tbuckley/cabot-search huggingface dataset:
Abstract 6985: Discovery of potent and selective USP1 inhibitors for the treatments of BRCA-deficient tumors
Authors: Seong Heon Kim, Hwa Sil Kim, Sukho Lee, Jieun Kim, Jinwoo Lee, Jong Woo Park, Yukyung Kim, Daehoon Kim, Doo-Young Kim, Min Ah Park
Journal: Cancer Research (2025)

Abstract Poly (ADP-ribose) polymerase 1 (PARP1) inhibitors are the first successfully approved synthetic lethal cancer treatments targeting BRCA1/2-mutated breast and ovarian cancers. However, limited responsiveness among patients with BRCA1/2 mutations and the emergence of resistance to PARP inhibitors highlight the growing need for alternative synthetic lethal drugs, either as monotherapy or in combination with PARP inhibitors. Ubiquitin-Specific Protease 1 (USP1), a member of the deubiquitinating enzyme (DUB) family, plays a crucial role in DNA repair processes. USP1 inhibitors induce cancer cell death by blocking Translesion Synthesis (TLS) and the Fanconi anemia pathway, both of which have been identified as synthetic lethal partners with BRCA1/2 mutations or other homologous recombination deficiencies (HRD). We identified HD-12093 and HD-12136 as potent and selective USP1 inhibitors. Both compounds exhibited strong potency in the BRCA1-mutant triple-negative breast cancer (TNBC) cell line, MDA-MB-436, and demonstrated excellent selectivity for BRCA1-mutant cells over BRCA wild-type cells. HD-12093 and HD-12136 also induced the accumulation of mono-ubiquitinated PCNA, a known substrate of USP1. In PARP inhibitor-resistant cells, these compounds showed synergistic growth-inhibitory effects when combined with a PARP inhibitor, highlighting their strong potential to effectively overcome PARP inhibitor resistance. HD-12093 and HD-12136 exhibit favorable drug-like properties and pharmacokinetic profiles suitable for once-daily oral administration. These results support further development of HD-12093 and HD-12136 as potential best-in-class USP1 inhibitors for BRCA-deficient cancers resistant to PARP inhibitors either as monotherapy or in combination with PARP inhibitors. Citation Format: Seong Heon Kim, Hwa Sil Kim, Sukho Lee, Jieun Kim, Jinwoo Lee, Jong Woo Park, Yukyung Kim, Daehoon Kim, Doo-Young Kim, Min Ah Park. Discovery of potent and selective USP1 inhibitors for the treatments of BRCA-deficient tumors [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 6985.
Abstract 7042: Role of Myc family proteins in the growth and oncogenic transformation of fusion-positive rhabdomyosarcoma
Authors: Pawan Kumar Raut, Bishwanath Chatterjee, Hana Kim, Frederic G. Barr
Journal: Cancer Research (2025)

Abstract Fusion-positive rhabdomyosarcoma (FP RMS) is a pediatric soft tissue cancer associated with the myogenic lineage and characterized by a PAX::FOXO1 fusion gene, either PAX3::FOXO1 or PAX7::FOXO1. Our previous studies demonstrated that a human myoblast model of FP RMS requires MYCN as well as PAX3::FOXO1 for oncogenic transformation. The MYC family proteins including MYC, MYCN or MYCL are often amplified or overexpressed in different cancers, and contribute to regulation of oncogenic properties. This study aims to investigate the expression of these Myc family proteins in FP RMS cell lines and their role in FP RMS growth and oncogenic transformation. The CRISPR-Cas9 system was utilized to knock down specific genes in these cell lines, and then focus formation, colony formation, and population growth were used to assess growth and oncogenic activity. Using western blot studies, the FP RMS cell lines were divided into three groups based on the expression profile of Myc proteins: MYC-dominant, MYCN-dominant, and MYC/MYCN-codominant. In contrast, there is no significant expression of MYCL in any of these FP RMS cell lines. As a positive control, knockdown of the specific PAX::FOXO1 gene in each cell line abrogated growth and oncogenicity in all three subsets of FP RMS cell lines. In MYC-dominant CW9019 cells, MYCN knockdown had a small effect on growth and oncogenicity while MYC knockdown markedly decreased these parameters and double knockdown of MYC and MYCN had an even stronger inhibitory effect. In contrast, MYCN knockdown in MYCN-dominant RH5 cells substantially reduced growth and transformation while MYC knockdown did not alter these activities and double knockdown of MYC and MYCN generated effects comparable to MYCN knockdown. Finally, knockdown of either MYC or MYCN only partially diminished growth and oncogenicity in MYC/MYCN-codominant FP RMS cell lines including RH30, RH41, and RH28, whereas double knockdown of MYC and MYCN had a stronger inhibitory effect. These findings indicate that MYC and MYCN are functionally redundant in most FP RMS cell lines whereas MYC or MYCN are functionally dominant in a smaller subset of FP RMS lines. Moreover, expression of these Myc family proteins contributes to regulation of growth and oncogenic transformation in FP RMS cell lines. Citation Format: Pawan Kumar Raut, Bishwanath Chatterjee, Hana Kim, Frederic G. Barr. Role of Myc family proteins in the growth and oncogenic transformation of fusion-positive rhabdomyosarcoma [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 7042.
Abstract 4363: Establishment of plasma inhibitory kinase assays (PIA) to detect functional drug levels in patient plasma
Authors: Lena Pilgermayer, Eva M. Egenter, Katharina Schaich, Daniel Feger, Jan E. Ehlert
Journal: Cancer Research (2025)

Abstract Anticipation of the in vivo activity of an investigational new drug (IND) is challenging. In the context of the living body, compounds are subjected to degradation, metabolic modification or binding to plasma proteins - mechanisms that are well described to potentially compromise the in vivo activity seen in the patient compared to its predicted potential to inhibit its target in specific in vitro assays. As such assays are performed in artificial cell-culture media, we had previously modified our proprietary cellular FLT3 kinase phosphorylation assay to measure the activity of FLT3 inhibitors directly in and from human plasma, similar as described by Levis et al. 1. We hence established a method to analyze the activity of kinase inhibitors in human or rodent plasma (plasma inhibitory activity assay, PIA) in ELISA-based cellular kinase assays. We have successfully applied this methodology to determine the pharmaco-kinetics of a newly developed inhibitor of FLT3 in the context of a clinical trial targeting FLT3. We have now expanded this methodology for the detection of further kinase targets of potential clinical relevance. We were able to compile in vitro PIA assay data for further kinases such as VEGFR2 and BCR-Abl which will allow us to better predict the in vivo effect of specific inhibitors of these kinases and to determine the amount of freely available active test substance in the blood/sera of treated cancer patients. 1: Levis et al. Blood. 2006; 108 (10):3477-3483 Citation Format: Lena Pilgermayer, Eva M. Egenter, Katharina Schaich, Daniel Feger, Jan E. Ehlert. Establishment of plasma inhibitory kinase assays (PIA) to detect functional drug levels in patient plasma [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 4363.
Abstract 7217: Synergistic anti-cancer effects of dual IGF-1R and EGFR targeting in uveal melanoma
Authors: Pei-Chi Tsai, Charles G. Eberhart, Su-Chan Lee
Journal: Cancer Research (2025)

Abstract Uveal melanoma arises from melanocytes in the eye, with approximately 7, 000 patients reported worldwide every year. IGF-1R plays an important role in uveal melanoma metastatic progression, and promotes tumor cell proliferation and survival. However, in previously reported clinical trials, targeting IGF-1R did not significantly inhibit uveal melanoma metastatic spread or patient survival. This could be due to compensatory activation of other receptor signaling pathways. Therefore, the aim of this study is to find other activated receptors in uveal melanoma cells following IGF-1R inhibition which could be co-targeted in a novel combination treatment for metastatic uveal melanoma. Using several uveal melanoma cell lines (Mel202, Omm2.3, Omm2.5, Omm1, 92.1, MP38 and MM28), we found that treatment with linsitinib, an IGF-1R inhibitor, increased EGFR protein expression and activity. Targeting IGF-1R alone with linsitinib, or EGFR alone with gefitinib, did not significantly inhibit growth of uveal melanoma cells. However, combination treatment with linsitinib (10µM) and gefitinib (5µM) significantly inhibited both cell growth and anchorage-dependent/independent colony formation abilities in uveal melanoma cultures. Moreover, Linsitinib and gefitinib co-treatment dramatically increased cleaved PARP protein, an apoptotic maker. Our research suggests that dual targeting of IGF-1R and EGFR could be a novel treatment strategy to inhibit uveal melanoma metastatic dissemination and growth. Citation Format: Pei-Chi Tsai, Charles G. Eberhart, Su-Chan Lee. Synergistic anti-cancer effects of dual IGF-1R and EGFR targeting in uveal melanoma [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 7217.
Abstract 7215: Targeting EZH2 in castration-resistance prostate cancer using a novel PROTAC
Authors: Qi Chu, Wanqing Xie, Galina Gritsina, Xiaodong Lu, Ka Wing Fong, Zhiquan Lei, Hongshun Shi, Lourdes Brea, Jonathan Zhao, Gary Schiltz, Jindan Yu
Journal: Cancer Research (2025)

Abstract Background: EZH2, a core subunit of the Polycomb Repressive Complex 2 (PRC2), is significantly upregulated in advanced Prostate Cancer (PCa), especially in Castration-Resistant Prostate Cancer (CRPC). However, enzymatic inhibitors of EZH2, such as EPZ-6438, have shown limited efficacy in PCa, while EZH2 knockdown has previously shown to lead to cellular senescence and major growth suppression, warranting the development of Proteolysis Targeting Chimera (PROTAC) to degrade all EZH2 proteins. Methods: Medicinal chemistry was utilized to develop a plethora of EZH2 PROTACs. Mass spectrometry and western blotting were used to assess target protein levels. RNA-seq and H3K27me3 ChIP-seq analyses were performed in PCA cells to evaluate transcriptional and histone modification changes. Senescence staining and flow cytometry were used to evaluate cellular senescence and analyze cell cycle progression. Cell proliferation was assessed in vitro using CellTiter-Glo and live-cell proliferation assays. In vivo efficacy was evaluated using 22Rv1 and VCaP xenograft mouse models. Results: Among several EZH2 PROTAC degraders, 6272 was chosen as the lead candidate due to its high specificity and efficiency in degrading EZH2. We showed that 6272 significantly inhibited 22Rv1 and VCaP cell proliferation compared to EPZ-6438, although this effect was not observed in LNCaP cells. RNA-seq analysis revealed that 6272 readily induced cellular senescence pathways, such as CDKN1A (p21) expression, in 22Rv1 and VCaP, but not LNCaP cells. Further, ChIP-seq showed no changes in H3K27me3 at the CDKN1A gene locus, indicating that 6272 regulates these genes in a catalytic function-independent manner. Lastly, we confirmed that 6272 also significantly reduced 22Rv1 and VCaP xenograft tumor growth. Conclusion: In this study, we developed a novel EZH2 PROTAC with superior efficacy compared to EPZ-6438 in suppressing some prostate cancer cells via rapidly promoting cellular senescence. Citation Format: Qi Chu, Wanqing Xie, Galina Gritsina, Xiaodong Lu, Ka Wing Fong, Zhiquan Lei, Hongshun Shi, Lourdes Brea, Jonathan Zhao, Gary Schiltz, Jindan Yu. Targeting EZH2 in castration-resistance prostate cancer using a novel PROTAC [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 7215.
Abstract 4362: Body mass index influences imatinib exposure in CML patients: Evidence fromTDM with adaptive dosing in real-world patients
Authors: Paul Maroselli, Raphaelle Fanciullino, Julien Colle, Laure Farnault, Pauline Roche, Geoffroy Venton, Regis Costello, Joseph Ciccolini
Journal: Cancer Research (2025)

Abstract Imatinib remains a mainstay of treatment for elderly or frail patients with chronic myeloid leukaemia (CML). Trough levels of around 1000 ng/mL are associated with a major molecular response with acceptable tolerability. We present data from 60 adult CML patients treated with imatinib on therapeutic drug monitoring (TDM) and adaptive dosing. Mean trough levels after treatment initiation were 994.2 ±560.6 ng/mL and a large inter-patient variability was observed (CV: 56%). Only 29% of patients were in the therapeutic range. All parameters associated with corpulence (i.e. body weight, height, body surface area, body mass index (BMI)) and age were significantly associated with imatinib plasma levels on univariate analysis. Age and BMI remained the only parameters associated with trough levels on multivariate analysis. As severe toxicities have been previously reported in patients with low BMI treated with standard imatinib, we evaluated the extent to which low BMI may lead to plasma overexposure. We found a statistically significant difference in trough imatinib levels in patients with BMI&amp;lt;18.5, with exposure +61.5% higher than in patients with 18.5&amp;lt;BMI&amp;lt;24.9 and +76.3% higher than in patients with BMI&amp;gt;24.9 (p&amp;lt;0.05, ANOVA). After TDM with adaptive dosing, a statistically significant difference in dosing between patients was observed, with doses ranging from 200 to 700 mg (p&amp;lt;0.001, ANOVA). No difference in toxicity or efficacy was observed regardless of BMI after adaptive dosing (p&amp;gt;0.05, Chi-2 test). Our data suggest that low BMI has a significant impact on imatinib exposure, but that pharmacokinetically-guided dosing limits its clinical impact in patients. Citation Format: Paul Maroselli, Raphaelle Fanciullino, Julien Colle, Laure Farnault, Pauline Roche, Geoffroy Venton, Regis Costello, Joseph Ciccolini. Body mass index influences imatinib exposure in CML patients: Evidence fromTDM with adaptive dosing in real-world 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 4362.
Abstract 5588: Efficacy of TGR-5 inhibition in cholangiocarcinoma using the novel small molecule inhibitor SBI-364
Authors: Enis Ozmert, Jennifer L. Tomlinson, Danielle M. Carlson, Rory L. Smoot
Journal: Cancer Research (2025)

Abstract Background: Cholangiocarcinoma (CCA) is a malignancy of the biliary epithelium with increasing incidence and poor survival. Despite the advances in targeted therapies, treatment success has been hindered by primary or acquired resistance. New therapeutic strategies are necessary to improve outcomes in this patient population. This study investigates the anti-tumor efficacy of TGR-5 inhibition in CCA using a novel small molecular inhibitor, SBI-364. Methods: Cell viability was assessed using a CellTiter-Glo assay in four unique CCA cell lines treated with SBI-364 at concentrations ranging from 1 nM to 100 µM for 48 hours. Viability was expressed as a percentage relative to untreated controls. Cell migration was assessed using a scratch wound healing assay at 0, 12, and 24 hours following SBI-364 treatment. Migration was reported as the percentage of wound closure relative to the initial scratch width. Apoptosis was assessed using the Caspase-Glo® 3/7 Assay (Promega) after 12 hours of treatment with SBI-364. Caspase activity was normalized to untreated controls and expressed as relative luminescence units. Results: SBI-364 reduced cell viability in a dose-dependent manner across all CCA cell lines with IC50 values ranging from 4.1-15.8 µM. Higher concentrations of SBI-364 induced increased cytotoxicity. In the scratch assay, untreated CCA cells achieved 100 % wound closure within 24 hours. Treatment with SBI-364 at 10 µM significantly inhibited cellular migration, with reduced wound closure compared to controls (p &amp;lt; 0.05). Apoptosis analysis revealed a significant increase in caspase-3/7 activity in three CCA cell lines following treatment with 10 µM SBI-364 for 12 hours (p &amp;lt; 0.01). Conclusion: TGR-5 inhibition using novel small molecule inhibitor SBI-364 demonstrates potent anti-tumor effects in CCA by reducing viability, inhibiting migration, and promoting apoptosis. These findings support further investigation of SBI-364 as a promising therapeutic strategy in CCA. Citation Format: Enis Ozmert, Jennifer L. Tomlinson, Danielle M. Carlson, Rory L. Smoot. Efficacy of TGR-5 inhibition in cholangiocarcinoma using the novel small molecule inhibitor SBI-364 [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 5588.
Abstract 5046: Three-dimensional genome landscape of primary human cancers
Authors: Yanding Zhao, Katie E. Yost, King L. Hung, Kaiyuan Zhu, Duo Xu, Ryan Corces, Shadi Shams, Bryan H. Louie, Shahab Sarmashghi, Laksshman Sundaram, Jens Luebeck, Stanley Clarke, Ashley S. Doane, Jeffrey M. Granja, Hani Choudhry, Marcin Imieliński, Andrew D. Cherniack, Ekta Khurana, Vineet Bafna, Ina Felau, Jean C. Zenklusen, Peter W. Laird, Christina Curtis, Cancer Genome Atlas Analysis Network, William J. Greenleaf, Howard Y. Chang
Journal: Cancer Research (2025)

Abstract Genome conformation underlies transcriptional regulation by distal enhancers, and genomic rearrangements in cancer can alter critical regulatory interactions. Here we profiled the 3D genome architecture and enhancer connectome of 69 tumor samples spanning 15 primary human cancer types from The Cancer Genome Atlas (TCGA). We discovered three archetypes of enhancer usage for over one hundred oncogenes across human cancers: static, selective gain, or dynamic rewiring. Integrative analyses revealed the enhancer landscape of non-cancer cells in the tumor microenvironment at genes related to immune escape. Deep whole genome sequencing and enhancer connectome mapping provided accurate detection and validation of diverse structural variants across cancer genomes, and revealed distinct enhancer rewiring consequences from noncoding point mutations, genomic inversions, translocations, and focal amplifications. Extrachromosomal DNA promoted more extensive enhancer rewiring of oncogenes among several types of focal amplification mechanisms. These results suggest a systematic approach to understand genome topology in cancer etiology and therapy. Citation Format: Yanding Zhao, Katie E. Yost, King L. Hung, Kaiyuan Zhu, Duo Xu, Ryan Corces, Shadi Shams, Bryan H. Louie, Shahab Sarmashghi, Laksshman Sundaram, Jens Luebeck, Stanley Clarke, Ashley S. Doane, Jeffrey M. Granja, Hani Choudhry, Marcin Imieliński, Andrew D. Cherniack, Ekta Khurana, Vineet Bafna, Ina Felau, Jean C. Zenklusen, Peter W. Laird, Christina Curtis, Cancer Genome Atlas Analysis Network, William J. Greenleaf, 1 Howard Y. Chang. Three-dimensional genome landscape of primary human cancers [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 5046.
Abstract 7127: The correlation between immune status and the therapeutic efficacy of immune checkpoint inhibitors in patients with non-small cell lung cancer with sarcopenia
Authors: Ryo Yamazaki, Satoshi Watanabe, Takaaki Masuda, Tomoya Wakabayashi, Yumi Ando, Kunihiro Shono, Naohiro Yanagimura, Masashi Arita, Miyuki Sato, Tomohiro Tanaka, Koichiro Nozaki, Yu Saida, Kenjiro Shima, Yosuke Kimura, Nobumasa Aoki, Yasuyoshi Ohshima, Toshiyuki Koya, Toshiaki Kikuchi
Journal: Cancer Research (2025)

Abstract Background: Our previous prospective study demonstrated that non-small cell lung cancer (NSCLC) patients (pts) with pre-sarcopenia or sarcopenia exhibited poor responses to immune checkpoint inhibitors (ICIs). In this study, we evaluated the relationship between immune status and the efficacy of ICIs in NSCLC pts with sarcopenia. Method: Pts with stage IV or recurrent NSCLC receiving ICI as first-line treatment at Niigata University Medical and Dental Hospital were eligible. Sarcopenia and pre-sarcopenia were diagnosed with physical performance and skeletal muscle mass. Before ICI treatments, peripheral mononuclear blood cells (PBMCs) were collected, and immune phenotypic data was obtained by flow cytometry. Result: PBMCs were obtained from 34 pts from December 2021 through September 2024. Six patients and 7 patients were diagnosed with sarcopenia and pre-sarcopenia, respectively. Pts with a higher percentage of Lineage-CD11b+CD14+CD33+DRlow monocytic myeloid-derived suppressor cells (M-MDSCs) or Lineage-CD11b+CD15+CD33+DRlow polymorphonuclear (PMN)-MDSCs significantly shorter OS (median, 12 months (95% CI, 2.9-26.5) vs 33.1 months (95% CI, 11.4-NR); HR 2.7; P=0.035) after ICI treatments. Further, pts with PD-L1+ cells in MDSCs also had poor OS (median, 12 months (95% CI, 2.9-26.5) vs 33.1 months (95% CI, 11.4-NR); HR 2.6; P=0.0387). The higher percentage of M-MDSC (P=0.0534) and the presence of PD-L1+ cells in MDSCs (P=0.0473) tended to be associated with pts with sarcopenia or pre-sarcopenia. Conclusion: MDSCs may play a critical role in immune suppression in NSCLC pts with sarcopenia and could be associated with poor OS following ICI treatment. To improve the survival outcome of pts with sarcopenia, it is essential to establish strategies to overcome MDSC-mediated immune suppression. Citation Format: Ryo Yamazaki, Satoshi Watanabe, Takaaki Masuda, Tomoya Wakabayashi, Yumi Ando, Kunihiro Shono, Naohiro Yanagimura, Masashi Arita, Miyuki Sato, Tomohiro Tanaka, Koichiro Nozaki, Yu Saida, Kenjiro Shima, Yosuke Kimura, Nobumasa Aoki, Yasuyoshi Ohshima, Toshiyuki Koya, Toshiaki Kikuchi. The correlation between immune status and the therapeutic efficacy of immune checkpoint inhibitors in patients with non-small cell lung cancer with sarcopenia [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 7127.