tbuckley/cabot-search huggingface dataset:
Abstract 7119: Clinic-ready Polθ inhibitor SYX1097 suppresses solid tumors in vivo
Authors: Yilan Zhang, Kai Jiang, Xiaokang Xu, Liu Wu, Chongxun Ge, Yue Xie, Hu He, Song Liu, Xuzhen Tang, Song Shi
Journal: Cancer Research (2024)

Abstract A large fraction of tumors with BRCA1 or BRCA2 mutations only have weak responses to PARP inhibitor (PARPi) treatment, and often develop PARPi resistance. To address these challenges, we have developed SYX1097, a selective and potent oral Polθ inhibitor as a single agent or in combination with PARPi for treating tumors with BRCA mutations. Both Polθ and PARP1 play key roles in microhomology-mediated end joining for DNA double-strand repair and in single-strand DNA gap filling during DNA replication. Using in vitro cellular assays and in vivo animal models, we show that SYX1097 alone or combined with PARPi without obvious side effects. SYX1097 dramatically inhibited proliferation in BRCA -/- isogenic cells with IC50 &amp;lt;20 nM, while only had very weak effect on their parental cells (&amp;gt;10000nM). SYX1097 also enhanced tumor cell sensitivity to Olaparib 5 to 15 times. SYX1097 in vivo efficacious started at 50mg/kg mono-therapy, and generate &amp;gt;50% tumor regression at 5mg/kg when combined with Olaparib. In a 20-day repeated dosing study, SYX1097 200mg/kg BID was fully tolerated by mice. When considering additive hematological toxicity, comparing with “ATRi + PARPi”, “SYX1097 + PARPi” manifested deep and durable tumor regression without significant body weight loss or reticulocytes decrease. Moreover, SYX1097 is found synthetic lethal with defect of genes not involved in homologous recombination repair and able to suppress tumors with specific gene defect in vivo, which indicated SYX1097 can be used as single agent guided by specific biomarker.SYX1097 has a clean safety profile tested with Safety-Screen 44TM Panel, and is well tolerated in mice, rats and dogs. It possesses remarkable pharmacokinetic properties in various species, with no hematological toxicity observed during the preclinical toxicity studies. SYX1097 is advancing towards IND filing in 2024.Collectively, SYX1097 is a promising small molecule that may be utilized as a single agent or in combination with PARPi for cancer treatment not only limited by HR deficiency. Citation Format: Yilan Zhang, Kai Jiang, Xiaokang Xu, Liu Wu, Chongxun Ge, Yue Xie, Hu He, Song Liu, Xuzhen Tang, Song Shi. Clinic-ready Polθ inhibitor SYX1097 suppresses solid tumors in vivo [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 7119.
Abstract 2264: Identifying and analyzing independent clonal populations in single Barrett’s esophagus biopsies
Authors: Mariya Kazachkova, Phoebe He, Ludmil B. Alexandrov
Journal: Cancer Research (2024)

Abstract Barrett’s esophagus (BE) is a non-obligate precursor of esophageal adenocarcinoma (EAC), often measuring multiple centimeters in length and characterized by columnar epithelium replacing normal squamous epithelium in the distal esophagus. Early studies in BE suggested that all cells within a patient’s Barrett’s segment are progenies of a single founder cell. However, in recent years this previously accepted model of BE as a monoclonal disease has been retired in favor of a multiclonal model with new evidence suggesting that a patient’s Barrett’s segment can be composed of multiple independent clones with independent founder cells. Nonetheless, single BE samples are still routinely assumed to be monoclonal, leading to independent sets of genomic aberrations erroneously being analyzed as a single set in the case of multiclonal samples. Here, we utilize a previously generated whole-genome sequenced BE dataset and repurpose an established pipeline for detecting subclonal populations to identify BE samples that are comprised of multiple independent clones. Additionally, we present a novel approach for validating multiclonality from sequencing data by phasing pair-end sequencing reads using germline variants. We demonstrate that 20/80 patients have at least one multiclonal sample and that the independent clones contained in these single biopsies can have drastically different genomic profiles. Further, we speculate that these multiclonal samples capture a snapshot of clonal competition and evolution within BE. These findings highlight the importance of accounting for multiclonality when studying BE and provide the first systematic analysis of multiclonal BE samples. Citation Format: Mariya Kazachkova, Phoebe He, Ludmil B. Alexandrov. Identifying and analyzing independent clonal populations in single Barrett’s esophagus biopsies [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 2264.
Abstract 1999: DCAF7 acts as a scaffold to recruit USP10 for G3BP1 deubiquitylation and facilitates chemoresistance and metastasis in nasopharyngeal carcinoma
Authors: Qing-Jie Li, Xue-Liang Fang, Ying-Qin Li, Jia-Yi Lin, Cheng-Long Huang, Shi-Wei He, Sheng-Yan Huang, Jun-Yan Li, Sha Gong, Kai-Lin Chen, Na Liu, Jun Ma, Yin Zhao, Ling-Long Tang
Journal: Cancer Research (2024)

Abstract Though docetaxel plus cisplatin and 5-fluorouracil (TPF) induction chemotherapy becomes the standard care for locoregionally advanced nasopharyngeal carcinoma (NPC), some patients could not benefit from this therapy. The underlying mechanisms remain unclear. We found that DCAF7 was highly expressed in TPF resistant NPC patients, and promoted the cisplatin resistance and metastasis of NPC cells. Mechanistically, DCAF7 facilitates the interaction between USP10 and G3BP1, resulting in the removal of K48-linked ubiquitylation of G3BP1 at Lys76 mediated by USP10, thus preventing the degradation of G3BP1 through ubiquitin-proteasome pathway, and facilitates the stress granule (SG)-like structures formation. Moreover, knockdown of G3BP1 successfully reversed the SG-like structures formation and oncogenic effects exerted by DCAF7. Importantly, NPC patients with elevated DCAF7 expression exhibited high risks of metastasis, and is associated with a poor prognosis. This study identifies DCAF7 as a pivotal cisplatin resistance gene, and sheds light on the underlying mechanism of TPF resistance in NPC patients. The DCAF7-USP10-G3BP1 axis provides potential therapeutic targets and biomarker for NPC treatment. Citation Format: Qing-Jie Li, Xue-Liang Fang, Ying-Qin Li, Jia-Yi Lin, Cheng-Long Huang, Shi-Wei He, Sheng-Yan Huang, Jun-Yan Li, Sha Gong, Kai-Lin Chen, Na Liu, Jun Ma, Yin Zhao, Ling-Long Tang. DCAF7 acts as a scaffold to recruit USP10 for G3BP1 deubiquitylation and facilitates chemoresistance and metastasis in nasopharyngeal carcinoma [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 1999.
Abstract 1741: AlidaBio EpiPlex: A platform for multiplexed detection of RNA modifications in clinical samples
Authors: Andrew Price, Zachary Miles, John Chevillet, Byron Purse, Richard I. Gregory, Gudrun Stengel
Journal: Cancer Research (2024)

Abstract It is becoming increasingly appreciated that RNA modifications are widespread in development and homeostasis, regulating RNA stability and translation, and that alterations to these modifications are associated with cancer development and progression. Although 170 different RNA modifications have been identified using mass spectrometry, there is a paucity of convenient, validated tools immediately available to cancer researchers to explore these modifications using relevant clinical samples in sufficient numbers, and accurately determine their suitability for use as diagnostic or drug targets. In addition, most existing methods concentrate only on m6A, the most prevalent modification in mRNA. Alida Bio has developed an end-to-end assay platform with an integrated bioinformatics solution that detects multiple modifications in the same reaction. This platform exploits targeted, multiplexed barcoding to reveal the quantitative abundance of modified transcripts, co-localization of multiple RNA modifications to the same gene, and gene expression profiles. Alida Bio's mission is to equip translational researchers with tools that will significantly improve their understanding of gene regulation through seamless measurement of RNA modifications. Citation Format: Andrew Price, Zachary Miles, John Chevillet, Byron Purse, Richard I. Gregory, Gudrun Stengel. AlidaBio EpiPlex: A platform for multiplexed detection of RNA modifications in clinical samples [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 1741.
Abstract 1190: NK cell subsets as potential correlates of antitumor immunity in HPV+ cancers
Authors: Madison O'Hara, Jagannadha Sastry
Journal: Cancer Research (2024)

Abstract High-risk type human papillomaviruses (HPV) are associated with genital and oral cancers, and the incidence of head and neck squamous cell cancers is fast increasing in the USA and worldwide. Survival rates for patients with locally advanced disease are poor and variable after standard of care (SOC) chemoradiation treatment (CRT). Identifying the antitumor host immune mediators important for treatment response and designing strategies to promote them are essential for improving clinical outcome. Antitumor immunity comprises of adaptive and innate immune effectors. The immediate innate immune response by natural killer (NK) cells is a critical component for antitumor efficacy. The effector function of NK cells is modulated by various receptors via a wide array of activation or inhibitory signals. Among these receptors is HLA-DR, a recognized activation marker on CD8 T and NK cells. Literature studies refer to HLA-DR+ NK cells as pre-mNK. Preclinical data demonstrated therapeutic vaccine mediated induction of pre-mNK equivalent to contribute to tumor-free long-term survival. In our studies with clinical samples from HPV+ cancer patients, we’ve observed a dysfunctional phenotype of circulating pre-mNK when compared to healthy donors, demonstrated by flow cytometry methods. The correlates for dysfunction include increased PD-1 expression, a known inhibitory receptor, and reduced CD16, an NK receptor for Antibody Dependent Cellular Cytotoxicity (ADCC). Further, we observed circulating pre-mNK cells in HPV+ head and neck patients gain functionality post-treatment, as shown by significant increases in granzyme B and CD16, both known contributors for NK cytotoxicity. In cervical cancer patients, we had the opportunity to analyze the tumor microenvironment (TME). Interestingly, we found a significant increased frequency of cytotoxic pre-mNK cells, shown by granzyme B, in the TME that was not present in circulation. Overall, pre-mNK represent a uniquely activated immune subset for antiviral and antitumor immunity. Citation Format: Madison O'Hara, Jagannadha Sastry. NK cell subsets as potential correlates of antitumor immunity in HPV+ cancers [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 1190.
Abstract 942: Response to systemic therapies in patient-derived cell lines from primary and recurrent adult granulosa cell tumors
Authors: Geertruid Brink, Nizar Hami, Sander Mertens, Ward Hofhuis, Jurgen Piek, Cor de Kroon, Christianne Lok, Eva Maria Roes, Luc van Lonkhuijzen, Hans Nijman, Hugo Snippert, Jolijn Groeneweg, Petronella Witteveen, Ronald Zweemer
Journal: Cancer Research (2024)

Abstract Introduction: In patients with adult-type granulosa cell tumor (aGCT), a rare subtype of ovarian cancer, surgery is the preferred treatment for both primary and recurrent disease. However, the probability of complete resection decreases after multiple recurrences, in which case systemic treatment is an alternative option. Response rates of systemic therapy are variable, resistance is a problem and it is difficult to predict which therapy will work in which patient. Drug screen testing on patient-derived aGCT cell lines may offer a solution. Methods: In a national prospective study on aGCT, fresh tissue was collected immediately after surgery. Tumor tissue was cultured and developed into 2D cell lines. Both clinically applicable and experimental drugs were tested on the patient-derived cell lines and two control cell lines. Dose-response curves and synergy were calculated using GraphPad Prism and Compusyn software. Results: We cultured 34 patient-derived cell lines from tissue of seven patients with primary aGCT and from 13 patients with recurrence. In eight patients multiple sites were cultured. A total of 27 drugs were tested, including 10 monotherapies and 17 combinations. Carboplatin/gemcitabine showed efficacy and synergy 33 of 34 patient-derived cell lines (97%), in contrast to the regular carboplatin/paclitaxel and carboplatin/etoposide combinations (50% and 74%, respectively). The experimental combinations alpelisib/fulvestrant and alpelisib/gemcitabine showed efficacy of more than 75%. Testing of anti-hormonal therapy was not sufficiently reliable with this technique. Conclusion: Drug screening on patient-derived tumor cell lines adequately reflects the reality of the variable response to systemic therapy in aGCT. In future research, this technique could be used to personalize the systemic treatment of aGCT patients. The response to carboplatin/gemcitabine in our patient-derived cell lines is striking. Citation Format: Geertruid Brink, Nizar Hami, Sander Mertens, Ward Hofhuis, Jurgen Piek, Cor de Kroon, Christianne Lok, Eva Maria Roes, Luc van Lonkhuijzen, Hans Nijman, Hugo Snippert, Jolijn Groeneweg, Petronella Witteveen, Ronald Zweemer. Response to systemic therapies in patient-derived cell lines from primary and recurrent adult granulosa cell tumors [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 942.
Abstract 7114: Exploring the landscape of PARP and PARG inhibitor selectivity in live cells using NanoBRET™ target engagement assays
Authors: Ani Michaud, Kelly Teske, Jennifer Wilkinson, Chad Zimprich, James Vasta, Cesear Corona, Min Zhou, Elizabeth Dominguez, Kaitlin Dunn-Hoffman, Matthew Robers
Journal: Cancer Research (2024)

Abstract The 17-member poly(ADP-ribose) polymerase (PARP) family of proteins mediate a number of cellular processes including gene transcription, cell-division and DNA-repair. PARPs catalyze the addition of poly- or mono- ADP-ribose chains on target proteins, modifying their function and/or recruitment in various pathways. Poly(ADP-ribose) Glycohydrolase (PARG) catabolizes PAR units and facilitates the recycling of PARP and other modified effector proteins. A number of PARPS are implicated in human disease, and PARP inhibitors (PARPi’s) have seen major clinical success, however, many PARPs (especially mono PARPs) are understudied and chemical tools for understanding cellular PARPi selectivity and potency across the entire family are lacking. Similarly, several PARG inhibitors have been developed to date, but tools for directly assessing target engagement in a cellular context are sorely needed. Here we describe the development and application of target engagement assays for characterizing PARP and PARG inhibitor selectivity and affinity in live cells. This method is based on the NanoBRET™ assay platform, which is a proximity-based probe displacement assay that operates in live cells. Using NanoBRET™ technology, we have developed a single probe that covers 12 out of 17 PARP family members. We explored the family-wide selectivity of a diverse panel of clinical and preclinical PARP inhibitors in live cells, representing the first family-wide, cell-based method for profiling PARP selectivity. We also describe the development of a second probe that reports on PARG target engagement. Target engagement of PARG was observed for three out of five tested inhibitors, suggesting a potential indirect mode of action for certain inhibitors on PARG glycohydrolase activity. These assays offer a complementary approach for studying target engagement within the PARylation cycle. Citation Format: Ani Michaud, Kelly Teske, Jennifer Wilkinson, Chad Zimprich, James Vasta, Cesear Corona, Min Zhou, Elizabeth Dominguez, Kaitlin Dunn-Hoffman, Matthew Robers. Exploring the landscape of PARP and PARG inhibitor selectivity in live cells using NanoBRET™ target engagement assays [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 7114.
Abstract 4368: USP36 SUMOylates EXOSC10 and Las1L to promotes their function in rRNA processing
Authors: Mushui Dai, Yanping Li, Yunhan Yang, Xiao-Xin Sun
Journal: Cancer Research (2024)

Abstract Eukaryotic ribosome biogenesis is a highly regulated multistep process to generate ribosomes, including transcription of pre-ribosomal RNA, rRNA processing, ribosome subunit assembly and export. Dysregulation of ribosome biogenesis is associated with various human diseases, including ribosomopathies and cancer. Therefore, it is crucial to understand how ribosome biogenesis is regulated during normal cell homeostasis and how it is deregulated in human diseases. Here, we report that the ubiquitin-specific protease USP36 acts as a novel SUMO ligase to promote nucleolar protein SUMOylation. Using affinity purification, we found that USP36 associates with a large number of nucleolar and ribosome biogenesis-related proteins, including all 10 components of the nucleolar RNA exosome complex, EXOSC1 to EXOSC10, as well as the Las1L-Nol9 endonuclease-kinase complex. We showed that USP36 interacts with the RNA exosome through EXOSC10 and SUMOylates ECOSC10 at Lys 583. Mutating K583 impaired the binding of EXOSC10 to pre-rRNAs and the K583R mutant failed to rescue the defects in rRNA processing and cell growth inhibition caused by knockdown of endogenous EXOSC10. Likewise, USP36 interacts with the Las1L-Nol9 complex and promotes Las1L SUMOylation at K565. In addition, USP36 deubiquitinates Las1L and Nol9 and regulates their protein stability. Mutating K565 does not affect the levels of Las1L and the formation of the Las1L-Nol9 endonuclease-kinase complex. However, induced expression of a K565R mutant of Las1L failed to rescue the defects in rRNA processing and cell growth inhibition caused by knockdown of endogenous Las1L. Together, these results suggest that USP36 plays an important role in regulating ribosome biogenesis by post-translationally regulating the function of RNA exosome and Las1L-Nol9 complexes. Citation Format: Mushui Dai, Yanping Li, Yunhan Yang, Xiao-Xin Sun. USP36 SUMOylates EXOSC10 and Las1L to promotes their function in rRNA processing [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 4368.
Abstract 7131: Base excision repair regulation of replication stress induced poly(ADP-ribose) checkpoints
Authors: Md Ibrahim, Md Maruf Khan, Rasha Q. Al-Rahaleh, Jennifer Clark, Faisal Hayat, Qingming Fang, Christopher A. Koczor, Marie E. Migaud, Robert W. Sobol
Journal: Cancer Research (2024)

Abstract PARP-inhibitors (PARPi) have been developed to treat homology-directed repair deficient cancers such as BRCA1/2-defective breast and ovarian tumors. However, acquired resistance to PARPi is now common, suggesting the need to identify new protein targets. To that end, a missed opportunity is found in the PARP1/PARP2 activation mechanism in response to DNA damage and replication stress and the resulting protein complexes and enzymes that depend on and coordinate PARP-mediated DNA repair processes. We have found that PARP1/PARP2 activation, whether from acute DNA damage, from replication stress or both triggers a temporal and coordinated interplay of base excision repair and single-strand break repair (BER/SSBR) proteins and enzymes. In turn, the recruitment of these BER and SSBR proteins suppresses PARP1/PARP2 activation, thereby functioning as a network of PARP1/PARP2 regulators, modulating the PARP-mediated response to replication stress. To that end, we find that loss of expression of these key BER/SSBR proteins releases a break on replication-stress induced PARP1/PARP2 activation, triggering un-restrained PARP1/PARP2 activation and elevated levels of replication-dependent poly(ADP-ribose) (PAR). We next confirmed that the loss of these downstream BER enzymes render cancer cells responsive to PARPi’s when the BRCA1/2 pathways are restored. Further, we show that BER expression regulates the cellular response to inhibitors of the PAR degrading enzyme PARG, suggesting that XRCC1-dependent BER proteins regulate replication-stress dependent PAR accumulation. The increase in PAR due to PARG inhibition, that is further regulated by BER, drives a strong intra-S phase response, indicated by activation of ATR and CHK1 signaling. As the checkpoint governed by ATR and CHK1 functions as a protective mechanism, we show that PARG inhibition is synthetically lethal with ATR and CHK1 inhibition and this may be explained by our demonstration of PARGi-mediated trapping of essential BER proteins at the site of damage and PAR accumulation. Together, these studies reveal a significant role for BER/SSBR proteins in regulating replication stress induced PARylation and the resulting intra-S phase checkpoint. Citation Format: Md Ibrahim, Md Maruf Khan, Rasha Q. Al-Rahaleh, Jennifer Clark, Faisal Hayat, Qingming Fang, Christopher A. Koczor, Marie E. Migaud, Robert W. Sobol. Base excision repair regulation of replication stress induced poly(ADP-ribose) checkpoints [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 7131.