tbuckley/cabot-search huggingface dataset:
Abstract 2497: Modeling the hidden danger of invisible tumor growth in the clinic
Authors: Bryan Hawickhorst, Amy H. Tang
Journal: Cancer Research (2025)

Abstract Tumor dormancy, relapse, and resistance are not fully understood. Residual and resistant tumor cells often persist and remain invisible for months or years, despite clean MRI/CT scans following neoadjuvant and/or adjuvant systemic therapies. In current literature reviews we see that residual tumor sizes and tumor detection thresholds can vary widely, further complicating patient prognosis and risk stratification. To address this unmet need, we developed an algorithm to model the timing, frequency, and imaging detection limits of tumor measurements to augment tumor relapse prediction with improved accuracy for clinical application, especially when tumors are below the current detection limits in the clinic. To visualize how long it takes an invisible residual tumor to recur, we generated multiple tumor growth curves to model the remission and relapse time course of 1, 101, 102, 103, and 104 tumor cells, and calculated the time for these therapy-refractory invisible tumors to develop into large 3cm3 MRI/CT-visible tumors. Firstly, we used simple exponential growth curves to model an unimpeded cancer cell doubling time ranging from 2 days to 30 days. Secondly, we used the Spratt model, a modified logistic model, to model the complex tumor growth curves in vivo. Tumor doubling times were varied from 5 to 30 days, indicative of tumor aggressiveness, dynamic tumor/tumor microenvironment interaction, and other tempo-spatial-context-dependency. Treatment frequency and duration were varied as biweekly, monthly, and 6-month office visits to simulate the time course of tumor resistance development following multiple rounds of therapeutic interventions. Additionally, tumor remission and relapse were modeled utilizing smaller residual tumors with longer remission periods. Using these parameters, we generated multiple growth curves to model how invisible and resistant residual tumor sizes, ranging from 10-2 mm3 to 10-6 mm3, will determine the time of diagnosis to time of relapse. Our dynamic tumor progression models demonstrate a rapid tumor relapse time course to reach the detection threshold, highlighting the need for invisible residual tumor modeling for diagnosis and relapse prediction in the clinic. This work highlights the importance of minimizing residual tumor size and reducing drug resistance. We will develop an invisible tumor model as a companion prognostic machine learning tool to identify and quantify therapeutic efficacy, risk stratify patients, and improve outcome and survival in the future. Citation Format: Bryan Hawickhorst, Amy H. Tang. Modeling the hidden danger of invisible tumor growth in the clinic [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 2497.
Abstract 2512: History and summary of current practices for assessment of drug-induced QT-prolongation in oncology drug development
Authors: Louis-Guillaume Marquier, Frederique Lemaux-Duvillier, Stephanie Le Goaller, Philippe L'Hostis, Eric Delpy, Mathieu Grace, Jean-Louis Pinquier
Journal: Cancer Research (2025)

Abstract The ICH E14 guideline issued in 2005 made the assessment of drug-induced QT-prolongation a mandatory step in the development of all new therapeutics. The guidance provided a clear requirement, however the means to achieve this requirement within the specific space of oncology clinical development remained challenging. Several updates to the guidelines, mainly in the form of Q&amp;As published in 2012, 2015 and 2022 helped to clarify regulator expectations and thus determine the strategies available in a field where a straightforward investigation performed in Healthy Subjects (i.e. the dedicated TQT trial) is not feasible for reasons of drug tolerability ; a dedicated trial in the patient population also poses significant ethical questions in addition to logistical hurdles. Today, following the different updates to ICH E14 we feel that a clear strategy may be implemented by sponsors developing new treatments in the field of oncology. These strategies, which include in vitro and in vivo testing and a specific approach for ECG recordings in phase I, are followed by several companies, but are not yet universally included in development plans from their start. We thus believe that a simplified roadmap should hold value for professionals looking to develop novel oncology therapeutics. The focused and precise assessment of drug-induced QT prolongation also meets the needs of clinicians looking to assess this risk in complex clinical setting with multiple risk factors1, 2. The purpose of our abstract will be to provide a clear history of the evolution of the ICH E14 guideline and illustrate what could be the current practice implemented for new therapeutics in the field of oncology. Our main interest will be for NCEs who cannot be safely administered to Healthy Participants however approaches for NBEs will also be described, with illustrations of results. This will include a description of the in vivo preclinical and clinical strategies which can be followed. Citation Format: Louis-Guillaume Marquier, Frederique Lemaux-Duvillier, Stephanie Le Goaller, Philippe L'Hostis, Eric Delpy, Mathieu Grace, Jean-Louis Pinquier. History and summary of current practices for assessment of drug-induced QT-prolongation in oncology drug development [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 2512.
Abstract 1713: Disrupting ER-AR crosstalk using AR degraders: a novel approach to treating endocrine resistant breast cancer
Authors: Matt Konda, Obdulia Covarrubias-Zambrano, Stefan H. Bossmann, Joan Lewis-Wambi
Journal: Cancer Research (2025)

Background: Estrogen receptor positive (ER+) breast cancer accounts for approximately 70% of all breast cancer cases and is the most diagnosed subtype amongst women. Current treatments include aromatase inhibitors (AIs), which block the biosynthesis of estrogens, tamoxifen (ER antagonist), and fulvestrant (ER degrader) (FUL). Despite therapeutic effectiveness, 30% of patients develop resistance, necessitating a deeper understanding of the underling mechanisms. Recent evidence points to the upregulation of androgen receptor (AR) signaling pathway as a potential mechanism of acquired resistance in breast cancer. To address the role of ER/AR crosstalk in acquired endocrine resistance, we generated an AI-resistant breast cancer cell line, MCF-7:5C (5C), mimicking the resistance seen in patients undergoing AI treatment. Methods: The inhibitory effect of FUL and ARCC4 (AR PROTAC degrader) on AI-resistant 5C and parental MCF-7 cells was examined using CellTiter-Blue® Cell Viability assay and trypan blue cell counting. Western blot, immunofluorescence, and nuclear fractionation assays were performed to determine ER and AR protein expression and cellular localization in response to FUL and ARCC4 treatments. siRNAs were used to knockdown ER and AR expression in resistant 5C cells to assess functional significance. Additionally, flow cytometry analysis using the RhodB-PTP (10mg/mL) was used to probe for surface expression of plectin in resistant cells. Results: AI-resistant 5C cells expressed markedly elevated levels of ER and AR and were more sensitive to the inhibitory effects of FUL and ARCC4 compared to parental MCF-7 cells. Immunofluorescence and nuclear fractionation assays revealed predominant nuclear localization of ER and AR in 5C cells compared to MCF-7 cells, and both proteins were markedly reduced (&amp;gt;95%) by FUL and ARCC4 treatments and siRNAs targeting both ER and AR. Notably, flow cytometry data revealed a strong correlation between ER, AR, and surface Plectin in 5C cells, thus identifying an additional target in these cells. Conclusions: Plectin is a cytoskeleton linker protein found in non-transformed cells, however, evidence suggests that its cancer-specific mislocalization to the cell surface contributes to its oncogenic function. As such, therapeutic targeting of surface plectin, along with ER/AR using FUL and ARCC4, represents an attractive opportunity to impede tumorigenesis and possible reverse endocrine resistance in breast cancer. Citation Format: Matt Konda, Obdulia Covarrubias-Zambrano, Stefan H. Bossmann, Joan Lewis-Wambi. Disrupting ER-AR crosstalk using AR degraders: a novel approach to treating endocrine resistant 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 1713.
Abstract 1969: Advancing metastatic prostate cancer diagnostics: STEAP1-based imaging flow cytometry for circulating tumor cell detection and characterization
Authors: Minzhi Sheng, Shuyang Feng, Omar Alawamry, Urban Emmenegger, Kristin Cimolini, Danny Vesprini, Andrew Loblaw, Laurence Klotz, Christopher S. Lim, Stanley K. Liu, Hon S. Leong
Journal: Cancer Research (2025)

Abstract Prostate cancer (PCa) is the most common cancer among Canadian men, with metastatic PCa (mPCa) patients experiencing a low 5-year survival rate of just 30%. Liquid biopsies using circulating tumor cells (CTCs) offer a non-invasive approach to diagnosing and monitoring treatment efficacy. Six transmembrane epithelial antigens of the prostate 1 (STEAP1) have been identified as a promising biomarker due to its significant overexpression in most PCa cases compared to normal tissues. We have developed monoclonal antibodies specifically targeting STEAP1 and propose their application in imaging flow cytometry (imFC) for identifying CTCs in mPCa patients. Our CTC staining and imFC protocols were validated and optimized using benign prostate hyperplasia and PCa cell lines. We also compared two CTC isolation techniques: density-based separation using Ficoll-Paque and microfluidic isolation with the BioRad Genesis Cell Isolation System for the best CTC purity. Isolated peripheral blood mononuclear cells (PBMCs) were labelled with our STEAP1 antibodies, DAPI for nuclear staining, CD45 antibodies for hematopoietic cells, and EpCAM antibodies, a widely used marker for CTCs. Additionally, we developed analytical pipelines leveraging imaging software with built-in machine-learning capabilities to classify probe binding patterns and identify subtypes of CTCs and cancer-derived extracellular vesicles (EVs) in immune cells. These optimized protocols were then tested on blood samples from patients with localized and metastatic PCa. CTCs were successfully detected in mPCa patients based on their expression of PCa biomarkers and lack of immune cell markers. Furthermore, STEAP1-positive vesicle-like signals were observed in association with hematopoietic cells, suggesting the uptake of PCa EVs by immune cells. Our findings demonstrate that STEAP1 antibodies in imFC can effectively detect and characterize CTCs. This approach represents a next-generation liquid biopsy for mPCa, offering improved diagnostic accuracy and the potential to enhance long-term outcomes for mPCa patients. Citation Format: Minzhi Sheng, Shuyang Feng, Omar Alawamry, Urban Emmenegger, Kristin Cimolini, Danny Vesprini, Andrew Loblaw, Laurence Klotz, Christopher S. Lim, Stanley K. Liu, Hon S. Leong. Advancing metastatic prostate cancer diagnostics: STEAP1-based imaging flow cytometry for circulating tumor cell detection and characterization [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 1969.
Abstract 1714: Understanding ADC resistance using preclinical enhertu-induced resistant models
Authors: Hongyan Sun, Yuan Fang, Fang Zhu, Jianming Xu, Xiang Gao, Jun Wang
Journal: Cancer Research (2025)

Abstract Antibody-drug conjugates (ADCs) combine the specificity of monoclonal antibodies (mAbs) with potent cytotoxic payloads, offering a promising approach for targeted cancer therapy. Enhertu (trastuzumab deruxtecan, DS-8201), an ADC targeting HER2-positive cancers, has demonstrated remarkable efficacy in clinical settings, setting new benchmarks for anti-HER2 ADCs. However, drug resistance remains a significant challenge, underscoring the need to elucidate resistance mechanisms and develop strategies to overcome them. To address this important question, we established a robust preclinical platform to study Enhertu resistance by subjecting HER2-positive JIMT-1 xenograft tumors to a series of in vivo passaging and drug induction. Massive parallel sequencing analyses, including RNA sequencing (RNA-Seq) and whole-exome sequencing (WES), revealed multiple resistance-associated pathways, with a particular emphasis on payload-resistance mechanisms. Flow cytometry and IHC analyses confirmed no significant changes in HER2 expression levels between resistant and parental tumors, ruling out target downregulation as the main resistance mechanism. Notably, the resistant tumor provided a valuable platform for studying interactions within the tumor microenvironment (TME), including stromal and immune components that may contribute to resistance development. The establishment of these preclinical Enhertu-resistant models offers a unique opportunity to investigate resistance mechanisms that may not yet be observed in clinics. Furthermore, these models provide a foundation for testing innovative therapeutic strategies, such as combination treatments targeting multiple pathways or the development of next-generation ADCs with improved payload efficacy. By enhancing our understanding of ADC resistance, these findings contribute to the advancement of personalized cancer therapies and may ultimately improve outcomes for patients with HER2-positive malignancies. Citation Format: Hongyan Sun, Yuan Fang, Fang Zhu, Jianming Xu, Xiang Gao, Jun Wang. Understanding ADC resistance using preclinical enhertu-induced resistant models [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 1714.
Abstract 1352: Extracellular adenosine suppress CD8+ T cell attraction resulting in poor prognosis in pancreatic ductal adenocarcinoma
Authors: Eriko Katsuta, Yasushi Ichikawa, Kazuaki Takabe, Subhamoy Dasgupta, Daisuke Ban
Journal: Cancer Research (2025)

Abstract Background: CD73 is a cell surface enzyme. Extracellular ATP and ADP are converted to AMP catalyzed by CD39, then AMP is converted to adenosine by CD73 in the tumor microenvironment (TME). Accumulating extracellular adenosine is known to play an immune suppressive role in TME of various cancers, however, its role in pancreatic ductal adenocarcinoma (PDAC) remains elusive. This study aimed to explore the role of CD73 in PDAC. Methods: To examine CD73 role in PDAC, we used both bioinformatical and experimental approaches. We employed a publicly available dataset, The Cancer Genome Atlas (TCGA) to analyze clinical relevance by bioinformatic approaches. In order to confirm the findings and explore the mechanisms from the bioinformatical analyses, we conducted in vitro, in vivo experiments. Murine PDAC cell line, Panc02 was used together with overexpression technique. Results: We found that high expression of CD73 was significantly associated with poor disease-free survival (P&amp;lt;0.001) and overall survival (P=0.002) in PDAC patients of TCGA cohort. Multivariate analyses revealed that CD73 was an independent prognostic factor in both disease-free (P=0.001) and overall survival (P=0.005). A deconvolution algorism, xCell showed that the CD73 high expression tumor showed less CD8+ T cell infiltration compared to the counterpart in TCGA cohort (P=0.009). There was no significant survival difference between the control and CD73 overexpressing PDAC cell bearing mice of carcinomatosis model when the experiment was conducted in immune deficient mice. On the other hand, when we implanted the cells into immune competent mice, CD73 overexpressing tumor showed significantly shorter survival (P&amp;lt;0.001). Further, the CD73 overexpressing tumor had less CD8+ T cell infiltration compared to the control mice (P=0.041). Co-culture experiments revealed that CD8+ T cell proliferation was suppressed when they were cultured with CD73 overexpression PDAC cells (P=0.011). Conclusion: We found that high expression of CD73 was associated with poor prognosis along with less CD8+ T cell infiltration in PDAC. These results suggest that accumulated adenosine in the TME suppressed CD8+ T cell infiltration in CD73 high expression tumor. Citation Format: Eriko Katsuta, Yasushi Ichikawa, Kazuaki Takabe, Subhamoy Dasgupta, Daisuke Ban. Extracellular adenosine suppress CD8+ T cell attraction resulting in poor prognosis in pancreatic ductal adenocarcinoma [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 1352.
Abstract 952: Intravesical instillation of a TME engineering viral vector increases survival in an orthotropic bladder cancer model
Authors: Emma Eriksson, Ioannis Nikoloudis, Mariela Mejia Cordova, Tanja Lövgren, Angelica Loskog
Journal: Cancer Research (2025)

Abstract Gene engineering of the tumor microenvironment (TME) with viral vectors encoding immunostimulatory genes can inflame the TME and create the basis for an immune response against the tumor cells. Adm703 is an adenoviral vector based on the AdEasy system. Adm703 encodes for two murine immunostimulatory genes, trimerized membrane-bound CD40L and 4-1BBL that are expressed by all infected cells (tumor and stroma). The transgenes can induce maturation of dendritic cells and expansion and memory formation of T cells as well as shift the general pro-tumorigenic environment towards anti-tumor state by influencing both tumor and stroma cells. Non-muscle invasive urinary bladder cancer is currently treated with bacillus Calmette-Guérin (BCG) instillations followed by nadofaragene firadenovec-vncg for BCG refractory patients. If the tumor becomes muscle invasive, the patients are subjected to radical cystectomy in which the urinary bladder is removed. This surgery is severely disabling and there is an urgent need to develop a treatment that will lead to a long lasting immune control with a possibility to delay or avoid surgery. We hypothesize that LOAd703, the human equivalent to Adm703, may be an interesting option for these patients. An orthotopic bladder cancer mouse model was treated intravesically with Adm703 to evaluate if Adm703 can control tumor growth. Bladders of female C57Bl/6 mice were incubated with poly-L-lysin to enhance tumor uptake before implantation of MB49 cells. The mice received four intravesical treatments with Adm703 or sodium chlorine (control) on day 1, 8, 15, 22 after tumor instillation. Mice were monitored for hematuria which is an early sign of tumor take. If more than 10 percent weight loss occurred the mice were sacrificed. The mice treated with Adm703 had less hematuria during treatment and had increased survival (mOS=40 days) compared to the control group (mOS=12 days). In conclusion, TME gene engineering with TMZ-CD40L and 4-1BBL increased survival of mice with orthotopic bladder cancer. Further studies investigating Adm703's effect on the immune system are planned. Citation Format: Emma Eriksson, Ioannis Nikoloudis, Mariela Mejia Cordova, Tanja Lövgren, Angelica Loskog. Intravesical instillation of a TME engineering viral vector increases survival in an orthotropic bladder cancer 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 952.
Abstract 563: AR-dependent castration-resistant prostate cancer relies on histone methyltransferase KMT2D for cell growth
Authors: Angela Bononi, Paul Redford, Weichao Zhang, Gabriella Cifelli, Sungtae Kim, Ian Gao, Kelly Werth, Peter Carman, Gilberto Valdes Garcia, Zane Taylor, Rachel Totoritis, Jess Schneck, Paul Bamborough, Markus Queisser, Georgia Maundrill, Dean Thomas, Hoang Tran, Sarvesh Varma, Biju Mangatt, Michael McCabe, Benjamin Schwartz, Kelly Choi
Journal: Cancer Research (2025)

The KMT2D histone H3 lysine 4 (H3K4) methyltransferase plays critical roles in enhancer-regulated gene activation. It is a large multi-domain protein with its C-terminal SET domain being responsible for this activity. High KMT2D expression is associated with reduced patient survival in prostate cancer. Cancer Dependency Map data show a correlation between KMT2D gene dependency and FOXA1 expression in prostate cancer cell lines. FOXA1 is a major regulator of Androgen Receptor (AR) transcription and recent findings showed that KMT2D establishes the chromatin competency to recruit AR and for FOXA1 to activate AR-dependent transcription. Since FOXA1 is predicted to be poorly tractable, we aimed to target the more tractable KMT2D in FOXA1-overexpressing AR-dependent castration-resistant prostate cancer (CRPC). CRPC cell lines with high FOXA1 (FOXA1high) and high AR (ARhigh) and/or AR constitutively active splice variants, such as AR-V7 (AR-V7+) were found to express high levels of KMT2D. KMT2D knockout (KO) reduced cell growth in these cells and in isogenic AR-V7+ 22Rv1 cells lacking full length AR. Additionally, KMT2D KO modulated AR target genes as demonstrated by reduced PSA mRNA and increased mRNA for IGFBP3 and EFNB2. Inactivating SET domain mutations demonstrated that these effects were mediated by KMT2D’s catalytic function thus supporting SET-domain inhibition as the desired target modality. This study highlights the potential of KMT2D as a therapeutic target for AR-dependent CRPC patients with constitutively active AR splice variants who have high unmet medical need due to AR variants being undruggable with currently available therapeutic agents. Citation Format: Angela Bononi, Paul Redford, Weichao Zhang, Gabriella Cifelli, Sungtae Kim, Ian Gao, Kelly Werth, Peter Carman, Gilberto Valdes Garcia, Zane Taylor, Rachel Totoritis, Jess Schneck, Paul Bamborough, Markus Queisser, Georgia Maundrill, Dean Thomas, Hoang Tran, Sarvesh Varma, Biju Mangatt, Michael McCabe, Benjamin Schwartz, Kelly Choi. AR-dependent castration-resistant prostate cancer relies on histone methyltransferase KMT2D for cell growth [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 563.