tbuckley/cabot-search huggingface dataset:
Abstract 3143: The ADC payload PNU-159682 is highly active in a wide range of cancer indications by inducing DNA damage and cell death via a distinct mode of action
Authors: Monika Kaiser, Ulrike Fiedler, Daniel Gerlach, Norbert Kraut, Lukas Bammert
Journal: Cancer Research (2024)

Abstract During the last decade antibody-drug-conjugates (ADCs) have become an important and validated treatment modality for cancer patients. Here, we introduce a unique next generation ADC platform based on Sortase-mediated antibody conjugation (SMAC-Technology) yielding in very homogenous and stable drug conjugates with limited systemic, but powerful anti-tumor activity. The highly potent payload used is a proprietary derivative of the Anthracycline PNU-159682. Our PNU-159682-based ADCs are known to not only induce DNA damage in the target cell, but importantly also trigger immunogenic cell death and thus, stimulating anti-tumor immunity offering untapped combination potential. ADCs based on the SMAC-Technology platform currently undergo clinical development. In this work, we present functional studies that were performed to further elucidate the mode of action (MoA) of the ADC payload PNU-159682 and to investigate any potential liabilities with respect to sensitivity, which could limit treatment options for cancer patients. Flow cytometry-based readouts verified that PNU-EDA, a derivative of PNU-159682, is a highly potent inducer of DNA damage, cell cycle arrest and cell death. Interestingly, PNU-EDA arrests cells and inhibits DNA synthesis in S-phase in contrast to other Anthracyclines such as Doxorubicin, which leads to a block in the G2/M-phase. High-throughput cell line panel sensitivity screens confirmed that the activity of PNU-EDA is broad and not restricted to specific cancer indications. Notably, a correlation between lower potency and increased ABCB1 (MDR1) expression levels was observed for PNU-EDA, but not for parental PNU-159682. More detailed mechanistic insights were obtained by performing a genome-wide CRISPR-Cas9 KO screen, which revealed a partial dependency of the PNU-EDA potency on the proficiency of the TC-NER DNA damage repair mechanism. This finding further highlights a distinct MoA of PNU-159682 compared to Doxorubicin or other DNA-targeting compounds such as Cisplatin. Overall, our screens and mechanistic studies verified that PNU-159682-based ADCs efficiently kill cancer cells via a particular MoA and thereby, offer highly promising therapeutic options to a diverse and large population of cancer patients. Citation Format: Monika Kaiser, Ulrike Fiedler, Daniel Gerlach, Norbert Kraut, Lukas Bammert. The ADC payload PNU-159682 is highly active in a wide range of cancer indications by inducing DNA damage and cell death via a distinct mode of action [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 3143.
Abstract 3845: High-intensity focused ultrasound ablation increases tumor specific lymphocytes in prostate cancer
Authors: Shengchen Su, Yanping Wang, Eric M. Lo, Hyung L. Kim
Journal: Cancer Research (2024)

Abstract The treatment of localized prostate cancer has been revolutionized by High-Intensity Focused Ultrasound (HIFU), an FDA-approved procedure. Thermal HIFU achieves the destruction of tumor tissue through the noninvasive delivery of ultrasonic energy, causing rapid heating of the targeted area. Given that prostate cancer typically exhibits a low presence of tumor-infiltrating lymphocytes crucial for antitumor immunity, this study aimed to investigate whether HIFU has the potential to activate antitumor immunity and enhance lymphocyte infiltration within the tumor. RM1 tumors were implanted on the flanks of syngeneic C57BL/6J mice, with one tumor subjected to HIFU treatment. The growth of the contralateral tumor was monitored, and at the end of the study, tumors were collected to evaluate immune cell infiltration. Blood samples were obtained from patients both before and after prostatectomy or HIFU treatment. Peripheral blood mononuclear cells (PBMCs) were then isolated to analyze the immune cell population. In murine experiments, the application of HIFU to one tumor resulted in a reduction in the growth of the contralateral (untreated) tumor, specifically when the contralateral tumor was of the same type, but not when it was a different tumor type. Notably, HIFU led to an augmented infiltration of CD4+ and CD8+ lymphocytes into the contralateral (untreated) tumor. Depletion studies further affirmed that the antitumor immune response triggered by HIFU relies on CD4+ and CD8+ lymphocytes. In human subjects, HIFU was observed to elevate the CD4+ and CD8+ lymphocyte populations in PBMCs. HIFU induces a potent antitumor immune response that effectively inhibits the progression of murine prostate tumors. This immune response is contingent upon CD4+ and CD8+ lymphocytes. HIFU demonstrates significant promise in activating antitumor immune responses in patients diagnosed with prostate cancer. Subsequent research endeavors should delve into models of metastatic prostate cancer, exploring the potential synergy of cytoreductive prostate tumor ablation with systemic immunotherapies to elicit a robust and comprehensive antitumor immune response. Citation Format: Shengchen Su, Yanping Wang, Eric M. Lo, Hyung L. Kim. High-intensity focused ultrasound ablation increases tumor specific lymphocytes in prostate 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 3845.
Abstract 5788: Targeting p97-NPL4 pathway by copper chelators
Authors: Martin Mistrik, Zdenek Skrott, Martin Loffelmann
Journal: Cancer Research (2024)

Abstract Copper chelators forming stable complexes, such as the bis(diethyldithiocarbamate)-copper complex (CuET), derived from Antabuse (disulfiram, DSF), have shown pronounced anticancer activity. CuET induces aggregation of NPL4, a crucial cofactor of the p97 segregase in the ubiquitin-proteasome system, leading to proteotoxic stress and subsequent cancer cell death. Our study investigates whether NPL4 inhibition is unique to CuET or extends to other dithiocarbamate-copper complexes and distinct copper chelators. Utilizing a cellular NPL4 aggregation screening assay, we examined various chelators for their ability to induce NPL4 aggregation. Our findings reveal that this capacity is relatively common among structurally diverse DTCs-copper complexes and other unrelated copper chelators. Compounds that caused NPL4 aggregation also triggered NPL4-p97 complex immobilization, polyubiquitinated protein accumulation, and unfolded protein and heat shock responses. These responses correlated strongly with cancer cell cytotoxicity, particularly potent at nanomolar concentrations, underscoring NPL4 as a critical target. Our results demonstrate the broad potential of copper chelators in targeting NPL4, inducing lethal proteotoxic stress in cancer cells, and offering significant implications for drug development. Citation Format: Martin Mistrik, Zdenek Skrott, Martin Loffelmann. Targeting p97-NPL4 pathway by copper chelators [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 5788.
Abstract 5605: <i>Cutibacterium acnes</i> invades prostate epithelial cells to induce BRCAness as a possible pathogen of prostate cancer
Authors: Shingo Ashida, Chiaki Kawada, Hiroko Tanaka, Atsushi Kurabayashi, Ken-ichi Yagyu, Shuji Sakamoto, Kazuhiro Maejima, Satoru Miyano, Masanori Daibata, Hidewaki Nakagawa, Keiji Inoue
Journal: Cancer Research (2024)

Abstract Abundant evidence suggests that chronic inflammation is linked to prostate cancer and that infection is a possible cause of prostate cancer. However, pathogen of prostate cancer remains to be found. To identify microbiota or pathogens associated with prostate cancer, we investigated the transcriptomes of 20 human prostate cancer tissues. We performed de novo assembly of non-human sequences from RNA-seq data and identified four bacteria as candidate microbiota in the prostate, including Moraxella osloensis, Uncultured chroococcidiopsis, Cutibacterium acnes, and Micrococcus luteus. Among these, C. acnes was detected in 19 of 20 prostate cancer tissue samples by immunohistochemistry. We then analyzed the gene expression profiles of prostate epithelial cells infected in vitro with C. acnes and found significant alterations in homologous recombination (HR) and Fanconi anemia pathway. Notably, electron microscopy showed that C. acnes invaded prostate epithelial cells and localized in perinuclear vesicles, whereas analysis of γH2AX foci and HR assay demonstrated impaired HR repair. In particular, BRCA2 was significantly down-regulated in C. acnes-infected cells. These findings suggest that C. acnes infection in the prostate could lead to HR deficiency and BRCAness which promotes DNA double-strand breaks, thereby increasing the risk of cancer development. Citation Format: Shingo Ashida, Chiaki Kawada, Hiroko Tanaka, Atsushi Kurabayashi, Ken-ichi Yagyu, Shuji Sakamoto, Kazuhiro Maejima, Satoru Miyano, Masanori Daibata, Hidewaki Nakagawa, Keiji Inoue. Cutibacterium acnes invades prostate epithelial cells to induce BRCAness as a possible pathogen of prostate 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 5605.
Abstract 385: Stress-induced pentraxin 3 enhances anoikis resistant-associated metastasis and post-chemotherapeutic recurrence in head and neck cancer
Authors: Ting-Wei Chang, Wen-Chang Chang, Ben-Kuen Chen
Journal: Cancer Research (2024)

Abstract Head and neck squamous cell carcinoma (HNSCC) is one of the most aggressive cancer with the properties of local recurrence and lymphatic metastasis. During metastatic process in blood circulation, cancer cells lose the interaction with extracellular matrix and encounter the anoikis stress, resulting in successfully extravasate and form micrometastasis in distal organs. However, most patients develop chemo-drug resistance during the metastatic recurrence which leading to poor prognosis. Thus, it is a pressing matter to elucidate the molecular mechanisms involved in cancer metastasis and the behaviors of the post-chemotherapy treated HNSCC cells. Our previous studies suggest that growth factor signaling stimulated HNSCC cells metastasis by the expression of pentraxin 3 (PTX3). Moreover, recent findings also reveal that chemotherapy mediated oxidative stress induce PTX3 expression and poor progression. Here, we raise the hypothesis that the expression of PTX3 through stress signal may promote cancer cells against from anoikis and promote the post-chemotherapeutic survival. The first, we identified that the secondary messenger-reactive oxygen species (ROS) dominate the gene activation of PTX3 by spheroid culture and platium-based agents’ treatment. The ROS scavenger, NAC, inhibited cisplatin (CDDP)-induced PTX3 expression and rescue the cell viability by decreasing the ROS level. The oxidative stress inducer-H2O2 treatment also verify the PTX3 expression through AKT and NF-κB pathways. In addition, both the spheroid selection and CDDP-induced PTX3 regulated the EMT phenotype and further strengthen the growth factor signaling. In addition, we found that PTX3 also regulate the survival during spheroid selection and drug treatment. The post-selected cells also exhibit the unique glycosylated modification on PTX3. Disrupted the PTM modification of PTX3 could inhibit the spheroid survival and cell invasion. The animal studies revealed that both spheroid selection and CDDP-treated HNSCC cells had stronger extravasation ability than parental cells in NOD-SCID mice. Depletion of PTX3 also repressed the HNSCC cells extravasation ability. The results indicate that PTX3 were essential for oxidative stress-induced tumor metastasis and recurrence. It also speculates that the combination of antioxidants and PTX3 antibody may prevent tumor metastatic recurrence after chemotherapy in HNSCC. Citation Format: Ting-Wei Chang, Wen-Chang Chang, Ben-Kuen Chen. Stress-induced pentraxin 3 enhances anoikis resistant-associated metastasis and post-chemotherapeutic recurrence in head and neck 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 385.
Abstract 5786: Epstein-Barr virus nuclear antigen 1 (EBNA1)-targeting probes stimulate interferon-β production by nasopharyngeal carcinoma (NPC) cells to enhance the natural killer cell-mediated cytotoxicity against NPC
Authors: Luo Chen, Xiao Han Liu, Hei Tung Yuen, William C. Cho, Ka-Leung Wong, Hong Lok Lung
Journal: Cancer Research (2024)

Abstract Introduction: The prevailing histologic subtype of nasopharyngeal carcinoma (NPC) in the endemic regions is non-keratinizing carcinoma which shows almost consistent association with latent infection by Epstein-Barr virus (EBV). Previously our group developed a series of Epstein-Barr virus nuclear antigen 1 (EBNA1)-targeting probes, which can disrupt the EBV latency maintained by EBNA1, and such lytic induction could alert the immune cells. Methods: Natural killer (NK) cells of the innate immunity play a significant role in controlling EBV infection. In this study, we investigated whether our EBNA1 probes (ZRL5P4 &amp; L2P4) could activate NK cells to eliminate NPC. Results: Studies of clinical specimens indicated that tumor infiltration of the cytotoxic NK cell subset is a favorable prognostic marker for NPC patients. Furthermore, the cytotoxicity of circulating NK cells derived from NPC patients is equally well the cells from healthy individuals. If those patients’ NK cells can be attracted to infiltrate into the tumors, the tumor burden should be relieved. Indeed, the NPC xenograft with the ZRL5P4 treatment showed heavy mouse NK cell infiltration and tumor size reduction. The essential role of those mouse NK cells was demonstrated. Next, we showed that ZRL5P4 could induce the production of a soluble factor by NPC cells to stimulate the NK cell cytotoxicity. Such NK cell activity was verified in a metastasis NPC model. Mechanistically, the EBNA1 probe treatment could induce the expression of EBV early lytic gene Rta and EBNA1 itself. Both Rta and EBNA1 are known transcription factors to drive the expression of LMP1, the NF-κB signaling was then activated, which turned on the production of the well-known NK cell activation cytokine IFN-β. Conclusion: Taken together, our results demonstrated that our EBNA1 probes can mobilize NK cells to the tumor sites and activate their anti-tumor activity via the EBV reactivation and stimulation of IFN-β production. Citation Format: Luo Chen, Xiao Han Liu, Hei Tung Yuen, William C. Cho, Ka-Leung Wong, Hong Lok Lung. Epstein-Barr virus nuclear antigen 1 (EBNA1)-targeting probes stimulate interferon-β production by nasopharyngeal carcinoma (NPC) cells to enhance the natural killer cell-mediated cytotoxicity against NPC [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 5786.
Abstract 1085: Exploiting bioenergetic vulnerabilities in chemotherapy resistant osteosarcoma
Authors: Valerie U. Nguyen, Laurie Graves, Veronica Colmenares, Abol Macabangon, Casey Syal, Kelsey Fisher-Wellman, William C. Eward, So Young Kim, Jason A. Somarelli
Journal: Cancer Research (2024)

Abstract BACKGROUND: Osteosarcoma (OS) is the most common bone cancer in children and young adults. Standard treatment involves chemotherapy and surgical resection, yet nearly 4 in 10 patients experience disease relapse, and almost all of these patients are resistant to additional chemotherapy. Therefore, there is an urgent need to understand the biology of chemo-resistant OS and identify new therapeutic strategies to treat this therapy-resistant disease state. METHODS: Using a CRISPR-Cas9 based lineage tracing system, RNA sequencing, and Seahorse XF assays in chemo-naïve, -resistant, and -released human 143b and patient-derived 173x OS cell lines, we modeled the evolution of chemoresistance and release from the selective pressure of chemotherapy in osteosarcoma. The phenotype of each cell state was assessed through in vitro and ex vivo cell proliferation assays, a comparison of cell viability upon re-challenge to standard-of-care chemotherapy, and comparison of cell viability in response to novel therapies targeting alterations in cell respiration. RESULTS: Chemo-resistant OS cells demonstrate a decrease in expression of proliferation-associated gene pathways and shift their resources toward expression and maintenance of multi-drug resistance ABC transporters. Chemo-released cells maintain elevated expression of ABC transporters while re-activating proliferation. Across the spectrum of chemotherapy exposure, OS cells demonstrate changes in respiratory capacity, with unique bioenergetic phenotypes observed in chemo-naïve, -resistant, and -released cells. CONCLUSIONS: Chemo-resistant and chemo-released OS cells demonstrate unique bioenergetic patterns that correlate with gene expression signatures and growth phenotypes. Evolution imposed by the selective pressure of chemotherapy may render OS cells vulnerable to therapies that disrupt cellular energetics and exploit multi-drug resistant ABC transporters. Citation Format: Valerie U. Nguyen, Laurie Graves, Veronica Colmenares, Abol Macabangon, Casey Syal, Kelsey Fisher-Wellman, William C. Eward, So Young Kim, Jason A. Somarelli. Exploiting bioenergetic vulnerabilities in chemotherapy resistant osteosarcoma [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 1085.
Abstract 1773: Deciphering the roles of germline predisposition variants and somatic mutations on breast cancer cells and the tumor microenvironment
Authors: Fernanda Martins Rodrigues, Kelsey Gallant, Reyka Jayasinghe, Michael Iglesia, Andrew Houston, Siqi Chen, Preet Lal, Ryan Fields, William Gillanders, Feng Chen, Li Ding
Journal: Cancer Research (2024)

Abstract While great progress has been made in the understanding and treatment of cancer, tumor heterogeneity remains a diagnostic and prognostic challenge. Single-cell sequencing techniques and high-resolution cellular imaging now afford researchers the ability to investigate the effects of germline variants (especially when compared to somatic mutations) on molecular characteristics of cancer cells and non-cancer cells in the tumor microenvironment (TME). Here, we investigated a breast cancer (BRCA) cohort of over 100 individuals, for which we have generated sc/sn RNA-seq, snATAC-seq, and CODEX imaging data as well as bulk whole exome sequencing and RNA-seq data. We identified 21 BRCA cases carrying pathogenic and likely pathogenic rare germline variants in known cancer predisposition genes, such as BRCA2, BRIP1, ATM, and TP53. These predisposition genes showed diverse expression patterns across stromal and immune cell types, indicating roles in cell types beyond breast epithelia. For cases carrying pathogenic germline variants in such genes, we use snRNA-seq/snATAC-seq to assess gene expression changes and pathway alterations (e.g.,HRD and apoptosis) across all cell types and investigate phenotypic changes associated with pathogenic germline variants in cancer cells compared to stroma and immune cells in the TME. By evaluating chromatin accessibility changes and allele-specific expression, we reveal the connection between epigenetic regulators and differential roles of germline variants across cell types. Finally, the integrated analysis of germline variants and somatic mutations from predisposition genes at single cell resolution broadened our understanding of the role of germline variants in TME during tumorigenesis. Citation Format: Fernanda Martins Rodrigues, Kelsey Gallant, Reyka Jayasinghe, Michael Iglesia, Andrew Houston, Siqi Chen, Preet Lal, Ryan Fields, William Gillanders, Feng Chen, Li Ding. Deciphering the roles of germline predisposition variants and somatic mutations on breast cancer cells and the tumor microenvironment [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 1773.
Physician perceptions, attitudes, and strategies towards implementing guideline‐directed medical therapy in heart failure with reduced ejection fraction. A survey of the Heart Failure Association of the <scp>ESC</scp> and the <scp>ESC</scp> Council for Cardiology Practice
Authors: Gianluigi Savarese, Felix Lindberg, Ruxandra M. Christodorescu, Marc Ferrini, Thomas Kumler, Konstantinos Toutoutzas, Giuseppe Dattilo, Antoni Bayes‐Genis, Brenda Moura, Offer Amir, Mark C. Petrie, Petar Seferovic, Ovidiu Chioncel, Marco Metra, Andrew J.S. Coats, Giuseppe M.C. Rosano
Journal: European Journal of Heart Failure (2024)

Aims Recent guidelines recommend four core drug classes (renin–angiotensin system inhibitor/angiotensin receptor–neprilysin inhibitor [RASi/ARNi], beta‐blocker, mineralocorticoid receptor antagonist [MRA], and sodium–glucose cotransporter 2 inhibitor [SGLT2i]) for the pharmacological management of heart failure (HF) with reduced ejection fraction (HFrEF). We assessed physicians' perceived (i) comfort with implementing the recent HFrEF guideline recommendations; (ii) status of guideline‐directed medical therapy (GDMT) implementation; (iii) use of different GDMT sequencing strategies; and (iv) barriers and strategies for achieving implementation. Methods and results A 26‐question survey was disseminated via bulletin, e‐mail and social channels directed to physicians with an interest in HF. Of 432 respondents representing 91 countries, 36% were female, 52% were aged &lt;50 years, and 90% mainly practiced in cardiology (30% HF). Overall comfort with implementing quadruple therapy was high (87%). Only 12% estimated that &gt;90% of patients with HFrEF without contraindications received quadruple therapy. The time required to initiate quadruple therapy was estimated at 1–2 weeks by 34% of respondents, 1 month by 36%, 3 months by 24%, and ≥6 months by 6%. The average respondent favoured traditional drug sequencing strategies (RASi/ARNi with/followed by beta‐blocker, and then MRA with/followed by SGLT2i) over simultaneous initiation or SGLT2i‐first sequences. The most frequently perceived clinical barriers to implementation were hypotension (70%), creatinine increase (47%), hyperkalaemia (45%) and patient adherence (42%). Conclusions Although comfort with implementing all four core drug classes in patients with HFrEF was high among physicians, a majority estimated implementation of GDMT in HFrEF to be low. We identified several important perceived clinical and non‐clinical barriers that can be targeted to improve implementation.