tbuckley/cabot-search huggingface dataset:
Abstract 3999: Single cell transcriptomic comparison of patient derived ovarian cancer organoids and primary tumor epithelial signatures
Authors: Bisiayo Fashemi, Vijayalaxmi Gupta, Yukihidi Ota, Moreniola Akande, Mary Mullen, Dineo Khabele
Journal: Cancer Research (2025)

Abstract High-grade serous ovarian cancer (HGSOC) is a rare but deadly disease. Platinum-based therapy along with PARPi maintenance therapy, is recommended to 80% of patients. However, acquired resistance to platinum and PARPi remains an ongoing clinical challenge, highlighting the need for the development of targeted therapies. To address this, there is a need for better in vitro models that mimic the tumor microenvironment (TME). Unlike traditional 2D culturing methods, patient-derived ovarian cancer organoids (PDOs) form 3D structures that more accurately recapitulate multilayered, multicellular tissue. The overall objective of this study is to examine how HGSOC PDOs can be used better understand tumor reprograming and how this relates to patient tumor behavior and response to therapy. Primary and metastatic tumor samples were collected from diagnosed HGSOC patients for organoid generation. Organoids were cultured for 1-5 passages before being submitted for sc-RNAseq. In addition to organoid samples, matched tumor FFPE samples were submitted for comparison. Our pilot study revealed that PDOs contain a mixture of epithelial, stromal, and immune cells. Using Monocle3, we assessed epithelial cell development and differentiation over time and identified distinct cell trajectory projections across all samples. We identified three distinct cell states: early, intermediate, and late. Our PDO sample exhibited multiple branch points within the intermediate cell state, which reflects different cell fate decisions. These findings suggest the presence of sub-populations within the intermediate cell state that are not detectable or are masked in whole tumor FFPE samples. Additionally, we examined cell-to-cell interactions using CellChat. Fibroblast cells were the most prolific producers of signaling messages across all cell types, while dendritic cells and macrophages received the highest volume of incoming signals. In conclusion, PDOs recapitulate key aspects of the TME, and can be used to investigate cell fate decisions of epithelial tumor cells, and cell-to-cell communications. This platform offers a promising tool for studying tumor behavior, therapeutic resistance, and developing more targeted and effective treatments. Citation Format: Bisiayo Fashemi, Vijayalaxmi Gupta, Yukihidi Ota, Moreniola Akande, Mary Mullen, Dineo Khabele. Single cell transcriptomic comparison of patient derived ovarian cancer organoids and primary tumor epithelial signatures [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 3999.
Abstract 2919: Homologous recombination deficiency in non-small cell lung cancer: genetic and epigenetic causes beyond HRR
Authors: Katerina Tsilingiri, Anna Chalari, Georgia Christopoulou, Alexandra Voutsina, Pantelis Constantoulakis, Konstantinos Potaris, Ioannis Vamvakaris, Dora Hatzidaki, Georgina Zachou, Giannis Vatsellas, Vassilis Georgoulias, Athanasios Kotsakis, Apostolos Klinakis
Journal: Cancer Research (2025)

Abstract Introduction: The mechanisms of homologous recombination deficiency (HRD) in non-small cell lung cancer (NSCLC) remain understudied, mainly due to the low prevalence of germline or somatic mutations in relevant genes such as BRAC1/2 in this cancer type. However, recent reports suggest that an important subset of patients present high genomic scarring score (GSS), indicating HRD, although the causes are not always clear. In this work, we examined a cohort of 147 patients and sought to correlate GSS, mutational profile and relevant gene expression with response to PARP inhibition in preclinical functional experiments. Experimental Procedures: We used next generation sequencing to evaluate the GSS of each primary tumor with a commercially available sequencing kit which also provides information on the genetic status of relevant HRR and other genes. We performed rt-PCR analyses to assess the expression of certain genes, and we established patient-derived xenografts to examine the response of high and low GSS (h-GSS and l-GSS respectively) tumors to PARP inhibition. Results: 42 out of 147 tumors (28.6%) presented a GSS&amp;gt;50 (h-GSS). The prevalence of germline or somatic mutations in HRR genes was not significantly different between h-GSS and l-GSS tumors (18/42 vs 37/105, p=0.388). On the contrary, TP53 mutation frequency (p&amp;lt;0.001) as well as variant allele frequency (p&amp;lt;0.0001) correlated significantly with GSS. Expression of HRR genes was marginally higher in h-GSS tumors, whereas expression of the epigenetic factor KMT2C was significantly lower in that subset and presented an inverse correlation with both GSS (p=0.0059) and TP53 variant allele frequency (p=0.02). The growth of h-GSS PDXs was significantly hampered upon PARP inhibition. Conclusions: Our data show that for early-stage NSCLC, the GSS might be a valuable biomarker to stratify patients who might benefit from PARP inhibition. As this is not dependent on HRR genetic status in this cohort, further experimentation is needed to elucidate the complex relationship between TP53 status, KMT2C expression and HRD. Citation Format: Katerina Tsilingiri, Anna Chalari, Georgia Christopoulou, Alexandra Voutsina, Pantelis Constantoulakis, Konstantinos Potaris, Ioannis Vamvakaris, Dora Hatzidaki, Georgina Zachou, Giannis Vatsellas, Vassilis Georgoulias, Athanasios Kotsakis, Apostolos Klinakis. Homologous recombination deficiency in non-small cell lung cancer: genetic and epigenetic causes beyond HRR [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 2919.
Abstract 4018: Primary gallbladder cancer association with cardiovascular mortality: A 20 year population-based retrospective study
Authors: Oboseh J. Ogedegbe, Olanipekin Ntukidem, Asfand Y. Cheema, Sakshi Bai, Kai He, Utkarsh Acharya
Journal: Cancer Research (2025)

Abstract Introduction: Primary gallbladder cancer (PGC) is the most common cancer of the biliary system. It is often late presenting, leading to a poor prognosis. While evolution and progress in medicine have resulted in reduced mortality rates in PGC, non-cancer deaths are at an increasing trend. Cardiovascular mortality (CVM) plays a significant role in this trend. We holistically evaluated the CVM risk in patients with PGC. Methods: We utilized the Surveillance, Epidemiology, and End Results (SEER) database to retrieve PGC patients with CVM from 2000-2021. CVM was defined as death from diseases of the heart, hypertension without heart disease, cerebrovascular diseases, atherosclerosis, aortic aneurysm and dissection, and other diseases of arteries, arterioles and capillaries. We then obtained the standardized mortality rates (SMR) and absolute excess risk (AER). Results: Total number of PGC patients who died from cardiovascular diseases was 706. Patients with non-cardiovascular causes of death and patients with unknown age, race and cancer stage were excluded. We compared the cardiovascular disease (CVD) mortality risk of each group to the general US population and noted significantly increased CVD SMRs. Regarding race, Asians or Pacific Islanders had the highest risk of CV mortality (SMR 6.80, CI 5.10-8.87, p &amp;lt; 0.05), followed by Blacks (SMR 6-15, CI 4.88-7.66, p &amp;lt; 0.05), then American Indians/Alaska Natives (SMR 5.89, CI 1.60-15.08, p &amp;lt; 0.05) and Whites (SMR 3.99, CI 3.67-4.33, p &amp;lt; 0.05). Based on cancer stage, distant had the highest risk of CV mortality (SMR 17.79, CI 14.62-21.44, p &amp;lt; 0.05) while localized had relatively the lowest risk (SMR 3.10, CI 2.59-3.69, p &amp;lt; 0.05) with regional being (SMR 4.52 CI 4.00-5.08, p &amp;lt; 0.05). In terms of age, patients aged 40-59 years had an SMR of 20.89 (CI 15.65-27.33, p &amp;lt; 0.05), 60-79 years had an SMR of 5.14 (CI 4.60-5.74, p &amp;lt; 0.05), while 80 years and above had an SMR of 3.34 (CI 2.99-3.72, p &amp;lt; 0.05). Conclusion: Our analysis examines the magnitude of CVD-related deaths in PGC patients. Compared to the general United States population, patients with PGC have a higher risk of cardiovascular mortality. Therefore, patients with PGC should be screened for CVD to provide more holistic care in this patient population. Citation Format: Oboseh J. Ogedegbe, Olanipekin Ntukidem, Asfand Y. Cheema, Sakshi Bai, Kai He, Utkarsh Acharya. Primary gallbladder cancer association with cardiovascular mortality: A 20 year population-based retrospective study [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 4018.
Abstract 2554: Caloric restriction ameliorates aging and tumor progression via tumor immunity in syngeneic mice model
Authors: Taichi Horino, Haruki Horiguchi, Yuji Miyamoto, Masaaki Iwatsuki, Yuichi Oike
Journal: Cancer Research (2025)

Abstract Background: Caloric restriction (CR) without malnutrition reportedly improves life span and ameliorates aging in preclinical models. Decreased expressions of aging-related genes and inflammation-related genes have been observed in CR mice. Moreover, CR decreases cancer risk and inhibits tumor progression, but the underlying mechanisms are not fully understood. Methods: In this study, we developed a syngeneic model using C57BL/6N male mice, and verified the tumor-suppressing mechanisms of CR. Mice were randomized into 2 groups: normal diet (ND) group fed with ad lib diet, and CR group with 30% reduced feeding compared with the ND group, started from 2 months age. MC38, murine colorectal adenocarcinoma cells, were implanted subcutaneously. We compared tumor growth and survival between the CR group and the ND group. Moreover, to verify the contribution of tumor immunity, we compared the tumor-suppressing effects of anti-PD-1 antibody between the CR group and the ND group. To clarify the impacts of CD8+ cytotoxic T cells, we also conducted CD8 depletion by anti-CD8 antibody. Results: Firstly, we observed significantly restricted tumor progression of the CR group in aged mice, but it was relatively modest in young mice. Secondly, the tumor-suppressing effect of anti-PD-1 was equivalent between the CR group and the ND group in aged mice, which suggests tumor immunity is essential to demonstrate anti-tumor effects in CR mice. However, CD8 depletion in CR mice showed only partial tumor-promoting effects, which suggests immune function excluding CD8+ T cells contributes to suppressing tumor progression in the CR group. Conclusion: Our findings suggest that CR ameliorates aging and tumor progression. Promoted immune function, especially immune cells excluding CD8+ T cells, might play a role in the tumor-suppressing effects of CR. CD4 depletion and comprehensive analyses of intratumoral T cells are currently underway to elucidate the underlying mechanisms of tumor suppression induced by CR. Citation Format: Taichi Horino, Haruki Horiguchi, Yuji Miyamoto, Masaaki Iwatsuki, Yuichi Oike. Caloric restriction ameliorates aging and tumor progression via tumor immunity in syngeneic mice model [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 2554.
Abstract 4020: Review of literature on the effect of stress and anxiety among African-American breast and endometrial cancer patients
Authors: Gabrielle Ford, Zakirah L. Abdul-Hameed, Amirah Burton, Brian M. Rivers, Desiree Rivers
Journal: Cancer Research (2025)

Abstract African American women face disproportionately higher rates of breast and endometrial cancer recurrence compared to their Caucasian counterparts, highlighting an urgent need to explore the role of stress in cancer progression and recurrence. This study conducts a systematic review of the literature to evaluate the efficacy of stress and anxiety interventions in reducing cancer risk among African American survivors. By analyzing 25 articles from 2014-2024, this review examines the correlation between psychological stress, biological stress markers, and cancer outcomes. The findings emphasize the significant impact of stress on health outcomes, particularly in the context of cortisol's role in metabolism and immune response. The review also explores coping mechanisms, including social support, diet, and exercise, tailored to African American women's cultural and socioeconomic needs. The results underscore the critical need for targeted interventions to address stress in this population, with implications for improving cancer survivorship and advancing healthcare equity. Citation Format: Gabrielle Ford, Zakirah L. Abdul-Hameed, Amirah Burton, Brian M. Rivers, Desiree Rivers. Review of literature on the effect of stress and anxiety among African-American breast and endometrial cancer patients [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 4020.
Deciphering enhancers of hearing loss genes for efficient and targeted gene therapy of hereditary deafness
Authors: Simeng Zhao, Qiuxiang Yang, Zehua Yu, Cenfeng Chu, Shengqi Dai, Hongli Li, Min Diao, Lingyue Feng, Junzi Ke, Yilin Xue, Qifang Zhou, Yan Liu, Hanhui Ma, Chao-Po Lin, Yong-Gang Yao, Guisheng Zhong
Journal: Neuron (2025)
Abstract 4036: Selective inhibition of the transcription factor Brachyury in chordoma and non-small cell lung cancer
Authors: Gaelle Mercenne, Yang Gao, Brian McEllin, Andrea Gutierrez, Julia Robbins, Bodhi Hueffmeier, Erin Broderick, Daniele Canzani, William Fondrie, Lindsay Pino, Alex Federation
Journal: Cancer Research (2025)

Abstract Chordoma is a rare and slow-growing cancer arising from remnants of the notochord, a structure present during embryonic development. It most commonly affects the sacrum and cervical spine, accounting for about 20% of primary spinal tumors and 3% of all bone tumors. While surgery and radiation are the primary treatments, the tumor's location often makes complete removal challenging, and recurrence is common. There are no approved therapies at this time. A hallmark of chordoma is the aberrant expression of the transcription factor (TF) Brachyury (TBXT) which plays a key role in notochord development but is normally silenced in adult tissues. In chordoma, Brachyury is reactivated and contributes to tumor initiation and progression, making it both a diagnostic marker, and a potential therapeutic target. Talus Bio has developed a groundbreaking technology, TF-Scan, the first cell-based global screening platform specifically designed to target TF. TF-Scan integrates functional proteomics, automated cell processing, and machine learning to evaluate a drug’s ability to modulate the activity of DNA-bound proteins in live human cells. Using our platform, we identified compounds that target TBXT. Hit validation and hit-to-lead optimization led to the development of a covalent small molecule, TAL61, that effectively modulates TBXT activity. In preclinical studies using a patient-derived xenograft (PDX) model for chordoma, TAL61 demonstrated significant efficacy in reducing tumor burden. TBXT has also been shown to be overexpressed in different cancers particularly lung cancer and breast cancer. We tested our lead compound in a model of NSCLC and were able to significantly decrease tumor burden by more than 50% and visualize additive effects while doing combination with a chemotherapy agent. We are conducting other studies to further characterize TAL61 and uncover new cancer indications where TBXT plays a key role. The development of TF-Scan represents a paradigm shift in drug discovery, enabling the identification of compounds capable of disrupting targets that were previously inaccessible to conventional approaches. Citation Format: Gaelle Mercenne, Yang Gao, Brian McEllin, Andrea Gutierrez, Julia Robbins, Bodhi Hueffmeier, Erin Broderick, Daniele Canzani, William Fondrie, Lindsay Pino, Alex Federation. Selective inhibition of the transcription factor Brachyury in chordoma and non-small cell lung 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 4036.
Abstract 3354: Hsp70 is an independent predictor of recurrence-free survival in differentiated thyroid cancer
Authors: Sandeep K. Parvathareddy, Zeeshan Qadri, Abdul K. Siraj, Padmanaban Annaiyappanaidu, Nabil Siraj, Khawla S. Al-Kuraya
Journal: Cancer Research (2025)

Background: Differentiated Thyroid Cancer (DTC) has an indolent nature and generally has favorable prognosis. However, tumor recurrence is a major concern and can be noted several years after initial treatment. Identifying markers that can predict recurrence could lead to better management of DTC. Heat shock protein 70 (Hsp70), a molecular chaperone, has been shown to be associated with tumor recurrence and poor prognosis in other tumors. However, its role in predicting outcome in DTC is not well explored. Methods: A total of 1710 DTC cases were included in the study. Hsp70 expression was evaluated by immunohistochemistry using tissue microarray to analyze the clinico-pathological associations. Kaplan-Meier curve analysis was used to compare recurrence-free survival (RFS). Cox proportional hazards model was used for multivariable analysis. Results: Hsp70 over-expression was noted in 71.6% (1224/1710) of DTC cases and was significantly associated with adverse clinico-pathological characteristics such as extrathyroidal extension (p = 0.0039), T4 tumors (p = 0.0002), lymph node metastasis (p = 0.0118), distant metastasis (p = 0.0130), advanced tumor stage (p = 0.0312) and tumor recurrence (p &amp;lt; 0.0001). Interestingly, HSP70 over-expression was found to be associated with shorter RFS (p &amp;lt; 0.0001). On multivariable analysis, HSP70 was an independent predictor of RFS (Hazard ratio = 1.82; 95% confidence interval = 1.33 - 2.55; p = 0.0001). Conclusion: Our data suggests that Hsp70 is associated with poor prognosis in DTC and is a useful biomarker for predicting tumor recurrence. DTC patients whose tumor shows over-expression of Hsp70 should be subjected to more intense follow-up to identify potential tumor recurrence. Citation Format: Sandeep K. Parvathareddy, Zeeshan Qadri, Abdul K. Siraj, Padmanaban Annaiyappanaidu, Nabil Siraj, Khawla S. Al-Kuraya. Hsp70 is an independent predictor of recurrence-free survival in differentiated thyroid 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 3354.
Abstract 2918: Wild-type IDH1 inhibition induces BRCAness to sensitize pancreatic cancer to PARP inhibitors
Authors: Mehrdad Zarei, Omid Hajihassani, Hallie J. Graor, Soubhi Tahhan, Alexander W. Loftus, Faith Nakazzi, Semmer A. Ali, Vinayak Uppin, Luke D. Rothermel, Jonothan R. Brody, Jordan M. Winter
Journal: Cancer Research (2025)

Introduction: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most fatal cancers in the United States. Homologous recombination (HR) deficiency has facilitated the development of targeted therapies like Poly (ADP-ribose) polymerase (PARP) inhibitors. However, only 10-20% of PDAC cases exhibit HR deficiency, leaving a majority of patients without targeted therapeutic options. This study identifies wild-type isocitrate dehydrogenase 1 (wtIDH1), a cytosolic metabolic enzyme, as a critical factor for HR repair in HR-proficient tumors. Inhibiting wtIDH1 disrupts genomic stability, sensitizing HR-proficient PDAC to PARP inhibitors. Methods: We evaluated wtIDH1 inhibition on HR and non-homologous end joining (NHEJ) activity using DNA repair protein quantification and reporter assays. We also examined its effect on histone methylation. Synergistic anti-tumor effects of IDH1 and PARP inhibitors were assessed through drug combination assays, DNA damage response analysis, and apoptosis quantification. In vivo efficacy was studied in xenograft and orthotopic murine PDAC models. Results: WtIDH1 inhibition impaired HR repair pathways, induced a BRCAness phenotype by reducing α-ketoglutarate levels, and promoted histone hypermethylation. Combination therapy with IDH1 and PARP inhibitors significantly reduced cell viability in vitro and amplified DNA damage and apoptosis markers. In murine models, co-administration of ivosidenib and olaparib synergistically reduced tumor growth and improved survival compared to monotherapies. Conclusion: This study uncovers a novel strategy to target HR-proficient PDAC using combined IDH1 and PARP inhibition, demonstrating significant preclinical efficacy. Future studies will focus on optimizing and translating this approach into clinical practice. Citation Format: Mehrdad Zarei, Omid Hajihassani, Hallie J. Graor, Soubhi Tahhan, Alexander W. Loftus, Faith Nakazzi, Semmer A. Ali, Vinayak Uppin, Luke D. Rothermel, Jonothan R. Brody, Jordan M. Winter. Wild-type IDH1 inhibition induces BRCAness to sensitize pancreatic cancer to PARP inhibitors [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 2918.