tbuckley/cabot-search huggingface dataset:
Abstract 4342: Breast cancer multi-omic single cell profiling identifies key progressive disease markers
Authors: Hugh Russell, Manisha Rao, Grant Duclos, Rogelio Aguilar, Nick Barkas, Megan Callahan, Ojasvi Chaudhary, Peter Gathungu, Chris Rands, Varsha Shankarappa, Daniel Stetson, Asaf Rotem, Maurizio Scaltriti, Brian Dougherty
Journal: Cancer Research (2024)

Abstract Breast cancer is one of the most diagnosed cancers and has a complex tumor microenvironment (TME). Breast tumors are subtyped by receptor expression, and all have a high degree of cellular heterogeneity. We analyzed tumors from 8 individuals with early-stage breast cancer. The patients had either triple negative breast (TNBC) or an estrogen receptor (ER) positive cancer. The tumors and normal adjacent tissue were profiled by single-nuclei gene expression (GEX) and ATAC data using the 10X multi-ome methodology. Gene set analysis identified specific epithelial clusters associated with the estrogen early/late response, epithelial mesenchymal transition, and several key cytokine pathways. From those epithelial cells, a subset highly proliferative in nature emerged. It consists of both ER positive and TNBC tumor types enriched for specific DNA transcriptional motifs including those for stem cell (Yamanaka) factors and other cellular proliferation motifs. GEX proliferation markers such as MKi-67 were also highly expressed. Overlaying GEX and ATAC data, it was possible to filter the numerous differentially expressed genes and peaks into a subset of genes specific to progressive breast cancer within the proliferative cluster. Those genes included ESRP1, POP4, CCNE1, and AAMDC all of which are associated with progressive breast cancer. To further elucidate the complexity of the TME, we examined clusters of fibroblasts from our dataset. A difference in cancer associated fibroblast marker gene expression was related to the level of ER expression expressed in the tumor epithelium. In general, ER-low tumor fibroblasts had higher expression of immune cancer associated fibroblasts (iCAFs) markers while ER-positive and TNBC tumors had greater expression of extracellular matrix associated markers (emCAFs). Specific clusters were enriched for emCAFs and iCAFs representing another critical part of the TME. In conclusion, using a multi-modal single-cell approach to the TME allowed the identification of an aggressive cluster of epithelial cells marked by genes for cellular proliferation and noted therapeutic targets while also characterizing other critical TME components especially, CAFs. Citation Format: Hugh Russell, Manisha Rao, Grant Duclos, Rogelio Aguilar, Nick Barkas, Megan Callahan, Ojasvi Chaudhary, Peter Gathungu, Chris Rands, Varsha Shankarappa, Daniel Stetson, Asaf Rotem, Maurizio Scaltriti, Brian Dougherty. Breast cancer multi-omic single cell profiling identifies key progressive disease markers [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 4342.
Abstract 4159: Noninvasive measurement of murine glioblastoma <i>in vivo</i> with a benchtop ultrasound instrument
Authors: Thomas M. Kierski, Juan D. Rojas, Morrent Thang, Shawn D. Hingtgen, Phillip G. Durham, Paul A. Dayton, Tomek J. Czernuszewicz, Ryan C. Gessner
Journal: Cancer Research (2024)

Abstract The purpose of this study was to evaluate a new in vivo approach for rapidly measuring tumor volumes in rodent models for glioblastoma (GBM). GBM is the most common primary brain tumor with &amp;lt;5% of patients surviving &amp;gt;5 years post diagnosis. These poor outcomes underscore the importance of researching new treatment options, and murine models play a vital role in this. Noninvasive measurements of murine GBM tumors are commonly performed using CT and MRI but these tools are costly and time-consuming to use. BLI can quickly detect the presence of GBM cells in vivo, but image data can be challenging to correlate to tumor volume. In this study we demonstrate the feasibility of imaging GBM in vivo through the intact mouse skull using a benchtop robotic ultrasound scanner. This approach could offer researchers a means to quickly size tumors in the murine brain noninvasively. To test feasibility of this approach, a female athymic nude mouse aged 16 weeks was implanted with 2e5 U87 GBM cells in the brain. The tumor was given 25 days to develop prior to ultrasound imaging. After imaging, the brain was harvested for ex vivo validation of tumor presence and volume. Imaging was performed using a Vega ultrasound system (Revvity, Waltham, MA, USA) with the mouse in supine position and fur removed from head with depilatory cream. In vivo imaging consisted of a contrast-enhanced acoustic angiography (AA) scan to assess tumor perfusion. An ex vivo B-mode scan of the brain was collected after sacrificing the animal to validate the location and size of the tumor without interference from the skull. The tumor volumes were measured in each image and compared. 3D segmentations in the ex vivo and in vivo images yielded volumes of 43.1 mm3 and 44.6 mm3, respectively, a 3.5% variance. In the in vivo AA image, the borders of the tumor were adequately well-defined for volume estimation, despite some shadowing from the sagittal suture of the skull. In the B-mode image of the excised brain, the tumor appeared hyperechoic compared to the contralateral hemisphere. Images were acquired in &amp;lt; 2 min. This pilot study demonstrates a potential alternative to CT and MRI for monitoring of GBM volumes in vivo. Citation Format: Thomas M. Kierski, Juan D. Rojas, Morrent Thang, Shawn D. Hingtgen, Phillip G. Durham, Paul A. Dayton, Tomek J. Czernuszewicz, Ryan C. Gessner. Noninvasive measurement of murine glioblastoma in vivo with a benchtop ultrasound instrument [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 4159.
Abstract 4778: Development of self-amplifying RNA vaccines targeting prostate tissue-restricted and tumor-associated antigens
Authors: Robert H. Shoemaker, Jesse H. Erasmus, Peter Berglund, Jason D. Marshall, Yuri Koboziev, Bradley M. Beckman, Brian D. Cholewa, Steven G. Reed
Journal: Cancer Research (2024)

Abstract Prostate cancer is the most frequent cancer type in men, with increasing incidence at advanced age. As this cancer is frequently slow growing, opportunities for cancer interception exist, particularly among men with low-grade tumors who frequently undergo active surveillance. A well-tolerated vaccine intervention would be ideal for this population. Self-amplifying RNA (saRNA) vaccines built on a replication-deficient alphavirus backbone such as VEEV, offer several advantages for vaccine development. Sequences for relatively large antigens can be encoded and efficiently expressed, at low vaccine doses. Practical and efficient delivery of the saRNA is possible with advanced nanoparticles such as cationic inorganic lipid nanoparticles (LION). Among candidate antigens for a prostate cancer interception vaccine, we selected prostein (SLC45A3), a protein whose natural expression is restricted to the prostate gland and prostate cancer and ERG, a member of the ETS family of transcription factors frequently involved in chromosomal translocations in prostate cancer. We generated saRNA constructs with several design strategies and demonstrated that upon in vitro transfection, both antigens are expressed as assessed by mass spectrometry and Western blot analysis. This was achieved using commercial transfection reagents and LION. Prostein expression was particularly notable in that this eleven-transmembrane protein could be detected in HEK-293 cells using flow-cytometry and cell-surface staining. Nearly 50% of the cell population stained positively. Immunogenicity of the vaccines was tested in mice. Following formulation with LION particles i.m. injection and boosting, saRNAs coding for prostein elicited strong cellular immunity as demonstrated by IFN-γ ELISPOT analysis. Detailed analysis of intracellular cytokine expression indicated a strong CD8 response. saRNAs coding for ERG also showed antigen-specific ELISPOTs. Using commercially available recombinant ERG protein, an ELISA was developed and a strong humoral response to the ERG saRNA vaccine was demonstrated. The saRNA vaccines will be further credentialled with additional preclinical studies including cancer preventive efficacy studies in genetically engineered mouse models of prostate cancer. Citation Format: Robert H. Shoemaker, Jesse H. Erasmus, Peter Berglund, Jason D. Marshall, Yuri Koboziev, Bradley M. Beckman, Brian D. Cholewa, Steven G. Reed. Development of self-amplifying RNA vaccines targeting prostate tissue-restricted and tumor-associated antigens [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 4778.
Abstract 5133: Gastric cancer carrying FAT4 mutations associated with favorable prognosis in comparison to wild-type: Results from Real-World Cohorts
Authors: Shu Wang, Haoyuan Wang, Yuxuan Ma, Yuhao Wang, Yan Zhao, Chaosheng Peng, Weiming Duan, Feilong Zhao, Jianjun Yang
Journal: Cancer Research (2024)

Abstract Introduction: Gastric cancer (GC) is a complex and heterogeneous disease with variable clinical outcomes. Identifying prognostic factors that can reliably predict patient outcomes is crucial for personalized treatment strategies. In this study, we aimed to investigate the impact of mutations in the FAT4 gene as potential prognostic factors in gastric cancer. Methods: We conducted a comprehensive analysis of genomic data from a cohort of 236 gastric cancer patients to identify mutations in the FAT4 gene and validated it using the TCGA cohort. The mutational landscape of FAT4 was analyzed using next-generation sequencing (NGS) techniques. Clinical data, including patient demographics, tumor characteristics, and survival outcomes, were collected and correlated with the presence of FAT4 cadherin mutations. Results: In the real-world cohort, the occurrence of mutations of FAT4 was 19.1% (45/236), while in the TCGA cohort, it was 21.0% (89/423). Specifically, the mutation rates in the single cadherin functional domain of FAT4 were 10.2% (24/236) in the real-world cohort and 8.0% (34/423) in the TCGA cohort. The mutation rates for multiple cadherin sites were 2.5% (6/236) and 2.1% (9/423) in the real-world and TCGA cohorts, respectively. Survival analysis revealed that patients with FAT4 mutations had a significantly better prognosis compared to those with wild-type FAT4 (p=0.0357). Patients with multiple cadherin mutations had a better prognosis compared to those with single cadherin mutations in real-world cohorts (p=0.0651). No significant difference was observed in the TCGA cohort between single and multiple cadherin mutations (p = 0.2003), although FAT4 mutations exhibited a significant improvement in prognosis compared to wild-type patients in the TCGA cohort (p = 0.0226). Conclusion: Our findings indicate that FAT4 mutations confer a favorable prognosis in gastric cancer patients. The presence of FAT4 mutations was associated with improved survival compared to patients with wild-type FAT4. These findings underscore the potential value of FAT4 mutation status as a prognostic factor, guiding personalized treatment approaches for individuals with gastric cancer. Citation Format: Shu Wang, Haoyuan Wang, Yuxuan Ma, Yuhao Wang, Yan Zhao, Chaosheng Peng, Weiming Duan, Feilong Zhao, Jianjun Yang. Gastric cancer carrying FAT4 mutations associated with favorable prognosis in comparison to wild-type: Results from Real-World Cohorts [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 5133.
Abstract 6057: Evaluation of a highly potent and selective STAT3 degrader as a new class of immunotherapy
Authors: Longchuan Bai, Haibin Zhou, Jiajia Zhou, Dimin Wu, Ranjan Kumar Acharyya, Hoda Metwally, Donna McEachern, Bo Wen, Duxin Sun, Weiping Zou, Shaomeng Wang
Journal: Cancer Research (2024)

Abstract STAT3 (signal transducer and activator of transcription 3) is a transcription factor and a promising therapeutic target for cancer and other human diseases. In addition to its role in regulation of tumor cells, STAT3 also plays a key role in regulation of immunity and is a promising therapeutic target for the development of new immuno-oncology drugs. Our laboratory has previously reported the development of potent and highly selective STAT3 degraders, including SD-36 and SD-91. Extensive optimization of SD-36 and SD-91 yielded new, highly potent, selective and efficacious STAT3 degraders. In direct comparison, our most potent, new STAT3 degrader (compound 1) is &amp;gt;50-times more potent than SD-36 in inducing STAT3 degradation in cells and demonstrates &amp;gt;500-fold degradation selectivity over other STAT members. A single intravenous administration of compound 1 in mice is highly effective in inducing complete depletion of STAT3 protein in tissues for 48-96 h without reducing the levels of other STAT proteins. Compound 1 is very effective in inhibition of tumor growth not only in tumor models responsive to immune checkpoint blockade (ICB) but also in tumor models resistant to ICB. Furthermore, combination of compound 1 with PD-1/PD-L1 antibodies greatly enhances the antitumor activity as compared to SD-1218 or ICB. Of significance, compound 1 is well tolerated in mice without any signs of toxicity in mice at highly efficacious doses. Our mechanistic studies show that STAT3 depletion has a major effect in modulation of the immune cells in mice. Collectively, our data suggest that selective STAT3 degradation hold great promise for new cancer immunotherapy. Citation Format: Longchuan Bai, Haibin Zhou, Jiajia Zhou, Dimin Wu, Ranjan Kumar Acharyya, Hoda Metwally, Donna McEachern, Bo Wen, Duxin Sun, Weiping Zou, Shaomeng Wang. Evaluation of a highly potent and selective STAT3 degrader as a new class of immunotherapy [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 6057.
Abstract 6607: Serine depletion promotes antitumor immunity throughmitochondrial DNA-mediated cGAS/STING1 activation
Authors: Suchandrima Saha, Monisankar Ghosh, Li Jinyu, Asher Wen, Lorenzo Galluzzi, Luis Martinez, David C. Montrose
Journal: Cancer Research (2024)

Abstract Serine is critical for supporting cancer metabolism, and as such, depriving malignant cells of this non-essential amino acid exerts anticancer effects, in large part, through disrupting their metabolic pathways. However, the impact of these metabolic defects on tumor-targeting immunity remains poorly understood. Here, we show that restricting endogenous and exogenous serine in colorectal cancer (CRC) cells results in mitochondrial dysfunction coupled to cytosolic mitochondrial DNA accumulation and cGAS/STING1-dependent type I interferon secretion. Serine-deprived tumors have suppressed growth, accompanied by type I interferon signaling and tumor infiltration by immune effector cells. Blocking cGAS/STING1 signaling in tumor cells limits the immunostimulatory and anticancer effects of serine deprivation. Moreover, serine-depleted tumors exhibit increased sensitivity to a programmed cell death 1 blocker. Lastly, transcriptomic data from human CRCs suggest that malignant lesions with reduced serine abundance have higher immune infiltration. Taken together, our findings reveal a novel role for serine as a gatekeeper of mitochondrial integrity and hence a suppressor of anticancerimmunity. Citation Format: Suchandrima Saha, Monisankar Ghosh, Li Jinyu, Asher Wen, Lorenzo Galluzzi, Luis Martinez, David C. Montrose. Serine depletion promotes antitumor immunity throughmitochondrial DNA-mediated cGAS/STING1 activation [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 6607.
Abstract 662: Vitamin B1 derivative, fursultiamine, prevents lung cancer cells growth
Authors: Noah Boekweg, Ryan Powers, Kota Ramana
Journal: Cancer Research (2024)

Abstract Lung cancer is the leading cause of cancer death in men and the second leading cause of cancer death in women worldwide. Cigarette smoke-induced oxidative and inflammatory responses are the major risk factors for the development of lung cancer. Several compounds have been tested for their efficacy in preventing lung cancer. However, very few compounds have gone through clinical studies. We hypothesize that with its potent anti-oxidative and anti-inflammatory actions, fursultiamine, a disulfide lipid-soluble derivative of vitamin B1 (thiamine), could prevent lung cancer growth and spread. Our results indicate that treatment of non-small cell lung cancer cells (A549 cells) with fursultiamine prevents A549 cells death in a dose-dependent manner. Similarly, live and dead cell staining assay also confirms that fursultiamine prevents proliferation of A549 cells. Further, fursultiamine prevents A549 cell proliferation by inducing the apoptotic cell death. It also promoted the activation of caspase-3 and cleavage of PARP protein. Fursultiamine also prevented reactive oxygen species in A549 cells. Further, fursultiamine regulated the expression of various anti-apoptotic (Bcl-2, Bcl-x) and pro-apoptotic (Cleaved Caspase-3), survival (Survivin) and anti-survival factors (Clusterin, p-Rad17) in A549 cells. We next planned to examine the effect of fursultiamine on lung cancer growth in vivo using athymic nude mice injected with A549 cells subcutaneously without or with a diet containing fursultiamine. In conclusion, our in vitro results suggest that vitamin B1 derivative, fursultiamine, by promoting the apoptotic pathways prevents lung cancer growth and has potential for further development as a chemoprevention drug. Citation Format: Noah Boekweg, Ryan Powers, Kota Ramana. Vitamin B1 derivative, fursultiamine, prevents lung cancer cells growth [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 662.
Abstract 6577: Chemoproteomic evaluation of PROTACs targeting estrogen receptor alpha for ER+ breast cancer
Authors: Zachary Sandusky, Myles Brown
Journal: Cancer Research (2024)

Abstract In our investigation of estrogen receptor (ER) targeted protein degraders for advanced ER+ breast cancer, we assessed three proteolysis targeting chimeras (PROTACs), ARV471, ERD308, and ERD3111. Global proteomic analysis unveiled off-target protein degradation of progesterone receptor (PR) and phosphodiesterase 6D (PDE6D) by ER targeted PROTACs, but not selective ER degraders (SERDs). PR and PDE6D have previously been implicated as targets in cancer treatment. Protein degradation is rescued in CRBN- or VHL-knockout cells. Co-treating ER+ breast cancer cells with ligands for PR or PDE6D outcompeted PROTAC-mediated degradation and stabilized the respective protein, demonstrating the PROTACs are targeting the PR and PDE6D ligand-binding domains. Competition assays in ER-negative cell lines confirmed PR and PDE6D protein degradation is ER-independent. These findings underscore the importance of understanding off-target effects for developing more selective and effective therapeutics in ER+ breast cancer. Citation Format: Zachary Sandusky, Myles Brown. Chemoproteomic evaluation of PROTACs targeting estrogen receptor alpha for ER+ breast 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 6577.
Abstract 6619: Dynamic prediction with repeated mammogram images improves 5-year breast cancer risk performance
Authors: Graham A. Colditz, Rulla M. Tamimi, Bernard Rosner, Shu Jiang
Journal: Cancer Research (2024)

Abstract Background: Increasing use of digital screening mammography opens potential to add individualized dynamic measures of breast image history to predict future breast cancer risk. Current prediction models use a single mammogram measure, usually breast density, at one point in time, to add to prediction models based on established risk factors. Our previous work has shown that change in each breast over time is related to risk of diagnosis with breast cancer. Methods: We apply a dynamic prediction model that includes full field digital mammogram in each breast to predict future 5-year risk. Data from Joanne Knight Breast Health Cohort (JKBHC) serve as training population with 290 pathology-confirmed breast cancer cases and 658 controls sampled with a total number of 8,712 craniocaudal (CC) view mammograms for analysis. Nurses’ Health Study 2 (NHS2) serves as the external validation with 188 cases and 462 controls sampled with a total number of 3,712 CC-views. The dynamic risk prediction model aims to estimate the probability of future breast cancer risk conditional on the past history of the longitudinal mammograms. We train the model on the JKBH cohort, retaining 20% for testing and 15% for validation. We report a time dependent AUC when evaluating model performance. Results: The mean age of women was 56.6 years at entry to cohort; 81.3% were white. Adding trajectory of mammogram images in each breast to a model improved performance. The mean number of mammograms conditional on 5 years of observation in JKBHC was 3.36 (1.49) and in NHS2 2.36 (1.53). We obtained a 5-year dynamic AUC of 0.81 (0.05) in the JKBHC internal validation and 0.77 (0.06) in the NHS2 external validation. Model performance was comparable in pre- and postmenopausal women. Because breasts with high mammographic density hinder detection of tumors we stratify analyses by dense and non-dense at baseline. Among women with dense breasts at baseline (BIRADS C and D), we observe a dynamic 5-year risk AUC = 0.77. In the subgroup with less dense breasts (BIRADS A and B) we observe AUC = 0.74. Conclusions: With this approach we can accommodate the irregularly observed time-varying images and project only partial information prior to doing the prediction. Adding trajectory of mammogram history in each breast improves 5-year breast cancer risk prediction beyond models used in clinic today. Citation Format: Graham A. Colditz, Rulla M. Tamimi, Bernard Rosner, Shu Jiang. Dynamic prediction with repeated mammogram images improves 5-year breast cancer risk performance [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 6619.