counteract inflammatory constituents at multiple levels by hampering pro-inflammatory factor release, alleviating inflammatory propagation, and attenuating tissue injury. It concurrently modulates oxidative stress by the blockage of the detrimental Nrf2 pathway when autophagy is impaired. Therefore, it exerts diverse therapeutic effects on a variety of pathological conditions associated with chronic metabolic diseases and age-related disorders. It shows multidimensional effects, including neuroprotection from neurodegenerative disorders and diabetic peripheral neuropathy, neuromodulation, mitigation of cardiovascular disorders, skin diseases, diabetic mellitus, liver and kidney injuries, and anti-pathogen and anti-tumor activities. Further validations are required to define its specific targeting molecules, dissect the underlying mechanistic networks, and corroborate its efficacy in clinical trials.