tbuckley/cabot-search huggingface dataset:
Abstract 7306: Selective and novel ALDH1 inhibitor enhances immune checkpoint blockade therapy in preclinical models of MSS colorectal cancer
Authors: Akinchan Kumar, Andrada Constantinescu, Ismail Ceylan, Mileidys Perez-Alea, Bassam Janji
Journal: Cancer Research (2025)

Abstract Colorectal cancer (CRC) is the second leading cause of cancer-related deaths globally and the third most frequently diagnosed cancer type, according to the Global Cancer Observatory. While the emergence of immune-checkpoint inhibitors (ICI) in the past decade has transformed cancer treatment paradigms, their efficacy in CRC is limited, particularly in the microsatellite-stable (MSS) subtype, which constitutes 85% of cases. MSS CRC is characterized by a low mutation burden and an immunosuppressive tumor microenvironment (TME), resulting in poor responsiveness to ICIs. Recent studies have identified elevated ALDH1 expression and its enzymatic products in MSS tumors, with retinoic acid (RA) produced by ALDH1 playing a pivotal role in fostering an immunosuppressive TME. This RA-mediated immunosuppression arises not only from tumor cells but also from tumor-associated immune cells, such as M2 macrophages and myeloid-derived suppressor cells (MDSCs), both of which exhibit high ALDH1 activity. Using syngeneic mouse models of MSS CRC, including MC38-CEA and CT26 cell lines, we evaluated the therapeutic potential of combining ABD0171, a selective ALDH1 inhibitor (ALDH1i), with anti-PD-1 therapy. Our findings reveal that ABD0171 significantly enhances the efficacy of anti-PD-1 therapy, leading to improved survival outcomes in MSS CRC models. This synergistic effect is associated with substantial alterations in the TME immune landscape, including an increase in pro-inflammatory M1 macrophages and reductions in both M2 macrophages and regulatory T cells (Tregs). Mechanistically, ALDH1 inhibition significantly reduces intratumoral RA levels, disrupting a key pathway responsible for the differentiation of immunosuppressive macrophages from monocytes. Ongoing studies are exploring the molecular mechanisms underlying these effects. Overall, our work underscores the potential of selective ALDH1 targeting as a strategy to overcome immunotherapy resistance in MSS CRC, offering new therapeutic opportunities for patients with this challenging cancer subtype. Citation Format: Akinchan Kumar, Andrada Constantinescu, Ismail Ceylan, Mileidys Perez-Alea, Bassam Janji. Selective and novel ALDH1 inhibitor enhances immune checkpoint blockade therapy in preclinical models of MSS colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7306.
Availability of Cardioprotective Medications for Type 2 Diabetes in the Medicaid Program
Authors: Anil N. Makam, Logan Bailey, Nigel Anderson, Kathy Bellitti, Sasha Skinner, Oanh Kieu Nguyen
Journal: Annals of Internal Medicine (2025)

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are the only type 2 diabetes medications that reduce cardiovascular disease and death, yet their availability in Medicaid is unclear. To assess the unrestricted availability of SGLT2is and GLP-1 RAs, using dipeptidyl peptidase-4 inhibitors (DPP4is) as a benchmark. National cross-sectional study using publicly available data. All 50 state Medicaid fee-for-service (FFS) plans and 273 nonelderly adult managed care organization (MCO) plans with comprehensive coverage in March 2024. Medicaid plans and enrollees with diabetes in those plans as of March 2024. Unrestricted availability was defined as having at least 1 medication in each class listed on the preferred drug list without prior authorization or step therapy. Of 50 FFS plans (including Washington, DC, and excluding 1 state, which had 5 MCO plans), 40 (80%) had unrestricted availability of SGLT2is, 30 (60%) of GLP-1 RAs, 41 (82%) of either, 29 (58%) of both, and 42 (84%) of DPP4is. Among 273 MCO plans (39 states; median, 6 plans [range, 2 to 24 plans]), 182 (67%) had availability of SGLT2is, 131 (48%) of GLP-1 RAs, 184 (67%) of either, 129 (47%) of both, and 204 (75%) of DPP4is. The proportion of MCO enrollees with availability varied markedly among states (SGLT2i range, 24% to 100%; GLP-1 RA range, 0% to 99%; DPP4i range, 41% to 100%). Primarily because of more MCO restrictions, 1.7 million enrollees (lower to upper bound, 1.33 million to 2.17 million enrollees; 25%) had restricted SGLT2i availability, 2.72 million (lower to upper bound, 2.12 million to 3.45 million; 40%) had restricted GLP-1 RA availability, and 1.5 million (lower to upper bound, 1.17 million to 1.90 million; 22%) had restricted DPP4i availability. Availability increased from 2020 to 2024, especially in FFS, but MCO GLP-1 RA availability has plateaued at below 60% since 2022. Tirzepatide was almost entirely restricted. Diabetes enrollment was estimated using plan size and state and national prevalence data. The appropriateness of prior authorization restrictions was unknown. Many Medicaid enrollees have restricted access to cardioprotective medications, particularly in MCO plans for GLP-1 RA medications, with substantial state variation. Formulary coverage is a potential lever to increase availability of these medications while balancing pharmaceutical costs. University of California, San Francisco, Action Research Center for Health Equity.
Abstract 6964: Dual inhibition of PKMYT1 and WEE1 kinases as a targeted therapy for ATIP3-deficient breast cancers
Authors: Maria M. Haykal, Marie Varin de Lapeyriere, Alexis Denis, Sylvie Rodrigues-Ferreira, Clara Nahmias
Journal: Cancer Research (2025)

Abstract ATIP3, a microtubule-associated protein with tumor suppressor functions, is frequently lost in aggressive breast cancers, particularly in 60-80% of triple-negative breast cancer (TNBC), where its absence correlates with poor prognosis. ATIP3 deficiency is associated with heightened aneuploidy, presenting a vulnerability exploitable by targeted therapies. WEE1 kinase, a critical regulator of the G2/M checkpoint, has demonstrated therapeutic promise in this context. Inhibiting WEE1 with AZD1775 selectively compromises ATIP3-deficient cells by exacerbating DNA damage, mitotic abnormalities and chromosome pulverization, ultimately leading to cell death. However, the clinical application of WEE1 inhibitors is constrained by dose-dependent toxicities, necessitating combination strategies to enhance efficacy while reducing toxicity. To address these challenges, we explored the complementary targeting of PKMYT1, another G2/M checkpoint kinase with distinct yet overlapping functions to WEE1. Using 3D cultures of breast cancer cell lines, we compared the responses of ATIP3-deficient and ATIP3-expressing cells to three PKMYT1 inhibitors—RP-6306, GSK1520489A, and MYT1-IN-I. ATIP3-deficient cells exhibited heightened sensitivity to all three inhibitors, particularly RP-6306, which achieved significantly lower IC50 values. To maximize therapeutic impact, we combined RP-6306 with AZD1775, resulting in a synergistic reduction in cell viability in ATIP3-deficient cells. Dual inhibition of WEE1 and PKMYT1 intensified replication stress, DNA damage, and abnormal mitoses, exceeding the effects observed with either inhibitor alone. Importantly, the dual-targeting approach enables the use of lower doses of WEE1 inhibitors, potentially mitigating the toxicities associated with high-dose monotherapies. Our findings establish PKMYT1 as a complementary target to WEE1 in ATIP3-deficient breast cancers. The synergistic effects of their combined inhibition not only enhance therapeutic efficacy but also address key limitations of current WEE1-based therapies. This dual-targeting strategy holds promise for improving outcomes in aggressive breast cancer subtypes. Furthermore, our work highlights the potential of ATIP3 as a predictive biomarker for patient stratification and the rational development of personalized therapies. Citation Format: Maria M. Haykal, Marie Varin de Lapeyriere, Alexis Denis, Sylvie Rodrigues-Ferreira, Clara Nahmias. Dual inhibition of PKMYT1 and WEE1 kinases as a targeted therapy for ATIP3-deficient breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6964.
Abstract 6965: Atypical protein kinase C-ι inhibitor suppresses the proliferation of malignant pancreatic ductal adenocarcinoma cells
Authors: Shreejana Rimal, Mildred Acevedo Duncan
Journal: Cancer Research (2025)

Abstract Pancreatic cancer is considered to be one of the most lethal malignant cancers as its diagnosis remains elusive if the disease progresses to an advanced stage. Moreover, pancreatic cancer is the third leading cause of cancer-related deaths in the U.S. Chemoresistance to various drugs for pancreatic cancer is the main reason for its aggressive nature. Atypical protein kinase is the family of protein kinases that contain two isoforms -ι and -ζ. These protein kinases which play a significant role in the signaling pathways have been proven to be involved in cancer cell proliferation and metastasis. (5-amino-1-((1R, 2S, 3S, 4R)-2, 3-dihydroxy-4-methyl cyclopentyl)-1H-imidazole-4-carboxamide-(ICA-1S), one of the specific inhibitors of Protein Kinase C-ι has been reported to inhibit the function of PKC-ι resulting to a decreased cell proliferation, decreased metastasis, and increased apoptosis. Our study focuses on using ICA-1S to inhibit PKC-ι in two pancreatic adenocarcinoma cell lines: ASPC1 and PANC1. Firstly, 50, 000 cells were seeded into 6 well plates and treated with different concentrations of ICA-1S (0.5µM, 5µM, 10µM, 20µM, and 50µM) in every 24 hours for three days. The drug-treated cells and the control were trypsinized to count the number of cells using Cellometer cell counting chambers. The highest percentage of inhibition by ICA-1S was observed at 10 µM for both the cell lines ASPC1 and PANC1 where the proliferation was observed to decrease at 52% in the case of ASPC1 and 49.8% in the case of PANC1 respectively. ICA-1S concentration of 10 µM is now used for further experiments. Western Blot analysis of both ASPC1 and PANC1 cell lines demonstrated the downregulation of the PKC-ι and PKC-ζ proteins. Similarly, the downregulation of apoptosis-related marker, Caspase 3 led us to hypothesize that apoptosis is induced in the drug-treated pancreatic cancer cells compared to the control. Mutation in KRAS is most common in pancreatic cancer where very few drugs have been approved by the FDA for the treatment of pancreatic adenocarcinoma. Thus, we will on the KRAS regulated pathway for further analysis. Further investigations would include the study of aPKC inhibitor-affected pathways using techniques like WST, immunoprecipitation assay, immunofluorescence, and Western blotting. Citation Format: Shreejana Rimal, Mildred Acevedo Duncan. Atypical protein kinase C-ι inhibitor suppresses the proliferation of malignant pancreatic ductal adenocarcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6965.
Abstract 6960: Specific BaF3 tumor platform for c-KIT and KRAS mutations
Authors: Ziwei Li, Hating Dai, Tianyu Pang, Jiali Liu, Wenbo Du, Wen-Jen Yu
Journal: Cancer Research (2025)

Abstract BaF3 cell line from mouse pro-B cell is rely on interleukin-3 (IL-3) for survival and widely used to evaluate the efficacy of kinase oncogenes, downstream signaling, and the blocking ability of small molecule kinase inhibitors by site specific mutation of target genes such as KRAS, EGFR, AKT, c-KIT, etc. However, few was known about the in vivo efficacy of BaF3 tumor models and the differences of efficacy from spontaneous mutation human cell lines. ICE bioscience constructed over 300 BaF3 point mutation stable cell lines as a good platform for high throughput screening in vitro. In this study, two specific BaF3 c-kit mutation tumor models (BaF3 c-KIT-V559-V560 del, BaF3 c-KIT-W557-K558 del-T670I) and BaF3 KRAS-G12C tumor models were established for efficacy evaluation of Imatinib, Sunitinib, and Sotorasib. The results showed that Imatinib 100 mpk inhibited BaF3 c-KIT-V559-V560 del tumor growth (TGI=111.10%, T/C=2.68%) and Sunitinib 40 mpk inhibited BaF3 c-KIT-W557-K558 del-T670I tumor growth (TGI=106.13%, T/C=2.03%), respectively. The efficacy of Sotorasib-30 mpk to Ba/F3 KRAS G12C tumor is significant and reached 89.37% TGI and 26.71% T/C. Although ASP3082 is a KRAS G12D inhibitor, the efficacy of ASP3082-3 mpk to KRAS-G12D GP2d CDX model is not relevant, only 37.29% TGI and 73.25% T/C values were found in this study. Western blotting showed that the BaF3 mutation tumor models are suitable for the drug discovery of specific point mutation anti-cancer drugs. Citation Format: Ziwei Li, Hating Dai, Tianyu Pang, Jiali Liu, Wenbo Du, Wen-Jen Yu. Specific BaF3 tumor platform for c-KIT and KRAS mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6960.
Abstract 4977: Knowledge and acceptance of the human papillomavirus vaccine in parents from the Colombian Caribbean
Authors: Ines Benedetti, Laura Mendoza Carmona, Valeria Duran Cordero, Sebastian Payares Florez, Ariel Marrugo Ortiz, Luis Alvis Estrada
Journal: Cancer Research (2025)

Abstract Introduction: cervical cancer ranks eighth in global cancer incidence and fourth among women worldwide. Its development is strongly associated with infection by the Human Papillomavirus (HPV) making vaccination a critical preventive measure. In 2012, Colombia’s Ministry of Health launched a free HPV vaccination program, positioning the country as one with the highest coverage rates globally. However, vaccination rates began to decline in 2014, with coverage for the second dose reported at 27% that year. This decline has been attributed to an incident occurred in 2014 in the municipality of El Carmen de Bolívar. The reasons behind this decrease and the current perceptions of parents regarding the vaccine remain unclear. The objective of this study was to identify factors influencing HPV vaccine acceptability among parents of girls under 13 in two Colombian Caribbean municipalities. Methods: a cross-sectional study was conducted among parents of girls under the age of 13 residing in two Colombian Caribbean municipalities. Data were collected using a structured survey administered, focused on exploring sociodemographic characteristics and knowledge related to the HPV vaccine. Results: a total of 238 participants were surveyed, with a mean age of 33 years old, 87.39% of whom were women. 78.1% belonged to the lowest socioeconomic stratum. All participants reported having daughters aged 13 years or younger. Vaccine acceptance was 76.8% (88% among those under 30 years old, n=84) and 70% among parents 30 years of age and older (n=154). Despite this, a significant proportion of participants lacked knowledge about how HPV is transmitted or prevented (38.6%, n= 92), and misconceptions about severe adverse effects, such as seizures, were common (between 32.79% and 35.34%). Conclusion: vaccine acceptance was associated with knowledge about HPV, and influenced by sociodemographic factors. In both communities, distrust regarding adverse effects remains a significant barrier to vaccination. Tailored educational interventions that address the specific needs and characteristics of each community are essential to address these challenges, improve HPV vaccine acceptance, and meet coverage goals, contributing to cervical cancer prevention and enhancing women’s quality of life. Citation Format: Ines Benedetti, Laura Mendoza Carmona, Valeria Duran Cordero, Sebastian Payares Florez, Ariel Marrugo Ortiz, Luis Alvis Estrada. Knowledge and acceptance of the human papillomavirus vaccine in parents from the Colombian Caribbean [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4977.
Risk for Stroke After Newly Diagnosed Atrial Fibrillation During Hospitalization for Other Primary Diagnoses
Authors: Husam Abdel-Qadir, Madison Gunn, Jiming Fang, Tomi Odugbemi, Irene Jeong, Peter C. Austin, Paul Dorian, Cynthia A. Jackevicius, Douglas S. Lee, Sheldon M. Singh, Karen Tu, Dennis T. Ko
Journal: Annals of Internal Medicine (2025)

Atrial fibrillation (AF) that is first diagnosed during hospitalization for other causes can subside with resolution of the inciting stressor. To describe the risk for stroke after newly diagnosed AF during hospitalization for other causes. Population-based retrospective cohort study. Ontario, Canada. Patients aged 66 years or older discharged alive from the hospital between April 2013 and March 2023 with a first diagnosis of AF. Newly diagnosed AF during hospitalization for other causes, categorized into cardiac medical, noncardiac medical, cardiac surgical, and noncardiac surgical. The primary outcome was hospitalization for stroke. The cumulative incidence function was used to estimate crude incidence, censoring on anticoagulant dispensation. Inverse probability of censoring weights were used to account for informative censoring. Atrial fibrillation was diagnosed in 20 639 patients (mean age, 77.1 years; 58.1% male) while hospitalized for other causes: 8340 (40.4%) for noncardiac medical, 7097 (34.4%) for cardiac surgical, 3553 (17.2%) for noncardiac surgical, and 1649 (8.0%) for cardiac medical diagnoses. At 1 year, anticoagulants were being dispensed to 26.4% of patients with CHA2DS2-VA scores of 1 to 4 and 35.2% of those with CHA2DS2-VA scores of 5 to 8. The 1-year risk for stroke without anticoagulation was 1.3% (95% CI, 0.7% to 2.3%) for cardiac medical, 1.2% (CI, 0.9% to 1.5%) for noncardiac medical, 1.1% (CI, 0.8% to 1.7%) for noncardiac surgical, and 1.0% (CI, 0.7% to 1.3%) for cardiac surgical patients. Patients with CHA2DS2-VA scores of 1 to 4 had a 1-year stroke risk of 0.7% (CI, 0.6% to 1.0%) without anticoagulation, compared with 1.8% (CI, 1.4% to 2.2%) at CHA2DS2-VA scores of 5 to 8. Long-standing AF may have been misclassified as newly diagnosed, leading to overestimation of stroke risk. Among patients with newly diagnosed AF during hospitalization for other causes, a substantial proportion with low CHA2DS2-VA scores receive anticoagulation, with modest increases in this proportion at higher scores. The stroke risk in patients with CHA2DS2-VA scores greater than 4 approximated the 2% threshold commonly used to initiate anticoagulation in AF. Canadian Cardiovascular Society.
Abstract 2116: 2MW7061, a novel LILRB4xCD3 bispecific T-cell engager targeting monocytic acute myeloid leukemia
Authors: Yu Pang, Cuicui Guo, Zhen Han, Fenglin Yun, Ao Li, Hai Wu, Xun Gui
Journal: Cancer Research (2025)

Abstract Background: Acute myeloid leukemia (AML) is a highly aggressive hematologic malignancy with a high recurrence rate, highlighting the urgent need for therapies that induce durable responses and improve survival outcomes. LILRB4 is highly expressed in FAB M4 and M5 subtypes of AML, while absent in normal hematopoietic stem and progenitor cells, making it an appealing target for selective immunotherapy. We developed 2MW7061, a bispecific LILRB4xCD3 T-cell engager, designed to target and eliminate LILRB4-expressing tumor cells by selectively activating T cells. Methods: 2MW7061 was generated through the screening and optimization of bispecific antibodies with varying geometries, formats, and CD3-binding affinities. The final construct utilizes a 1+2 format, with two Fab arms targeting LILRB4 and one single-chain variable fragment (scFv) arm targeting CD3. The affinity of 2MW7061 was measured using Octet, and its binding to T cells and AML cell lines was assessed. Functional activity was evaluated using Jurkat NF-AT reporter assays, T-cell activation assays, and tumor-directed cytotoxicity assays (TDCC). In vivo anti-tumor efficacy was tested in B-NDG/hu-PBMC and B-NCG/hu-PBMC mouse models implanted with THP-1-luc and MOLM-13 tumors, respectively. Safety and tolerability were evaluated in cynomolgus monkeys. Results: 2MW7061 demonstrated reduced binding to T cells in the absence of tumor cells, effectively minimizing off-target T-cell activation and mitigating the risk of cytokine release syndrome (CRS). In vitro, 2MW7061 exhibited tumor-associated antigen (TAA)-dependent binding and induced potent cytotoxicity. In vivo, 2MW7061 significantly inhibited tumor growth in both THP-1 (high LILRB4 expression) and MOLM-13 (low LILRB4 expression) xenograft models, indicating that its anti-tumor activity is LILRB4-dependent. In non-human primates, 2MW7061 administration resulted in minimal and transient increases in serum cytokines and C-reactive protein, with no significant signs of toxicity observed. Conclusion: 2MW7061 is a bispecific T-cell engager with potent LILRB4-dependent anti-tumor activity in preclinical models of monocytic AML. Its low nonspecific T-cell binding and favorable safety profile in non-human primates support its continued development as a promising therapeutic candidate for clinical evaluation in AML. Citation Format: Yu Pang, Cuicui Guo, Zhen Han, Fenglin Yun, Ao Li, Hai Wu, Xun Gui. 2MW7061, a novel LILRB4xCD3 bispecific T-cell engager targeting monocytic acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2116.