tbuckley/cabot-search huggingface dataset:
Abstract LB167: Acetalax (Oxyphenisatin acetate, NSC 59687) and bisacodyl (dulcolax) cause oncosis in triple negative breast cancer by poisoning the ion exchange membrane protein TRPM4
Authors: Makito Mizunuma, Christophe Redon, Liton Saha, Naoko Takebe, Yves G. Pommier
Journal: Cancer Research (2024)

Abstract Triple negative breast cancer (TNBC) is generally unresponsive to current therapies, and the development of new anticancer agents is needed. Oxyphenisatin acetate, called Acetalax, which was used as a laxative in the 1950’s, has recently been reported to have anticancer activity in several murine cancer models. In this study we demonstrate that Acetalax and its structural analog laxative analog bisacodyl (Dulcolax) exhibit potent antiproliferative activity in TNBC cell lines. We show that both cause oncosis, a non-apoptotic cell death characterized by cellular and nuclear swelling and cell membrane blebbing that leads to mitochondrial dysfunction and ATP depletion. Acetalax was further shown to enhance immune and inflammatory responses and inhibit protein synthesis. Mechanistically, we provide evidence that TRPM4 (Transient Receptor Potential Melastatin member 4) is poisoned by Acetalax and bisacodyl. By blocking TRPM4, a monovalent cation channel, Acetalax and Bisacodyl cause oncosis, and TNBC cells without endogenous TRPM4 expression as well as TRPM 4 knockout TNBC cells were found to be Acetalax- and Bisacodyl resistant. TRPM4 was also lost in cells with acquired Acetalax resistance. Moreover TRPM4 is rapidly degraded the ubiquitin-proteasome system upon acute exposure to Acetalax and bisacodyl. Together, these results demonstrate that TRPM4 is a previously unknown target of Acetalax and Bisacodyl and that TRPM4 expression in cancer cells is a predictor of Acetalax and Bisacodyl efficacy, and could be used for the clinical development of these drugs as anticancer agents. Citation Format: Makito Mizunuma, Christophe Redon, Liton Saha, Naoko Takebe, Yves G. Pommier. Acetalax (Oxyphenisatin acetate, NSC 59687) and bisacodyl (dulcolax) cause oncosis in triple negative breast cancer by poisoning the ion exchange membrane protein TRPM4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB167.
High‐Resolution Additive Manufacturing of a Biodegradable Elastomer with A Low‐Cost LCD 3D Printer (Adv. Healthcare Mater. 9/2024)
Authors: Vahid Karamzadeh, Molly L. Shen, Hossein Ravanbakhsh, Ahmad Sohrabi‐Kashani, Sargol Okhovatian, Houman Savoji, Milica Radisic, David Juncker
Journal: Advanced Healthcare Materials (2024)
Abstract LB223: The molecular landscape of injury-induced mammary epithelial cell fate switching
Authors: Queralt Vallmajó Martín, Nikki K. Lytle, Divya Murali, Sumana Srinivasan, Zhibo Ma, Kavitha Mukund, Christopher Dravis, Liliana Zamora, Ana Peterson, Galina Khramtsova, Funmi Olopade, Shankar Subramaniam, Geoffrey M. Wahl
Journal: Cancer Research (2024)

Abstract The most aggressive cancers, such as triple negative basal-like breast cancer (TNBC), have high intratumoral heterogeneity that is often attributed to cell state reprogramming and contributes to cancer progression, treatment resistance, and ultimately cancer death. Tissue injury and microenvironmental changes can cause adult differentiated cells to acquire a plastic “developmentally unstable hybrid cell state” (DUHCS) enabling transdifferentiation into other cell types to effect repair. Yet, the relevant mechanisms that enable cell state reprogramming to arise remain under-explored. Here, we used CRISPR mediated homologous recombination to generate mice in which the mammary basal and luminal cells could be distinguished by their expression of Krt14-mClover-NLS or Krt18-tdTomato-NLS, respectively. We used this novel system to identify mammary epithelial cells undergoing cell state transitions in real time. Using a transplantation paradigm, we found that transplanted basal cells rapidly exhibited a DUHCS resembling mammary embryonic progenitors expressing Sox11, a tightly regulated differentiation factor shut off before birth. We discovered that Sox11 is also expressed in many murine models of TNBC and in single cell transcriptomes from untreated human BRCA1 mutant TNBCs. This suggests that Sox11-expressing cells might be developmentally plastic intermediates in TNBC malignant progression. In a preliminary cohort of patient-derived xenografts from TNBC patients diagnosed at different stages, we detected SOX11-expressing cells in earlier but not in advanced stages. Re-expression of Sox11 in TNBC is consistent with TNBCs being transcriptomically related to fetal mammary stem cells and p53 dysfunction resulting in enhanced cellular plasticity. Taken together, these studies highlight a role for mammary epithelial cell state reprogramming in early breast tumorigenesis, and reveals actionable steps to mitigate tumor heterogeneity by halting tumor progression. Citation Format: Queralt Vallmajó Martín, Nikki K. Lytle, Divya Murali, Sumana Srinivasan, Zhibo Ma, Kavitha Mukund, Christopher Dravis, Liliana Zamora, Ana Peterson, Galina Khramtsova, Funmi Olopade, Shankar Subramaniam, Geoffrey M. Wahl. The molecular landscape of injury-induced mammary epithelial cell fate switching [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB223.
Abstract LB279: The combination therapy with B7-H3 antibody drug conjugates for effective radiation treatment
Authors: Gawon Son, Eunjin Ju, Jin Park, Seolhwa Shin, Eunjeong Ko, Miri Kwon, Hyewon Lee, Beomseok Seo, Sangkwang Lee, Seoksoon Park, Seongyun Jeong, Siyeol Song, Eunkyung Choi
Journal: Cancer Research (2024)

Abstract Purpose: Antibody-drug conjugate (ADC) is a promising treatment modality because it enables effective tumor-specific delivery of anticancer drugs by targeting cancer antigens with antibodies. By using ADC, each treatment can be used at an optimal dose, thereby minimizing side effects, and maximizing treatment effects. The ADC used in this experiment targets B7-H3, and the B7-H3 protein is highly expressed in various cancer types. Recent studies have shown that B7-H3 is increased by radiation in various cancer cells. This study aims to demonstrate the efficacy of the B7-H3 ADC and confirm its combined effect with radiotherapy. Method: In vitro, colony forming assay, CCK-8 assay, FACs and western blotting were performed in JIMT-1 and HCT116 cell lines. In vivo, JIMT-1, HCT116 and Colon PDX models were developed to monitor tumor growth and survival rate. Biodistribution was performed through the IVIS (In Vivo Imaging System) spectrum. Result: The B7-H3 ADC used in the experiment was developed by combining DUBA as a toxin with anti-B7-H3 antibody In in vitro experiments, the combined treatment of radiation and B7-H3 ADC reduced cell viability via apoptosis more effectively than treatment alone. In the in vivo mouse models, we observed that the combined treatment of radiation and B7-H3 ADC was more effective in inhibiting tumor growth than the single treatment groups. The survival rate of the mice was also improved when the radiation was combined with B7-H3 ADC treatment compared to the other treatment groups alone. In the biodistribution results, the accumulation of B7-H3 ADC-Cy7 was further enhanced when irradiated. Conclusion: The results show that B7-H3 ADC can be used as a promising therapeutic agent and the combined treatment with radiation can obtain an improved anticancer effect than the single treatment, suggesting another cancer treatment method. Citation Format: Gawon Son, Eunjin Ju, Jin Park, Seolhwa Shin, Eunjeong Ko, Miri Kwon, Hyewon Lee, Beomseok Seo, Sangkwang Lee, Seoksoon Park, Seongyun Jeong, Siyeol Song, Eunkyung Choi. The combination therapy with B7-H3 antibody drug conjugates for effective radiation treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB279.
Abstract LB300: RNA splicing variants of the novel long non-coding RNA, CyKILR, exhibit distinct possess divergent biological functions in lung cancer
Authors: Xiujie Xie, Patrick H. Macknight, Amy L. Lu, Charles E. Chalfant
Journal: Cancer Research (2024)

Abstract The cyclin-dependent kinase inhibitor 2A (CDKN2A) gene encodes the tumor suppressors, p16(INK4A) and p14(ARF), and is found inactivated or deleted in non-small cell lung cancer at a high percentage. In this study, a novel, uncharacterized long non-coding RNA (lncRNA) (ENSG00000267053) located on chromosome 19p13.12 was found overexpressed in non-small cell lung cancer (NSCLC) cells with a wild-type and active CDKN2A gene. The expression of this Cyclin-Dependent Kinase Inhibitor 2A-regulated lncRNA (CyKILR) was also associated with the expression of the tumor suppressor, Liver kinase B1 (LKB1), a product of the STK11 gene. Characterization of CyKILR identified distinct RNA splicing variants classified into two groups based on their exon 3 inclusion/exclusion status, CyKILRa (exon 3 included) and CyKILRb (exon 3 excluded). The CDKN2A and STK11 gene products not only regulated the expression of CyKILR mRNA in non-transformed cells, but also the interplay between these genes synergistically regulated inclusion of exon 3 into the mature CyKILR RNA as shown by dramatic loss of exon 3 inclusion when mRNAs from both tumor suppressor genes were downregulated by siRNA. Functionally, CyKILRa predominantly localized to the nucleus, and targeted downregulation of the CyKILRa using antisense RNA oligonucleotides (ASOs) significantly enhanced cellular proliferation, migration, and clonogenic survival in mechanistic studies. In contrast, CyKILRb predominantly localized to the cytoplasm, and downregulation of CyKILRb using siRNA significantly reduced cell proliferation, migration, and clonogenic survival. Additionally, downregulation of CyKILRb, in stark contrast to CyKILRa, reduced tumor growth in vivo. Interrogation of cell signaling pathways by transcriptomics analyses demonstrated that CyKILRa suppressed key mitogenic pathways further demonstrating the tumor suppressive role of this CyKILR variant. On the other hand, CyKILRb induced key survival pathways further corroborating the oncogenic nature of this variant. Taken together, our findings shed light on the complexity of lncRNA expression and the alternative RNA splicing of lncRNAs as well as their roles in cell signaling and tumorigenesis. Citation Format: Xiujie Xie, Patrick H. Macknight, Amy L. Lu, Charles E. Chalfant. RNA splicing variants of the novel long non-coding RNA, CyKILR, exhibit distinct possess divergent biological functions in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB300.
Abstract LB150: The effect of a technology-based intervention on various needs for help among Asian American breast cancer survivors
Authors: Eun-Ok Im, Wonshik Chee
Journal: Cancer Research (2024)

Abstract Purpose: Asian American breast cancer survivors reportedly have high needs for help during their cancer survivorship process. Especially, the recent COVID19 pandemic with Anti-Asian racism exacerbated their situation with lack of information and support. To address their needs for help, there is a clear necessity for an innovative method of delivering information and coaching/support mainly due to their cultural stigma attached to breast cancer. A technology-based approach would work well for this specific population because of non-face-to-face interactions. Thus, a technology-based information and coaching/support program was developed based on the Bandura’s self-efficacy theory and pilot-tested among this specific population. In this study, the effect of the technology-based program was examined on various needs for help among a larger group of Asian American breast cancer survivors. Methods: This study used a randomized clinical trial design with repeated measures. The study included 199 participants who were recruited through both online and offline communities/groups for Asian Americans. With multiple measurement scales related to background characteristics and theory-based mediators, the Support Care Needs Survey-34 Short Form (SCNS) was used to measure various needs for help. The SCNS included five subscales on psychological, information, physical, support, and communication needs. Data were analyzed using an intent-to-treat approach and mediation analyses. Results: All types of needs except support needs decreased over time (p &amp;lt; .001). However, there were no significant group * time effects. Among all the theory-based mediators, only social support significantly mediated the effects of the program on psychological, information, and support needs at the pre-test and the post-1 month. Conclusions: This study supported significant effects of the technology-based program on various needs for help among Asian American breast cancer survivors. Future research needs to be conducted with other racial/ethnic minority groups of cancer survivors to confirm the findings reported in this presentation. Citation Format: Eun-Ok Im, Wonshik Chee, TICAA Research Team. The effect of a technology-based intervention on various needs for help among Asian American breast cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB150.
Abstract LB289: Single-cell CRISPR screens at scale to understand T cell biology
Authors: Nicole Untermoser, Johanna Irnstorfer, Anatoly Vasilyev, Nikola Vinko, Sumit Pawar, Anke Loregger, Adam Krejci, Henrik Schmidt, Tilmann Bürckstümmer
Journal: Cancer Research (2024)

Abstract CRISPR screens have become the primary discovery engine in modern biology and are widely used to uncover novel targets in immuno-oncology. However, these genetic screens are usually coupled to rather simplistic read-outs such as cell fitness. In contrast, CROP-Seq (or “CRISPR Droplet” Sequencing) screens combine CRISPR perturbation with single-cell transcriptomics, enabling high-content phenotyping at single-cell resolution. Briefly, cells are perturbed with a pooled sgRNA library and transcriptomic profiles of each cell are recorded using conventional single-cell RNA sequencing platforms. Currently, the scale of these screens is limited to the perturbation of a couple of hundred genes, possibly up to 1.000 genes, because of increased costs for single-cell library preparation and next generation sequencing (NGS). At Myllia, we have built a platform allowing high-content CROP-Seq screens in both CRISPR-ready cancer cell lines as well as primary immune cells, e.g., human T cells. Using CRISPR KO, CRISPR interference or CRISPR activation workflows, we can help accelerate the identification of target genes and regulatory networks involved in immuno-oncology. Primary T cells are of great interest in the immunotherapy community as they are key players in autoimmune and inflammatory disease. Engineered T-lymphocytes such as CAR-T cells are currently developed as novel cellular medicines, yet many T cell-intrinsic features involved in CAR-T potency remain elusive. To enable the discovery of novel targets, we have performed multiple customized CROP-Seq CRISPR KO screens in primary human T cells investigating T cell stemness and effector phenotypes as well as CD4+ T helper cell differentiation towards Th1, Th2, or Th17 subsets. Here, we present screens for regulators of functional T cell plasticity and Th2 commitment in which we aimed to identify genes determining critical T cell fate decisions, potentially linking gene (dys)function to either autoimmune/inflammatory disease or functional persistence of cytotoxic T cells for cancer immunotherapy. Overall, the advanced CROP-Seq platform combining large-scale perturbations and targeted sequencing (TA) read-outs will catalyse a paradigm shift for CROP-Seq enabling high-throughput functional genomic screens that support the validation of drug targets in autoimmunity, inflammation and immuno-oncology. Citation Format: Nicole Untermoser, Johanna Irnstorfer, Anatoly Vasilyev, Nikola Vinko, Sumit Pawar, Anke Loregger, Adam Krejci, Henrik Schmidt, Tilmann Bürckstümmer. Single-cell CRISPR screens at scale to understand T cell biology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB289.
Abstract LB140: Age difference in cervical cancer stigma among Caribbean population
Authors: Kamilah Thomas-Purcell, Gaole Song, Diadrey-Anne Sealy, Althea Bailey, Kimlin T. Ashing
Journal: Cancer Research (2024)

Abstract Introduction Cervical cancer (CCA) is the second most common cancer and one of the leading causes of death among women in the Caribbean region. CCA stigma impedes women from seeking and obtaining relevant healthcare. This study aimed to evaluate age difference in cancer stigma among non-patient populations in Jamaica, Grenada, and Trinidad and Tobago, utilizing a culturally trans-created scale. Methods A cross-sectional study involving 1207 participants was conducted. The survey comprised the adapted Cancer Stigma Scale, supplemented with questions on cervical cancer knowledge and beliefs. Participants' knowledge and attitudes towards the HPV vaccine were also assessed. Data was collected online from October 2022 to March 2023. Statistical analysis was performed using SAS. Results This study included 33.4% of total participants aged 18-25 years, 23.4% aged 26-35 years, 21.4 aged 36-45 years, 10.7% aged 46-55 years, 7.5% aged 56-65 years, and 3.6% aged 65+ years. Chi-squared tests showed age is significantly related to respondents’ opinions on women with CCA are treated with less respect than usual by others (p&amp;lt;.0001), women with CCA must keep it a secret (p=0.03), women with CCA are rejected by family members (p=0.0007), women with CCA are rejected by intimate partners (p&amp;lt;.0001), and intimate partners blame women for having CCA (p=0.003). Additionally, age has significant associations with agreements on negative views of cervical cancer from the community (p&amp;lt;.0001) and family (p&amp;lt;.0001) may discourage women from seeking and obtaining screening and treatment and community members believe CCA is viewed as shameful (p=.0001). Notably, there are more younger respondents (18-25 years) who agreed that women with CCA are rejected by intimate partners (32.3%), and the fear of family reaction and rejection may discourage women from getting further diagnosis after an abnormal Pap smear (48.1%). Discussion Age is an important factor that influences cervical cancer stigma even in Caribbean contexts. Findings of this study indicate younger people may have a more serious stigma, which calls for proper educational programs for cervical cancer screening and treatment. Citation Format: Kamilah Thomas-Purcell, Gaole Song, Diadrey-Anne Sealy, Althea Bailey, Kimlin T. Ashing. Age difference in cervical cancer stigma among Caribbean population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB140.
Abstract LB363: A novel humanized NKP46 mouse model to support xenograft studies evaluating NK cell-based cancer immunotherapies
Authors: Zhenlan Niu, Yongshun Li, Xiaofei Zhou, Jiawei Yao, Qingcong Lin, Meiqi Zhang, Qingqing Xu
Journal: Cancer Research (2024)

Abstract The NKP46 receptor is expressed by all NK cells, and plays a key role in the recognition and activation of NK cells against tumor cells. Cross-linking of NKp46 by monoclonal antibodies triggers both NK cell cytotoxic activity and cytokine release. As the only NCR present in mice, NKP46 is well conserved, but differences between the murine and human NKP46 protein necessitate use of humanized mice for evaluating preclinical efficacy of novel NKP46-targeting antibodies. Previously, we established humanized NKP46 mice on immunocompetent backgrounds for evaluating antibody efficacy in preventing growth of syngeneic tumor models. However, xenograft models in immunodeficient mice have also been widely employed as important in vivo models. Here, we describe a novel humanized NKP46 mouse on the CB-17-SCID background in order to inoculate human tumor cells for therapeutic efficacy testing. In this model, using gene editing technology, the portion of the mouse NKp46 gene encoding the extracellular domain was replaced by the corresponding human NKP46 coding sequences. Human NKP46 protein expression was confirmed on NK cells derived from splenocytes and bone marrow of B-hNKP46 mice(CB17-SCID) by flow cytometry. Subsequently, assessment of leukocyte populations in the humanized model indicated no significant alterations in the percentages of NK cells, dendritic cells, granulocytes, monocytes and macrophages in the spleen, bone marrow or blood of the humanized mice compared with wild-type CB17-SCID mice. Finally, tumor efficacy studies demonstrate that treatment with an anti-human NKP46 antibody significantly reduced BxPC-3 tumor growth at a range of doses in homozygous hNKP46 mice compared to PBS-injected controls. In summary, humanized B-hBKP46 mice(CB17-SCID) provide a suitable model for evaluating the efficacy of anti-human NKP46 antibody candidates. Citation Format: Zhenlan Niu, Yongshun Li, Xiaofei Zhou, Jiawei Yao, Qingcong Lin, Meiqi Zhang, Qingqing Xu. A novel humanized NKP46 mouse model to support xenograft studies evaluating NK cell-based cancer immunotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB363.