tbuckley/cabot-search huggingface dataset:
Abstract 5987: Mutations in <i>PIK3R1</i> activate multiple targetable pathways in triple-negative breast cancer
Authors: Abde M. Abukhdeir, Kelly Cagin, Jeffrey Borgia, Melody Cobleigh
Journal: Cancer Research (2025)

Abstract Background: Approximately 5% of triple-negative breast cancers (TNBCs) carry mutations in the PIK3R1 gene (PIK3R1MUT). Our prior studies showed that breast cancer cells lacking PIK3R1 protein had increased MEK activation, enhancing their responsiveness to the MEK inhibitors trametinib and binimetinib. Alpelisib targets the PI3K pathway. We hypothesized that alpelisib might also inhibit growth of PIK3R1MUT TNBC. This study tested binimetinib and alpelisib in PDX models with PIK3R1MUT. Methods: Five TNBC PDX models harboring either PIK3R1wt or PIK3R1MUT were studied (Table 1 ). Animals were treated with vehicle, binimetinib (10 mg/kg BID), alpelisib (35 mg/kg QD), or both for 28 days. Tumor volumes were recorded biweekly. All PDXs harbored PIK3CAwt but had mutations in other PI3K or MAPK genes. Mass spectrometry will be used to elucidate downstream protein and phosphoprotein expression. Results: Single-agent binimetinib or alpelisib did not result in significant tumor growth reduction in Models A and B. Binimetinib alone resulted in a slightly significant effect in Model C. However, a highly significant effect of both single agents was observed in Model D (p=0.0001). Binimetinib and alpelisib in combination significantly reduced tumor growth in all models, particularly in model D (p=0.0126, p=0.009, p=0.0011, and p&amp;lt;0.0001 in Models A-D, respectively). The mass spectrometry results, and efficacy data from Model E will be presented at the meeting. Conclusions: Mutations in PIK3R1 sensitize TNBCs to combined MEK and PI3K pathway inhibition. NF1 mutations alone do not confer sensitivity to single agents but enhance response when combined with binimetinib and alpelisib. These findings support the combination of MEK and PIK3CA inhibitors as a potential strategy for treating PIK3CAMUT TNBCs. Disclaimer: AMA is employed by AstraZeneca but contributed to this publication in his own capacity. The views expressed are his own and do not necessarily represent the views of AstraZeneca. Citation Format: Abde M. Abukhdeir, Kelly Cagin, Jeffrey Borgia, Melody Cobleigh. Mutations in PIK3R1 activate multiple targetable pathways in triple-negative breast 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 5987.
Abstract 1398: Caspase-1 dependent lytic cell death influences intra-tumoral neutrophil-to-lymphocyte ratio that limits chemotherapy efficacy
Authors: Stephen (Qi Rong) Wong, Ethan Subel, Kazukuni Hayashi, Hongbo Gao, Fotis Nikolo, Keith Chan
Journal: Cancer Research (2025)

Abstract Chemotherapy remains a cornerstone in the treatment of bladder cancer, with most studies emphasizing its direct cytotoxic effects to induce tumor cell death. However, the influence of various cell death modalities—such as apoptosis, pyroptosis, necroptosis, and ferroptosis—on the immune system remains underexplored. These modalities can either promote an immunogenic response or foster immunosuppression, notably through mechanisms such as altering the neutrophil-to-lymphocyte ratio (NLR), which can impact chemotherapy efficacy. In our study, we observed that gemcitabine treatment in a murine bladder cancer model enriched for a caspase-1-dependent lytic cell death that was non-immunogenic and contributed to an immunosuppressive tumor microenvironment by increasing intra-tumoral NLR. Notably, genetic deletion of caspase-1 shifted this non-immunogenic cell death to an immunogenic form. Additionally, pharmacological inhibition of caspase-1 using VX-765 provided therapeutic benefits by reducing NLR, significantly suppressing tumor growth. While lytic or pyroptotic cell death may be advantageous in the context of infections, our findings highlight a paradox: in the context of chemotherapy treatment, caspase-1-dependent lytic cell death/ pyroptosis can play a detrimental role by promoting an immunosuppressive environment that limits efficacy. These results underscore the importance of understanding and modulating cell death pathways to optimize therapeutic outcomes in cancer. Citation Format: Stephen (Qi Rong) Wong, Ethan Subel, Kazukuni Hayashi, Hongbo Gao, Fotis Nikolo, Keith Chan. Caspase-1 dependent lytic cell death influences intra-tumoral neutrophil-to-lymphocyte ratio that limits chemotherapy efficacy [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 1398.
Abstract 1855: Insights from drug development experts: Surveying challenges and outcomes for large-volume subcutaneous oncology drugs
Authors: Mehul Desai, Omar Rahman, Beate Bittner, Wei Chen, Maxwell Koobatian, Deepa Rajagopalan
Journal: Cancer Research (2025)

Abstract With several well-known large-volume subcutaneous (SC) oncology drugs, such as daratumumab, trastuzumab, rituximab, nivolumab, and pembrolizumab, either approved or in trials, understanding how administration volume impacts drug development is critical. Patients generally prefer SC over intravenous administration. However, SC adoption is often limited by the perception that delivery volumes must stay below 3 milliliters without a permeation enhancer. This misconception hampers SC oncology drug prioritization and stifles innovation. To better understand these challenges, a survey was conducted to investigate decision-making processes surrounding large-volume SC oncology drug candidates. The online survey, conducted November 20-26, 2024, targeted 80 drug development professionals with SC drug development experience equally representing new product planning, drug formulation, combination products, and clinical development. Of the participants, 43 primarily worked in oncology. The 23-item survey explored perceptions of SC volume thresholds, factors influencing the deprioritization of oncology drug candidates, the potential of large-volume delivery solutions in oncology, and how organizations track and revisit deprioritized candidates. The oncology respondents stated that 32% of drugs are abandoned due to challenges with drug volume. The most common reason for abandonment of the asset was lack of experience with large-volume formulations or devices. Similarly, the respondents stated that 29.5% of drugs are deprioritized due to difficulties in reducing subcutaneous drug volumes. When it came to deprioritizing assets, the primary reason was that large-volume drugs are only pursued if they address a unique unmet need regardless of the competitive landscape. Participants rated the commercial potential of these abandoned or deprioritized drugs at a 3 on a scale of 1-4 (1 = low potential, 4 = high potential) indicating that these drugs had worthwhile commercial potential. Fortunately, participants ranked the organizations willingness to revisit these drug candidates at a 3 on a scale of 1-4 (1 = not open at all, 4 = extremely open). The results suggest that oncology molecules with worthwhile commercial potential remain unexplored within companies due to misconceptions around large-volume SC delivery, with a high willingness to revisit these candidates. Citation Format: Mehul Desai,1 Omar Rahman,1 Beate Bittner,2 Wei Chen,3 Maxwell Koobatian,4 Deepa Rajagopalan5. Insights from drug development experts: Surveying challenges and outcomes for large-volume subcutaneous oncology drugs [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 1855.
Robot-assisted Single-docking Approach for Level III Inferior Vena Cava Tumor Thrombectomy: Surgical Technique and Outcomes
Authors: Shengzheng Wang, Gaurab Pokhrel, Jinshan Cui, Shuanbao Yu, Yafeng Fan, Zhaowei Zhu, Jin Tao, Xuepei Zhang
Journal: European Urology (2025)
Abstract 1399: Selective induction of apoptosis in pancreatic ductal epithelioid carcinoma PANC-1 cells and normal pancreatic ductal epithelial HPDE6c7 cells by Chinese medicinal herbs <i>Scutellaria barbata</i> and <i>Oldenlandia diffusa</i>
Authors: Abby Shim, Jessica Lee, Ryan Hayes, Brian Yuen Yau Wong
Journal: Cancer Research (2025)

Abstract Pancreatic cancer is a highly lethal disease, marked by late-stage diagnosis and rapid metastasis. Despite treatment advances, chemoresistance persists, leading to poor survival outcomes. Conventional therapies often lack selectivity, causing damage to healthy cells. Scutellaria barbata (SB) and Oldenlandia diffusa (OD) are traditional Chinese medicinal herbs used in treatment formulas in Taiwanese hospitals. We previously showed that SB and OD significantly induce apoptosis in PANC-1 cancer cells. To investigate their potential selective ability, aqueous extracts of these herbs were used on pancreatic ductal epithelioid carcinoma PANC-1 cells derived from a 56-year-old male and on normal pancreatic ductal epithelial HPDE6c7 cells obtained from the pancreatic duct of a 63-year-old female. This study used a green/red/blue fluorescent Apoptosis/Necrosis Detection Kit and Human Apoptosis Antibody Array - Membrane (43 Targets) Test (Abcam). Our fluorescent apoptosis data showed that a 2-hour treatment with 1.0 mg/mL aqueous extract of SB induced a statistically significant percentage of apoptosis in PANC-1 cells as compared to the negative control (88.9 ± 5.6% &amp;gt; 2.7 ± 0.9%); p&amp;lt;0.05. In contrast, there was no notable induction of apoptosis in the normal HPDE6c7 cells under SB treatment (1.75 ± 0.25%). Similar apoptotic induction was observed under OD treatment in PANC-1 cells (92.0 ± 0.1% &amp;gt; 2.7 ± 0.9%); p&amp;lt;0.05, while HPDE6c7 cells remained non-induced (5.25 ± 4.25%). Furthermore, antibody array membrane data revealed significantly higher upregulation of various pro-apoptotic proteins – such as Caspase 8, IGFBP-3, sTNR-R2, and TRAILR-1 – in PANC-1 cells under OD treatment in comparison to normal HPDE6c7 cells. Modulation of pro-apoptotic proteins was also observed under SB treatment. Both OD and SB treatments led to higher expression of anti-apoptotic proteins in HPDE6c7 cells compared to PANC-1 cells. These results suggest that SB and OD contain phytochemicals capable of selectively inducing apoptosis in pancreatic ductal cancer cells PANC-1 while leaving normal HPDE6c7 cells non-induced. Further research could reveal their precise impact on regulating apoptotic pathways, which may uncover their potential as chemopreventive and therapeutic agents for pancreatic cancer. Citation Format: Abby Shim, Jessica Lee, Ryan Hayes, Brian Yuen Yau Wong. Selective induction of apoptosis in pancreatic ductal epithelioid carcinoma PANC-1 cells and normal pancreatic ductal epithelial HPDE6c7 cells by Chinese medicinal herbs Scutellaria barbata and Oldenlandia diffusa [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 1399.
Progressing towards the 2030 health-related SDGs in ASEAN: A systematic analysis
Authors: Yafei Si, Lei Guo, Shu Chen, Xinyu Zhang, Xiaochen Dai, Daniel Wang, Yunguo Liu, Bach Xuan Tran, Paul Michael Pronyk, Shenglan Tang
Journal: PLoS Medicine (2025)

Background The Sustainable Development Goals (SDGs) articulate an ambitious global agenda and set of targets to achieve by 2030. Among the health-related SDGs, many formidable challenges remain in settings like the Association of Southeast Asian Nations (ASEAN) which face wide-ranging social, economic and health inequalities. In advance of the 2030 horizon, charting the trajectory of the health SDGs is critical for informing policy and programmatic course corrections to advance health and well-being among ASEAN’s 10 member countries with its 667 million people. Methods and findings We used estimates from the Global Burden of Disease (GBD) Study 2021 and surveillance data to identify 27 health-related SDG indicators. The indicators were classified into 7 thematic areas: (i) nutrition, (ii) maternal, child and reproductive health (MCH), (iii) infectious diseases, (iv) non-communicable diseases (NCDs), (v) environmental health, (vi) universal health coverage (UHC), and (vii) road injuries. We developed an attainment index ranging from 0 to 100 for each SDG indicator by referencing the SDG targets and projected their progress to 2030. We find an overall positive progress towards the health-related SDG targets in ASEAN from 1990 to 2030. At the aggregate level by 2030, 2 member countries, Singapore and Brunei, are projected to achieve their targets (attainment score ≥ 90). At a wider regional level, ASEAN is projected to make substantial progress in nutrition, MCH, and UHC, with a majority of countries projected to come close to or achieve their targets. However, progress is projected to be slower in the areas of reducing the incidence of infectious disease (i.e., HIV and AIDs, hepatitis B, TB, and neglected tropical diseases), NCD-related mortality and its risk factors (i.e., harmful alcohol use and smoking), environment-related mortality and its risk factors (i.e., unsafe water and poor hygiene, and air pollution), and road injuries. Substantial disparities are identified in the region, with Singapore, Brunei, Malaysia and Thailand generally performing better than elsewhere. A limitation of our study was its reliance on historical trends which may not fully capture future political, social, or technological changes. Conclusions As a regional bloc, ASEAN faces persistent challenges in achieving health-related SDG targets by 2030, with unequal progress between countries. Moreover, epidemiological transitions and worsening environmental threats further compound potential gains. At the country level, efforts to enhance health system financing, quality and equity will need to be coupled with wider approaches that address structural drivers of disease. Furthermore, coordinated regional efforts will be essential to effectively respond to emerging threats posed by pollution and environmental risks.
Abstract 5495: Screens to identify TCR-specific epitopes using engineered antigen-presenting cells
Authors: Debbie Deng, Tianbing Liu, Kitt Paraiso, Paul Diehl, Alex Chenchik
Journal: Cancer Research (2025)

Abstract Despite the key role of T-cell receptors (TCRs) in adaptive immune responses, experimental validation of interactions between activated TCRs and cognate antigens remains a holy grail in developing novel molecular and cell-based therapeutics. To facilitate efficient screening of TCR-antigen interactions, we engineered both reporter Jurkat-NFAT-GFP cells to express candidate-activated TCRs, and antigen-presenting K562-HLA cells (APC) expressing a library of predicted peptide epitopes. To detect antigen-activation of Jurkat cells interacting with cognate epitopes, the K562 cells were engineered to express a single-chain variable fragment (scFv) which could bind IL2 released by the activated Jurkat-TCR cells. Jurkat-TCR reporter cells co-cultured with K562-APC cells induce expression of the HLA cognate epitope, which enables them to be labeled with PE anti-IL2 antibody and purified by FACS. The cognate epitope is characterized using NGS. To validate this TCR-epitope library screening system, we constructed and expressed a library of ∼100 cancer-associated epitopes in K562-HLA_A02:01 cells. The K562-HLA-epitope library was then co-cultured with the Jurkat reporter cells expressing MART1 TCR, NY-ESO-1 TCR or, as a control, CMV TCR. After staining with the IL2 antibody and FACS selection, stained APC cells detected specific epitopes with high specificity for cancer-associated and control TCRs. Citation Format: Debbie Deng, Tianbing Liu, Kitt Paraiso, Paul Diehl, Alex Chenchik. Screens to identify TCR-specific epitopes using engineered antigen-presenting 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 5495.
Abstract 1573: MW-C1, a novel CLDN1-targeting ADC demonstrates compelling anti-tumor efficacy and favorable safety profile in preclinical studies
Authors: Zhongfei Li, Jun Yang, Peng Fang, Rongrong Hu, Cuicui Guo, Xiaoding Tan, Hai Wu, Xun Gui
Journal: Cancer Research (2025)

Abstract Background: Claudins are a family of tight junction proteins characterized by four transmembrane domains, with critical roles in epithelial cell junction formation. While claudins localize to tight junctions in healthy tissues, their overexpression in solid tumors leads to aberrant exposure outside of these junctions, making them attractive targets for ADC therapies. CLDN1, in particular, is overexpressed in several solid tumors, including head and neck squamous cell carcinoma (HNSCC), lung squamous cell carcinoma (LUSC), and hepatocellular carcinoma (HCC), where its expression correlates with tumor proliferation, invasion, metastasis, and poor prognosis. Here, we developed a novel CLDN1-targeting ADC, MW-C1, that has shown potent anti-tumor activity across various preclinical models, along with an encouraging safety profile in non-human primates (NHPs). Methods: MW-C1 was engineered by conjugating monomethyl auristatin E (MMAE) to a CLDN1-targeting monoclonal antibody using site-specific interchain-disulfide conjugation technology and a cleavable linker, resulting in a drug-to-antibody ratio (DAR) of 4. In vitro, the internalization and cytotoxicity of MW-C1 were assessed in SCC4, Cal27, Huh7, and OVCAR3 cell lines, which express varying levels of CLDN1. In vivo efficacy was evaluated in multiple cell-line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Toxicology and pharmacokinetic studies were conducted in cynomolgus monkeys. Results: CLDN1 was found to be overexpressed in 85.7% of HNSCC, 91.7% of HCC, 58% of LUSC, and 77% of cervical cancer samples. MW-C1 demonstrated robust binding, rapid internalization, and potent cytotoxicity in CLDN1-positive cancer cell lines. In in vivo studies, MW-C1 induced significant and durable tumor regression in both CDX and PDX models, with varying CLDN1 expression levels. Pharmacokinetic studies revealed favorable properties for MW-C1 in both mice and cynomolgus monkeys, which were attributed to its optimized biophysical characteristics and site-specific conjugation. In a non-GLP NHP toxicology study, MW-C1 was well tolerated, with no significant off-target toxicity or adverse events observed. Conclusions: MW-C1 demonstrated potent anti-tumor efficacy and a favorable safety profile, highlighting its potential as a transformative therapeutic candidate for the treatment of CLDN1-overexpressing malignancies. Citation Format: Zhongfei Li, Jun Yang, Peng Fang, Rongrong Hu, Cuicui Guo, Xiaoding Tan, Hai Wu, Xun Gui. MW-C1, a novel CLDN1-targeting ADC demonstrates compelling anti-tumor efficacy and favorable safety profile in preclinical studies [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 1573.
Abstract 1485: BRCA2 haploinsufficiency leads to mitotic DNA synthesis at common fragile sites in human mammary epithelial cells
Authors: Kavya Vipparthi, Ariana Bellare, Mihriban Karaayvaz
Journal: Cancer Research (2025)

Abstract Germline mutations in BRCA2 confer up to a 70% lifetime risk of developing breast cancer due to BRCA2’s critical roles in homologous recombination repair, replication fork stability, and cell cycle regulation. In BRCA2 mutation carriers, mammary epithelial cells are haplo-insufficient, meaning a single functional allele is inadequate to maintain genomic stability and suppress tumorigenesis. Genomic instability, a hallmark of cancer, frequently involves fragile site instability, particularly at common fragile sites (CFSs), which are hotspots for chromosomal rearrangements under replication stress. While the association between fragile site instability and cancer has been documented, the specific link between BRCA2 haploinsufficiency and CFS instability remains unexplored. To address this gap, we modeled BRCA2 haploinsufficiency in human mammary epithelial cells using small-interfering RNA (siRNA)-mediated knockdown and induced replication stress with the DNA polymerase inhibitor aphidicolin (APH). Cytogenetic analysis using DAPI banding revealed increased CFS instability, particularly at FRA18B, in BRCA2-deficient cells compared to controls. Furthermore, we observed elevated levels of mitotic DNA synthesis (MiDAS) in BRCA2-deficient cells, a process typically activated at under-replicated regions of CFSs during mitosis to preserve genome integrity. These findings demonstrate that BRCA2 haploinsufficiency promotes CFS instability and aberrant MiDAS, uncovering novel mechanisms of genomic instability in preneoplastic mammary epithelial cells. By elucidating these early molecular events in BRCA2-associated breast cancer, our study provides critical insights into the etiology of tumorigenesis and lays the groundwork for innovative strategies to stabilize the genome in high-risk individuals, potentially improving breast cancer prevention and outcomes. Citation Format: Kavya Vipparthi, Ariana Bellare, Mihriban Karaayvaz. BRCA2 haploinsufficiency leads to mitotic DNA synthesis at common fragile sites in human mammary epithelial 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 1485.