tbuckley/cabot-search huggingface dataset:
Abstract 4737: IGF and insulin system in regulating hallmarks of cancer
Authors: Bhumika Rajoria, Douglas Yee
Journal: Cancer Research (2025)

The Insulin-like growth factor (IGF) and insulin system is implicated in various cancers and is known to regulate cell growth, proliferation, and metabolism. Type 1 IGF receptor (IGF-1R) targeting strategies have been unsuccessful, probably due to its characteristic to form heterotetrameric hybrids with the homologous insulin receptor (IR). This introduces multiple IGF-1 binding sites and draws focus on IR and its isoforms - IR-A and IR-B, as potential therapeutic targets. A high IR-A to IR-B ratio is observed in tumors including breast cancer. IR-A regulates fetal growth and development while IR-B is predominantly found in the liver and skeletal muscle where glucose uptake is regulated via glucose transporter GLUT4. Non-specific IR targeting likely leads to metabolic imbalance and thus necessitates delineating IR isoform roles to develop efficient targeted strategies. Ideally, targeting IR-A specifically, and leaving IR-B unaffected, might be an effective IGF and insulin system targeting approach. Our group developed IR K/O MCF-7L (ER+ breast cancer cell line) and introduced IR-A or IR-B to generate isoform-specific cell lines. The real-time ATP production rates suggest IGF-1 promotes glycolytic ATP production in MCF-7L, MDA MB 231, MCF-7L IR K/O, and MCF-7L IR-B K/I while insulin at physiological concentration doesn’t affect ATP production. Therefore, IR-B may maintain the metabolic demand of ER+ breast cancer cells when activated by IGF-1. Additionally, IR inactivation and metabolic stimulation via IGF-1 suggest investigating alternative fuels to glucose. Our group previously showed IGF-1 activates cystine/glutamate transporter: xC-, in ER+ cells through PI3K/Akt signaling, sequentially regulating ROS. This further supports proliferation, metastasis, and drug resistance. Glutamine is the rate-limiting step for this transporter exchange and hence a potential candidate driving the observed glycolytic phenotype. Preliminary data suggests MCF-7L maintains the metabolic demand through glucose and glutamine when stimulated with IGF-1. IGF-1 also stimulated migration in MCF-7L and MDA MB 231 cell lines while insulin promoted this phenotype in MDA MB 231 only. This suggests that the IGF and insulin system maintains the metabolic demand of cancer cells to promote cancer aggressiveness. Further investigation will elucidate IR isoform roles in cellular hallmarks of cancer. Citation Format: Bhumika Rajoria, Douglas Yee. IGF and insulin system in regulating hallmarks of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4737.
Abstract 5464: A novel T-cell-engager targeting BCMA and GPRC5D with balanced killing efficacy to overcome potential resistance mechanisms in multiple myeloma treatment
Authors: Xiaochuan Ma, Hanxiao Ying, Chunhong Yu, Ting Qiu, Shu Wang, Pu Pu, Zhibin Xu, Zhendong Xue, Shuyu Cai, Jun Feng, Min Hu, Feng He
Journal: Cancer Research (2025)

Abstract B-cell maturation antigen (BCMA) and G protein-coupled receptor class C group 5 member D (GPRC5D) are critical surface markers expressed on multiple myeloma (MM) cells. BCMA-targeting T cell engagers (TCEs) and CAR-T therapies have achieved significant success in late-line MM treatment. However, antigen loss or downregulation, as well as point mutations, can result in relapse and resistance. Presence of soluble BCMA in circulation due to protein shedding also jeopardized the efficacy of BCMA-targeted therapies. GPRC5D exhibits both overlapping and independent expression profiles with BCMA, making it a compelling complementary target. Dual-targeting strategies leveraging these two antigens thus offer a promising approach to overcome resistance, improve therapeutic durability, and enhance clinical outcomes. Here, we developed a novel tri-specific TCE targeting BCMA, GPRC5D, and CD3 to optimize T cell-mediated cytotoxicity in MM. This molecule exhibited potent and selective tumor cell lysis in T cell-directed killing assays. Notably, it demonstrated balanced killing activity in cells expressing either BCMA or GPRD5D, reducing dependency on a single target antigen. Moreover, the molecule maintained its efficacy and potency in the presence of high levels of soluble BCMA (sBCMA) and overcame resistance associated with BCMA point mutations observed in patients treated with current approved TCEs. The molecule displayed potent anti-tumor efficacy in vivo in RPMI8226 cell-derived-xenograft models with hPBMC reconstitution. In addition, the molecule was well tolerated in cynomolgus monkeys with favorable pharmacokinetics and deep B cell depletion. In summary, this dual-target TCE offers a promising therapeutic option for addressing resistance of current approved TCEs, and further improving clinical outcomes in MM patients. Citation Format: Xiaochuan Ma, Hanxiao Ying, Chunhong Yu, Ting Qiu, Shu Wang, Pu Pu, Zhibin Xu, Zhendong Xue, Shuyu Cai, Jun Feng, Min Hu, Feng He. A novel T-cell-engager targeting BCMA and GPRC5D with balanced killing efficacy to overcome potential resistance mechanisms in multiple myeloma treatment [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 5464.
Abstract 1514: CRISPRi screening reveals RNA editing as a major determinant of platinum sensitivity in high-grade serous ovarian cancer
Authors: Yi Wen Kong, Erika D. Handly, Robin A. Lu, Molly A. Bird, Jack W. Schaeffer, Samkyu P. Yaffe, Michael B. Yaffe
Journal: Cancer Research (2025)

Abstract Platinum-based chemotherapeutic drugs induce intra- and interstrand purine crosslinks causing DNA damage and tumor cell death. Although these drugs are widely used as front-line treatment for multiple human cancers, particularly high-grade serous ovarian cancer (HGSOC), platinum resistance and tumor recurrence remains a common clinical problem. Here we report results from both a genome-wide CRISPRi screen and an RNA-binding protein-focused CRISPRi screen for modulators of sensitivity and resistance of HGSOC cells to two widely used platinum agents, cisplatin and oxaliplatin, and an microtubule-targeting taxane. Using an in vitro approach that mimics clinical treatment protocols, we found that cell lethality after cisplatin or oxaliplatin treatment in p53-defective ovarian cancer cells is markedly enhanced by suppressing genes in the Fanconi anemia (FA) and homologous recombination (HR) pathways, but considerably less enhanced by suppressing genes in the nucleotide excision repair (NER) pathway, despite the well-established importance of NER in reversing platinum-induced intrastrand crosslinks, particularly for cells in G1. Our findings suggest that cell death induced by platinum-DNA crosslinks results from replication stress, which can be further exacerbated by interference with error-free DNA repair mechanisms known to be particularly active during the S- and G2 phases of the cell cycle. These screens further implicated several known and novel RNA-binding proteins (RBPs) as potent sensitizers of HGSOC to both platinum agents and taxanes, including the RNA-modifying enzyme ADAR1, that catalyzes the deamination of adenosine-to-inosine in RNA, altering mRNA coding potential, modifying RNA structure, and regulating RNA localization. Additionally, ADAR1 has been implicated in controlling the integrated stress response (ISR), a signaling network that allows cells to adapt to changes in environment. These findings suggest that activation of an ADAR1-dependent ISR underlies the resistance of HGSOC cells to both platinum-based agents and anti-microtubule drugs that form the current clinical standard of care for HGSOC treatment. Citation Format: Yi Wen Kong, Erika D. Handly, Robin A. Lu, Molly A. Bird, Jack W. Schaeffer, Samkyu P. Yaffe, Michael B. Yaffe. CRISPRi screening reveals RNA editing as a major determinant of platinum sensitivity in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1514.
Abstract 6946: Targeting PDGFRa-SHP2 signaling enhances radiotherapy in IDH1 mutant glioma
Authors: Xiaozhou Yu, Xiao Song, Deanna Tiek, Runxin Wu, Maya Walker, Craig Horbinski, Bo Hu, Shi-Yuan Cheng
Journal: Cancer Research (2025)

Abstract Background: Isocitrate dehydrogenase mutant (IDH-mut) gliomas represent a distinct subtype of glioma with a somewhat better prognosis. However, despite this, they remain incurable due to the limited availability of effective treatments. Targeting SHP2, a non-receptor protein tyrosine phosphatase, shows promise as a therapeutic strategy for cancers, including IDH wildtype (WT) glioblastoma (GBM). However, it is unknown whether IDH-mutant gliomas respond to SHP2 inhibition. Methods: Bioinformatic and biological analyses revealed increased expression and activation of the PDGFRα-SHP2-ERK pathway in IDH-mutant gliomas and patient-derived IDH-mut glioma stem-like cells (GSCs). The effects of SHP2 inhibition, alone or with radiation therapy (RT), were assessed through assays including cell growth, sphere formation, cell differentiation, flow cytometry, immunoblotting, orthotopic brain tumor xenografts, and immunohistochemistry. Results: PDGFRα expression was elevated in IDH-mut gliomas and GSCs, activating the SHP2-ERK pathway. SHP099, a SHP2 inhibitor, reduced GSC tumorigenicity in vitro and in vivo by disrupting SHP2-ERK signaling and promoting differentiation. SHP099 also enhanced cytotoxicity of RT, the standard treatment for IDH-mut glioma, on IDH-mut GSCs and orthotopic glioma models. Mechanistically, the PDGFRα-SHP2-ERK axis is activated in IDH-mut gliomas and RT further activates this pathway. Targeting SHP2 suppressed ERK signaling thereby enhancing the therapeutic effect of RT. Conclusion: Combining SHP2 inhibition with RT shows promising therapeutic efficacy for IDH-mut glioma by suppressing the activated SHP2-ERK axis. Citation Format: Xiaozhou Yu, Xiao Song, Deanna Tiek, Runxin Wu, Maya Walker, Craig Horbinski, Bo Hu, Shi-Yuan Cheng. Targeting PDGFRa-SHP2 signaling enhances radiotherapy in IDH1 mutant glioma [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 6946.
Abstract 4963: The role of education level in cervical cancer screening adherence among deaf, deafblind, and hard of hearing women
Authors: Ciara Luttrell, Hiruni Hewapathiranage-Mayadunne, Erika Bergeron, Poorna Kushalnagar
Journal: Cancer Research (2025)

Abstract Background: Deaf, deafblind, and hard of hearing (DDBHH) women using American Sign Language (ASL) experience disparities in cancer screening and cancer-related health outcomes. Barriers to cancer screenings and cancer care have been well documented, owing to social determinants of health ranging from communication barriers to systemic inequalities within the healthcare system. There is a need to further clarify the roles of education status and English proficiency in DDBHH women’s adherence to the U.S. Preventive Services Task Force (USPSTF) screening guidelines for cervical cancer. Methods: Using the NCI Health Information National Trends Survey in ASL, we surveyed adult participants to assess the USPSTF guidelines’ age-appropriate adherence to cervical cancer screening. Associations between pap smear adherence (screened vs not screened), self-reported English proficiency (well vs not well), and education status (HS degree or less, some college, college) were assessed using Pearson Chi-squared tests. A two-sided p&amp;lt;=.05 was considered significant. Results: Over 475 DDBHH adult participants (21-65 years), recruited in-person and virtually between July 2023 and October 2024, answered screening questions for cancer screening in ASL and English. Within this group, 67% self-reported screening adherence for pap smear. In a published study, similarly aged hearing women reported 73.9% adherence in the English version of the National Health Interview Survey (NHIS). Chi-square results indicated that more years of education was significantly associated with screening adherence [X2 (2, 484) = 7.613, p= 0.02]. Self-reported English proficiency was not associated with cervical screening adherence [X2 (1, 477) = 1.104, p= 0.30]. Discussion: With a 67% adherence rate, the DDBHH community has lower adherence to the recommended screening guidelines compared to the general hearing population. Within this group, those who self-report as HS graduates and/or have left college demonstrate lower adherence to cervical cancer screening guidelines. These findings show that education is key in preventive health behaviors, highlighting the need for targeted interventions to address educational gaps and achieve the Healthy People 2030 target of 79.2% screening adherence. Such research will also aid the Center for Deaf Health Equity in actively working with this DDBHH group to improve strategies for increasing cervical cancer screening adherence. Citation Format: Ciara Luttrell, Hiruni Hewapathiranage-Mayadunne, Erika Bergeron, Poorna Kushalnagar. The role of education level in cervical cancer screening adherence among deaf, deafblind, and hard of hearing women [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 4963.
Abstract 6948: A PP2A molecular glue restores heterotrimer formation for the treatment of high-grade uterine cancers
Authors: Irene Peris, Derek Taylor, George Trainor, Analisa V. DiFeo, Caitlin O'Connor, Goutham Narla
Journal: Cancer Research (2025)

Abstract Uterine cancer incidence and mortality have been increasing, particularly in the aggressive high-grade subtypes, including uterine serous carcinomas (USC) and uterine carcinosarcomas (UCS). For the high-grade subtypes, surgery remains the mainstay of treatment, and while the approval of the combination of Pembrolizumab and Lenvatinib is a promising treatment strategy, there is only a 50% response rate in women with recurrent disease, highlighting the need for additional therapeutic options. Molecularly, these tumors harbor few mutations and are hallmarked by copy number alterations. However, almost every USC tumor harbors a TP53 mutation, and 30-40% of patients also harbor a co-occurrent mutation to PPP2R1A. Heterozygous hotspot mutations in PPP2R1A are drivers of the most aggressive forms of uterine cancer. PPP2R1A encodes for the Aα scaffolding subunit of the heterotrimeric phosphatase PP2A. The PP2A heterotrimeric complex is comprised of a catalytic (C) subunit, a scaffolding (A) subunit, and a substrate-directing regulatory (B) subunit. The binding of different classes of regulatory B subunits directs PP2A’s serine/threonine phosphatase activity. We, and other groups, have shown that these hotspot mutations result in a biased pool of heterotrimers, where the formation of tumor-suppressive holoenzymes is abrogated while leaving tumor-promoting heterotrimers intact. Here, we identify small molecular glues that could therapeutically correct trimer formation to the mutant scaffold. A small molecule library was designed to fit into the pocket at the interface of Aα/B56α/Cα. The molecule RPT04402 promoted B56α heterotrimerization to the AαP179R and AαS256F mutant scaffolds. In mice, RPT04402 treatment presented tumor regressions and median survival extensions in multiple independent cell-derived and patient-derived xenografts. Importantly, this activity was abrogated upon knockout of B56α. This molecule has undergone preclinical toxicology studies and is well tolerated in multiple species. Combined, these data demonstrate that PP2A molecular glues are a promising novel therapy for PPP2R1A mutant uterine cancer patients and represent the first small molecule approach targeting a driver of this aggressive disease. Citation Format: Irene Peris, Derek Taylor, George Trainor, Analisa V. DiFeo, Caitlin O'Connor, Goutham Narla. A PP2A molecular glue restores heterotrimer formation for the treatment of high-grade uterine 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 6948.
Abstract 3799: <i>CDKN2ALow </i>cancer cells outcompete macrophages for microenvironmental zinc to drive immunotherapy resistance
Authors: Raquel Buj, Katherine M. Aird
Journal: Cancer Research (2025)

Abstract Approximately 50% of cancers exhibit decreased CDKN2A expression (CDKN2ALow), which is linked to resistance to immune checkpoint blockade (ICB). The mechanisms driving ICB resistance due to CDKN2A loss alone remain largely unexplored. While CDKN2A is traditionally recognized as a tumor suppressor and cell cycle regulator, we have previously put forth a new paradigm demonstrating its role in intracellular metabolic reprogramming. Whether the metabolic derangement as a consequence of CDKN2A loss alters metabolites within the tumor microenvironment (TME) and how that affects the immune compartment and ICB response has never been investigated. Here we found that CDKN2ALow cancer cells reorganize zinc compartmentalization by upregulating the zinc importer SLC39A9 in the plasma membrane, leading to intracellular zinc accumulation and concurrent zinc depletion in the TME. This reorganization results in zinc-starved macrophages, leading to reduced phagocytic activity. Remarkably, restoring zinc levels in the TME through dietary intervention primes macrophage phagocytic activity in response to ICB. Unexpectedly, zinc-reeducated macrophages alone can initiate a robust ICB response in CDKN2ALow tumors whereas T cells are not required. Clinically, macrophages from CDKN2ALow cancer patients have decreased zinc signatures corresponding to reduced phagocytosis signatures. Moreover, patients with low circulating zinc levels have reduced time-to-event outcomes compared to those with higher zinc levels. Our work reveals a previously unrecognized mechanism through which CDKN2ALow cancer cells directly disrupt macrophage function and ICB efficacy by altering zinc compartmentalization within the tumor. Our data also indicates that zinc dietary intervention may offer a cost-effective and clinically feasible strategy to overcome ICB resistance and improve treatment outcomes in patients with CDKN2ALow tumors. Citation Format: Raquel Buj, Katherine M. Aird. CDKN2A Low cancer cells outcompete macrophages for microenvironmental zinc to drive immunotherapy resistance [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 3799.
Abstract 6933: Ru(II)-thymine complex inhibits NF-κB activation, suppressing acute myeloid leukemia stem cells
Authors: Maiara de S. Oliveira, Ingrid R. Dias, Rafaela G. Costa, Ana Carolina B. Rodrigues, Suellen L. Silva, Milena B. Soares, Rosane B. Dias, Ludmila F. Valverde, Clarissa A. Rocha, Alzir A. Batista, Rodrigo S. Correa, Valdenizia R. Silva, Eugênia T. Pina, Daniel P. Bezerra
Journal: Cancer Research (2025)

Abstract Acute myeloid leukemia (AML) is a deadly blood cancer caused by leukemia blasts that fail to develop properly. AML has a significant relapse rate, which is attributed to a subset of cells known as leukemia stem cells (LSCs). Herein, we evaluated the ability of a Ru(II)-thymine complex (RTC) with the formula [Ru(PPh3)2(Thy)(bipy)]PF6 (where PPh3 = triphenylphosphine, Thy = thymine, and bipy = 2, 2'-bipyridine) to suppress AML LSCs. RTC exhibited strong cytotoxicity against solid and hematologic malignancies and inhibited primary AML LSCs, as evidenced by a decrease in the CD34+CD38- cell population. RTC decreased the number of CD34+ and CD123+ cells in the AML cell line KG-1a, which has a similar population to LSC. RTC-treated NSG mice bearing KG-1a xenografts had a reduced number of leukemic blasts in the bone marrow. RTC-treated KG-1a cells showed increased DNA fragmentation, active caspase-3 and cleaved PARP (Asp 214) levels, and mitochondrial superoxide. The pancaspase inhibitor Z-VAD-(OMe)-FMK, but not the antioxidant N-acetylcysteine, partially reduced RTC-induced cell death in KG-1a cells, demonstrating that RTC causes caspase-mediated apoptosis via an oxidative stress-independent pathway. In molecular mechanism investigations, transcripts of the NF-κB inhibitor NFKBIA were increased, and the level of NF-κB p65 phosphorylated at Ser529 residue was reduced in RTC-treated KG-1a cells. This suggests that RTC may block NF-κB signaling. Altogether, these data suggest the anti-AML potential of RTC in AML LSCs via suppression of NF-κB signaling. Citation Format: Maiara de S. Oliveira, Ingrid R. Dias, Rafaela G. Costa, Ana Carolina B. Rodrigues, Suellen L. Silva, Milena B. Soares, Rosane B. Dias, Ludmila F. Valverde, Clarissa A. Rocha, Alzir A. Batista, Rodrigo S. Correa, Valdenizia R. Silva, Eugênia T. Pina, Daniel P. Bezerra. Ru(II)-thymine complex inhibits NF-κB activation, suppressing acute myeloid leukemia stem cells [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 6933.
Abstract 4497: Discovery and optimization of a covalent AKR1C3 inhibitor for evaluation in hormone-dependent cancers
Authors: Robert J. Grams, Robert J. Seal, James Veccia, Ku-Lung Hsu
Journal: Cancer Research (2025)

Aldo-keto reductase family 1 member C3 (AKR1C3) is a member of the AKR superfamily of enzymes that metabolizes androgen, estrogen, and prostaglandin substrates to produce potent drivers of proliferation in hormone-dependent cancers. Interest in developing selective inhibitors have produced tool compounds for inactivation or degradation of AKR1C3 with varying degrees of selectivity among the 15 known AKR proteins. Selectivity of AKR1C3 inhibitors across the AKR family is critical since a clinical candidate failed due to hepatotoxicity from off-target inhibition of AKR1D1. Here, we report development of a sulfonyl-triazole (SuTEx) covalent AKR1C3 inhibitor (RJG-2051) that site selectively engages a non-catalytic tyrosine residue on AKR1C3 in cells. Importantly, RJG-2051 exhibited negligible cross-reactivity with detectable AKRs or other proteins across thousands of tyrosine and lysine sites quantified by chemical proteomics. The disclosure of a covalent and proteome-wide selective inhibitor for potent AKR1C3 inactivation in cells will expedite cell biological studies for testing the therapeutic potential of this metabolic target. Citation Format: Robert J. Grams, Robert J. Seal, James Veccia, Ku-Lung Hsu. Discovery and optimization of a covalent AKR1C3 inhibitor for evaluation in hormone-dependent 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 4497.