tbuckley/cabot-search huggingface dataset:
Abstract 6277: Tall cell variant papillary thyroid carcinoma from Middle Eastern patients have worse outcome than classical papillary thyroid carcinoma using propensity score matching
Authors: Khawla S. Al-Kuraya, Sandeep K. Parvathareddy, Abdul K. Siraj, Saeeda O. Ahmed, Nabil Siraj, Manal Manakhan, Hassan Aldossari
Journal: Cancer Research (2024)

Abstract The tall cell variant of Papillary Thyroid Carcinoma (TCV-PTC) is the most common aggressive variant of PTC. The impact of TCV-PTC on patients’ prognosis still remains controversial. Moreover, the clinico-pathological and prognostic effect of TCV-PTC from Middle Eastern ethnicity remains unexplored. We aimed to study TCV-PTC in comparison to classical PTC in Middle Eastern patients and their impact on prognosis. We performed a retrospective cohort study of tall cell variant (TCV-PTC) and classic variant of papillary thyroid carcinoma (CV-PTC) after post-surgical radioactive iodine therapy. We used the propensity score matching (1:3 matching ratio) to account for differences between recipients of TCV-PTC vs CV-PTC. Univariate and multivariate analysis were performed to assess the independent factors for persistent/recurrent disease. Kaplan-Meier curve analyses were used to compare disease-free survival (DFS). In total, 174 (16.3%) patients with TCV-PTC and 891 (83.7%) patients with CV-PTC were included. After propensity score matching, 174 pairs of patients were selected (TCV-PTC, n = 174; CV-PTC, n = 522). In the matched analysis, higher proportions of TCV-PTC experienced persistent/recurrent disease compared with CV-PTC (25.7% vs 31.4%; p = 0.0119). In multivariate analyses of clinical and tumor characteristics, histological type of TCV-PTC (odds ratio, 2.09; 95% confidence interval, 1.28-3.40; p = 0.0031) was associated with increased risk of persistent/recurrent disease. The five-year DFS rates for the TCV-PTC and CV-PTC groups were 48.5% and 73.1%, respectively. The Kaplan- Meier analysis indicated that the TCV-PTC group (p &amp;lt; 0.0001) had shorter DFS. In conclusion, when other clinico-pathological factors were similar, this propensity score matched analysis showed that histological subtype TCV-PTC is by itself an independent predictive marker of persistent/recurrent disease in Middle Eastern patients. Therefore, individualized therapeutic approaches might be needed for this aggressive PTC subtype. Citation Format: Khawla S. Al-Kuraya, Sandeep K. Parvathareddy, Abdul K. Siraj, Saeeda O. Ahmed, Nabil Siraj, Manal Manakhan, Hassan Aldossari. Tall cell variant papillary thyroid carcinoma from Middle Eastern patients have worse outcome than classical papillary thyroid carcinoma using propensity score matching [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 6277.
Abstract 3128: HRA00184-C004, preclinical characterization of a novel tissue factor-targeted antibody-drug conjugate
Authors: Hanxiao Ying, Lingfeng You, Ning He, Shaoyu Xu, Pu Pu, Sophie Lin, Jun Feng, Zhe Zhang, Xin Ye, Min Hu, Feng He
Journal: Cancer Research (2024)

Abstract The physiological function of tissue factor (TF) is to initiate coagulation cascade by forming complex with plasma Factor VII after vascular injury. For Tisotumab vedotin (Tivdak), a TF targeting antibody-drug conjugate (ADC) approved for the treatment of cervical cancer, bleeding events were prespecified as adverse effects (AEs) of interest, besides ocular toxicity and peripheral neuropathy (known MMAE payload related AE). In order to mitigate the bleeding risk, a next generation of TF-targeting ADC is developed by Hengrui Pharmaceuticals. HRA00184-C004 is a novel ADC comprising a differentiated TF-targeted antibody (HRP07132) conjugated to a proprietary topoisomerase I inhibitor (Dxh, an exatecan derivative) via a protease-cleavable linker. In contrast to most TF-targeting antibodies, the naked HRP07132 does not interfere the interaction between TF and Factor VII or Factor X, has no impact on coagulation function in prothrombin time and thrombin generation assay, therefore reduced bleeding incidence is expected for HRA00184-C004. Meanwhile, HRA00184-C004 exhibited not only potent growth inhibition against multiple TF-expressing cancer cell lines but also bystander-killing effect in vitro. HRA00184-C004 also displayed robust and sustained anti-tumor activities in the PDAC HPAFII (TF high), TNBC MDA-MB-231 (TF moderate) and NSCLC H358 (TF low) TF-expressing xenograft models. Furthermore, in cynomolgus monkey, HRA00184-C004 is well-tolerated over a 6-week period with 12 mg/kg dosing every 3 weeks with acceptable PK profile. Notably, neither coagulation disorder nor skin rash was observed, which are superior to the historical NHP data reported by Tivdak. In conclusion, with the encouraging efficacy in preclinical study and promising safety profiles in NHPs, HRA00184-C004 has demonstrated the best-in-class potential and is scheduled to advance into clinical development. Citation Format: Hanxiao Ying, Lingfeng You, Ning He, Shaoyu Xu, Pu Pu, Sophie Lin, Jun Feng, Zhe Zhang, Xin Ye, Min Hu, Feng He. HRA00184-C004, preclinical characterization of a novel tissue factor-targeted antibody-drug conjugate [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 3128.
Abstract 464: Chromatin associated long non-coding RNAs involved in dormancy for late recurrence of ER-positive breast cancer
Authors: Noriko Saitoh, Maierdan Palihati, Hiroaki Tachiwana
Journal: Cancer Research (2024)

Abstract Late recurrence is one of the major problems for hormone receptor-positive breast cancer patients. It is suggested that the risk of recurrence may be maintained by cancer cells that have been already disseminated in the body at surgery. They enter long-term dormancy, thus evade immune surveillance and become resistant to therapies. The detailed molecular mechanism for this process is largely unknown.Nuclear long noncoding RNAs, which are not translated to proteins, often function as epigenetic regulators and determine the phenotype of cells and individuals. We found that a cluster of long noncoding RNAs, ELEANORS, is specifically expressed in ER (estrogen receptor)-positive recurrent breast cancer cells, forms a molecular condensate (RNA cloud) in the nucleus, and activates the ESR1 gene that encodes ER. ELEANORS define a large chromatin domain, the 0.7 Mb topologically associated domain (TAD), which contains the ESR1 and three other breast-cancer-associated genes. ELEANORS also regulates the three-dimensional genome architecture. They mediate a long-range chromatin interaction of ESR1 and FOXO3 genes, which are 42.9 Mb apart, and contribute to their cooperatively activate transcription, equilibrating cell proliferation (ESR1) and apoptosis (FOXO3). Upon ELEANOR knockdown, the ELEANOR clouds are disappeared, and ESR1 gene transcription is repressed. Further, the two genes are dissociated and only the FOXO3 gene remains transcriptionally active, resulting in the induction of apoptosis.Further analysis of clinical specimens revealed that ELEANOR expression in primary tumors correlates with recurrences over 5 years after surgeries, suggesting that ELEANORs are involved in late recurrence. We also found that ELEANOR activates transcription of CD44, a breast cancer stem cell marker gene. Cancer stem cell maintenance and equilibration of proliferation and apoptosis by ELEANOR may be involved in long-term tumor dormancy in late recurrence. This study suggests the possibility of ELEANORS as a biomarker to predict late recurrence, as well as a therapeutic target for ER-positive breast cancer. (References)Abdalla, MOA. et al., Nat. Commun, 10, 3778 (2019) Tomita, S. et al., Nat. Commun, 6, 6966 (2015) Citation Format: Noriko Saitoh, Maierdan Palihati, Hiroaki Tachiwana. Chromatin associated long non-coding RNAs involved in dormancy for late recurrence of ER-positive 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 464.
Abstract 5810: The impact of scaffold, linker, homogeneity and payload selection on the efficacy and tolerability of anti-tubulin ADCs
Authors: Scott D. Collins, Natalie Keirstead, Marc Damelin, Dorin Toader, Katsu Ishida, Niyanta N. Kumar, Kelly L. Lancaster, Kalli C. Catcott, Annika Yau, Mohan Bala, Timothy B. Lowinger
Journal: Cancer Research (2024)

Abstract Antibody-drug conjugates (ADCs) achieve targeted drug delivery to a tumor and have demonstrated clinical success in many tumor types. The properties of an ADC, including its activity and safety profile, can be highly influenced by its characteristics and individual components, commonly viewed as the antibody, payload, linker, and drug-to-antibody ratio (DAR). However, multiple other characteristics can also significantly influence an ADC’s overall drug-like properties, including DAR homogeneity, method of bioconjugation, hydrophilicity, and charge balance. Due to the multiparametric nature of ADC platform optimization, there are few examples in preclinical research, and even fewer in the clinical realm, where comparisons across platforms have been investigated for the same target, both preclinically and clinically, to elucidate how deliberate modifications in molecular design can improve drug-like properties and clinical outcomes. To that end, here we describe the improvements observed in preclinical characteristics, as well as their translational relevance to corresponding clinical characteristics. Two anti-NaPi2b ADCs were produced using two different platforms, XMT-1536 (Dolaflexin platform) and XMT-1592 (Dolasynthen platform), conjugated to the same antibody and employing the same payload. The Dolasynthen platform was deliberately designed, taking into account preclinical and clinical learnings from earlier ADC platforms, to improve both safety and efficacy. In addition, comparisons to clinically approved anti-tubulin ADC platforms are made to provide further context. Citation Format: Scott D. Collins, Natalie Keirstead, Marc Damelin, Dorin Toader, Katsu Ishida, Niyanta N. Kumar, Kelly L. Lancaster, Kalli C. Catcott, Annika Yau, Mohan Bala, Timothy B. Lowinger. The impact of scaffold, linker, homogeneity and payload selection on the efficacy and tolerability of anti-tubulin ADCs [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 5810.
Abstract 3860: Characterizing peripheral immune correlates of tumor response in breast cancer patients immunized with the P10s-PADRE vaccine
Authors: Fariba Jousheghany, John P. Lee, Bernice Nounamo, Vinay Raj, Jennifer L. Faulkner, Eric Siegel, Issam Makhoul, Thomas Kieber-Emmons, Behjatolah Monzavi-Karbassi
Journal: Cancer Research (2024)

Abstract Introduction: We demonstrated that vaccination of HR+/HER2− breast cancer subjects with P10s-PADRE cancer vaccine in combination with standard-of-care chemotherapy led to generation of antibodies (Ab), activation of Natural Killer (NK) and T cells, increases in IFNγ and TNFα, and increases in TILs and stromal CD3+ T cells. The current study was conducted to assess the vaccine's efficacy, particularly focusing on tumor shrinkage and pathologic Complete Response (pCR). Additionally, it aims to explore the association of specific peripheral-blood immune responses, such as antibody levels and NK and T-cell activation, with pCR and objective reduction in primary tumor size. Methods: Blood samples collected at baseline and after treatment of at least 25 subjects were used in characterization of immune responses. Serum and plasma samples were used in ELISA, cytokine, and glycan-array assays to measure anti-peptide and anti-glycan antibodies and blood-cytokine levels. Peripheral blood mononuclear cells (PBMCs) were interrogated by RNA-seq, flow cytometry, and ELISpot assays. Results: We observed that high levels of anti-peptide and anti-GD2 antibody responses correlated with pCR. Ab response was positively correlated with differential expression of CD56, GZMA, IFNγ, NKp46, and CD8b, among which GZMA and NKp46 showed a statistically significant association. Vaccine-induced functional cellular immune responses (measured by differential expression of IFNγ, GZMA, CD8, CD69, NKp46, CD56, and PRF1) correlated with reduction of primary tumor size. We also observed substantial differences among immune responders vs non-responders in immune gene expression and in cytokine production in post-immune PBMCs after specific and polyclonal stimulation. Conclusions: The data suggest that immunization of HR+/HER2− breast cancer patients with P10s-PADRE in combination with chemotherapy leads to both humoral and cellular immune responses. While induction of a robust antibody response is a good marker for potential clinical efficacy, vaccine-associated increases of the ratio of CD8+ cells and the expression of CD69, CD8b, GZMA, IFNγ, NKp46, and PRF1 seem to serve as additional efficacy indicators. Future studies are underway to validate these findings and establish reliable prognostic biomarkers. Citation Format: Fariba Jousheghany, John P. Lee, Bernice Nounamo, Vinay Raj, Jennifer L. Faulkner, Eric Siegel, Issam Makhoul, Thomas Kieber-Emmons, Behjatolah Monzavi-Karbassi. Characterizing peripheral immune correlates of tumor response in breast cancer patients immunized with the P10s-PADRE vaccine [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 3860.
Abstract 5878: ZNF397 loss triggers TET2-driven epigenetic rewiring, lineage plasticity, and AR-targeted therapy resistance
Authors: Ping Mu, Yaru Xu, Su Deng
Journal: Cancer Research (2024)

Abstract Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming, which allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified Zinc Finger Protein 397 (ZNF397) as a bona fide co-activator of the androgen receptor (AR), essential for the transcriptional program governing AR-driven luminal lineage. ZNF397 deficiency facilitates the transition of cancer cell from an AR-driven luminal lineage to a Ten-Eleven Translocation 2 (TET2)-driven lineage plastic state, ultimately promoting resistance to therapies inhibiting AR signaling. Intriguingly, our findings indicate that TET2 inhibitor can eliminate the AR targeted therapies resistance in ZNF397-deficient tumors. These insights uncover a novel mechanism through which prostate and breast cancers acquire lineage plasticity via epigenetic rewiring and offer promising implications for clinical interventions designed to overcome therapy resistance dictated by lineage plasticity. Citation Format: Ping Mu, Yaru Xu, Su Deng. ZNF397 loss triggers TET2-driven epigenetic rewiring, lineage plasticity, and AR-targeted therapy resistance [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 5878.
Abstract 1662: Evaluation of TEAD inhibitor, VT03989 treatment on growth of aggressive meningioma preclinical models
Authors: Siddhi Desai, Anil Thaghalli Shivanna, Mariya Stavnichuk, Elizabeth Hayes, Sonam Patel, James McNamara, Anita DeSantis, Nader Sanai, An-Chi Tien, Shwetal Mehta
Journal: Cancer Research (2024)

Abstract Background: Aggressive meningiomas (WHO grade II/III) are incurable brain tumors and despite surgery and radiation therapy, tumors recur frequently without approved systemic treatment options. Hence, there is an unmet need for targeted inhibition therapy and biomarkers that predict vulnerability to targeted therapies in aggressive meningioma patients. Hippo signaling pathway has been shown to be dysregulated in meningioma, resulting in activation of its target TEAD as a transcriptional factor. We hypothesize that targeted inhibition of TEAD in recurrent high-grade meningioma with NF2 loss will lead to increased inhibition of tumor growth. Here, we investigated the effect of VT3989, a potent TEAD inhibitor, in meningioma cell lines with NF2 wild-type or NF2 loss genotype. Methods: Two meningioma cell-lines: IOMM-Lee (NF2 wild-type) and MG309, a grade III meningioma patient-derived cell line with NF2 loss were treated with various doses of VT3989 and cell viability was assessed. Relative expression of direct targets of TEAD including CTGF and CYR61 was determined with quantitative PCR (qPCR) to ensure target engagement. Global transcriptomic changes were examined via RNAseq analysis on RNA isolated from MG309 cells treated with VT03989 compared to vehicle treated cells. Results: VT3989 treatment significantly decreased viability of both IOMM-Lee and MG309 cells. Canonical downstream targets of TEAD such as CTGF, CYR61, BIRC5, BCL-2 were downregulated in VT3989 treated cells compared to control. Furthermore, VT03989 treatment resulted in downregulation in cell cycle regulation and DNA damage response (DDR) pathway genes. Ongoing work is focused on combining VT3989 with agents targeting cell cycle and DDR pathways. Conclusion: VT3989 treatment led to downregulation of TEAD direct targets CTGF and CYR61 and inhibited cell viability of both IOMM-Lee cell and MG309 meningioma lines. RNA-seq analysis identified cell cycle and DDR pathway genes to be downregulated upon TEAD inhibition. Citation Format: Siddhi Desai, Anil Thaghalli Shivanna, Mariya Stavnichuk, Elizabeth Hayes, Sonam Patel, James McNamara, Anita DeSantis, Nader Sanai, An-Chi Tien, Shwetal Mehta. Evaluation of TEAD inhibitor, VT03989 treatment on growth of aggressive meningioma preclinical models [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 1662.
Abstract 1835: Discovery of HSN003839, a highly potent inhibitor of ubiquitin-specific protease USP21 for cancer therapy
Authors: Xiaohui Liu, Ying Wang, Dongliang Xia, Wei Zhang, Yan He, Shijie Tian, Xuerong Feng, Xia Yang, Qi Zhang, Fei Liu, Shiyi Jiang, Ran Hu, Ming Tang, Xuelin Tang, Yuqing Liu, Weijiao Yuan, Xuedan You
Journal: Cancer Research (2024)

Abstract USP21 belongs to the ubiquitin-specific protease (USP) subfamily of deubiquitinating enzymes (DUBs), which catalyze the removal of ubiquitin chain from targeted proteins. Numerous efforts over the last decade have identified a wide range of USP21 substrates and revealed the momentous and multifaceted role of USP21 in physiological and pathological states, especially in tumorigenesis, indicating that USP21 is an appealing target for the therapy of many correlative diseases. Nevertheless, progress in the development of potent USP21 inhibitors remains limited. Herein, we present the discovery of HSN003839, a highly potent and selective USP21 inhibitor with excellent anticancer activity and drug-like properties. Following screening tool compounds to identify hits and subsequent optimization, we discovered a series of compounds with strong enzymatic inhibition for USP21 with IC50 &amp;lt; 100 nM. Among them, HSN003839 displayed low nanomolar cancer cells proliferation inhibitions and excellent ADMET properties. The mouse oral bioavailability (F) is 76.5% at 10 mg/kg. In a preliminary mouse CDX model, monotherapy of HSN003839 showed 105% tumor growth inhibition (TGI) at 30 mg/kg with no obvious body weight reduction. Further biological characterization, efficacy and toxicity studies are ongoing. The structure of HSN003839 was not presented and will not be disclosed at the time of presentation at AACR meeting. Citation Format: Xiaohui Liu, Ying Wang, Dongliang Xia, Wei Zhang, Yan He, Shijie Tian, Xuerong Feng, Xia Yang, Qi Zhang, Fei Liu, Shiyi Jiang, Ran Hu, Ming Tang, Xuelin Tang, Yuqing Liu, Weijiao Yuan, Xuedan You. Discovery of HSN003839, a highly potent inhibitor of ubiquitin-specific protease USP21 for cancer therapy [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 1835.
Abstract 1834: Discovery of a novel and highly selective PARP7 inhibitor for cancer immunotherapy
Authors: Xiaohui Liu, Ying Wang, Dongliang Xia, Wei Zhang, Shijie Tian, Yan He, Xuerong Feng, Xia Yang, Qi Zhang, Shiyi Jiang, Meifeng Wu, Jianfeng Deng, Yeye Wang, Yuxi Su, Min Yao, Weijiao Yuan, Xuedan You
Journal: Cancer Research (2024)

Abstract Poly-ADP-ribose polymerase 7 (PARP7) is a member of the wider PARP enzyme family that modulate protein function by using nicotinamide adenine dinucleotide (NAD+) as a substrate to transfer an ADP-ribose monomer onto specific amino acid acceptor residues of target proteins. PARP7 acts as a key repressor of type I interferon (IFN) signaling. Its inhibition combats tumor regression by enhancing antitumor immunity that depends on STING pathway. Therefore, PARP7 is emerging as a promising drug target for new immunotherapy. Using structure-based drug design and optimization, we discovered a novel PARP7 inhibitor, HSN002066, with high inhibitory potency (Enzyme assay IC50 = 0.96 nM) and high selectivity for PARP7 over PARP1/2/12/5A/5B/10 (IC50 =163.4/4.7/345.2/1790/110.2/&amp;gt;10000 nM, respectively). In addition, HSN002066 has excellent ADMET profiles with CYPs inhibition, IC50 &amp;gt;10 μM, human LMS T1/2 &amp;gt; 60 min, hERG inhibition, IC50 &amp;gt; 30 μM,mouse oral bioavailability (F) 98.1%. Notably, HSN002066 and RBN-2397, the only PARP7 inhibitor currently in Ph 1/2 clinical development, displayed differentiated antiproliferative activities in cell line NCI-H1373 (IC50 are 387.8 nM and 15.2 nM, respectively). However, HSN002066 revealed remarkable antitumor effects as monotherapy (TGI 77% at 100 mg/kg) or combination with PD-1 antibody in CT-26 allograft model. The structure of HSN002066 was not presented and will not be disclosed at the time of presentation at AACR meeting. Citation Format: Xiaohui Liu, Ying Wang, Dongliang Xia, Wei Zhang, Shijie Tian, Yan He, Xuerong Feng, Xia Yang, Qi Zhang, Shiyi Jiang, Meifeng Wu, Jianfeng Deng, Yeye Wang, Yuxi Su, Min Yao, Weijiao Yuan, Xuedan You. Discovery of a novel and highly selective PARP7 inhibitor for cancer 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 1834.