tbuckley/cabot-search huggingface dataset:
Abstract LB191: The natural compound KH617 targets pediatric and adult high-grade gliomas
Authors: Manqian Zhao, Liang Ye, Litao Liu, Xiao Ke, Jian Teng, Bakhos A. Tannous
Journal: Cancer Research (2025)

Abstract Background: Pediatric and adult high-grade gliomas (HGGs) are highly aggressive brain tumors characterized by poor clinical outcomes due to intrinsic chemotherapy resistance and challenges in drug delivery. Effective therapeutic options remain limited, necessitating the development of novel agents. Methods and Results: The efficacy of KH617 (β-elemene, β-ELE), a natural compound, was evaluated through preclinical and clinical investigations. Preclinical Results: KH617 demonstrated potent cytotoxic effects across 29 brain cancer cell cultures, including primary and secondary glioblastoma cells, temozolomide (TMZ)-resistant sublines, pediatric diffuse intrinsic pontine glioma (DIPG) cultures, and mouse glioma lines. These effects were independent of molecular characteristics, including MGMT status, stemness, and metastatic potential, indicating a distinct mechanism from TMZ. In orthotopic xenograft models: Clinical Results: KH617’s clinical translation has progressed through investigational new drug (IND) approval by the FDA on July 28, 2022, and National Medical Products Administration (NMPA) clinical trial notification on September 22, 2022. A Phase I open-label trial was initiated to determine the recommended Phase II dose (RP2D) in patients with recurrent GBM (rGBM) and advanced solid tumors.To date, over 20 patients have been enrolled in the dose-escalation stage, reaching the maximum dose level without dose-limiting toxicities. Safety outcomes have exceeded expectations, and tumor volume reductions demonstrated a dose-dependent response, supporting the preclinical findings. Conclusions: Integrating robust preclinical data and encouraging early clinical outcomes, KH617 emerges as a promising therapeutic candidate for pediatric and adult HGGs, addressing critical unmet needs in neuro-oncology. Citation Format: Manqian Zhao, Liang Ye, Litao Liu, Xiao Ke, Jian Teng, Bakhos A. Tannous. The natural compound KH617 targets pediatric and adult high-grade gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB191.
Abstract LB163: Novel multiplex immunoassay for simultaneous profiling of human and mouse immunomodulatory proteins in humanized models
Authors: Anthony J. Saporita, Jonathan F. Khan, Tina Raeber, Brice Martin, Parwiz Abrahimi, Brooke Gilliam, Shane Curran, Rick Wiese, Mark M. Souweidane, Jedd D. Wolchok, Taha Merghoub
Journal: Cancer Research (2025)

Abstract Multiplex immunoassay kits are essential for profiling a wide array of immunomodulatory proteins, including cytokines, chemokines, and growth factors in humans and animal models. Humanized mice are genetically modified to express human genes or engraft human cells, allowing researchers to study human immune responses, vaccine efficacy, and immune-related diseases. However, the high cross-species homology of many immune-related proteins complicates the distinction between human and mouse homologues within the same sample. Therefore, reliable tools that can differentiate these homologues are crucial for researchers using humanized mouse models. We describe the development of a novel multiplex immunoassay featuring both mouse-specific and human-specific antibody pairs against cytokines, chemokines, and growth factors. Specificity was confirmed by testing individual mouse and human recombinant proteins. This kit was optimized for mouse serum and plasma samples, detected by mouse-analyte capture beads, while human-analyte capture beads showed no reaction. To evaluate the platform's ability to measure human cytokines, we spiked human PBMC supernatant into mouse serum and plasma samples. The exogenous human analytes from the PBMC supernatant were specifically detected on the human beads in the spiked mouse serum. We further validated this platform by analyzing serum collected from immunodeficient NSG mice bearing human glioma xenografts treated with tumor-targeting or non-targeting human CAR T cells. Peripheral levels of human interferon gamma were lower in cohorts treated with locoregional administration of CAR T cells compared to cohorts receiving systemic administration of CAR T cells, highlighting the real-world applicability of this novel multiplex immunoassay kit. In summary, this study demonstrates the feasibility and utility of measuring mouse and human proteins simultaneously via multiplex immunoassay, providing a powerful tool for advancing research in humanized mouse models. Citation Format: Anthony J. Saporita, Jonathan F. Khan, Tina Raeber, Brice Martin, Parwiz Abrahimi, Brooke Gilliam, Shane Curran, Rick Wiese, Mark M. Souweidane, Jedd D. Wolchok, Taha Merghoub. Novel multiplex immunoassay for simultaneous profiling of human and mouse immunomodulatory proteins in humanized models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB163.
Abstract LB166: OP-3136, a selective KAT6 inhibitor, demonstrates anti-tumor activity in prostate, ovarian, and non-small cell lung cancer preclinical models
Authors: Gopinath S. Palanisamy, Susanna A. Barratt, Chelsea Hope, Srinivasan Jayaraman, Brandon Robello, Guadalupe Peña, Raymond A. Ng, David C. Myles
Journal: Cancer Research (2025)

Abstract Histone lysine acetyltransferases KAT6A and KAT6B are frequently dysregulated in cancer and are mechanistically linked to key oncogenic processes. Small-molecule inhibitors of KAT6 have shown promising clinical efficacy, particularly in ER/HER2- metastatic breast cancer. However, KAT6 inhibitors remain largely unexplored in other solid tumors despite strong biological and mechanistic rationale for KAT6 as a potential target. Here, we report for the first time that the inhibition of KAT6 using OP-3136, a highly selective KAT6 inhibitor currently in Phase 1 clinical trials, demonstrates robust anti-tumor activity in preclinical models of prostate cancer, ovarian cancer, and non-small cell lung cancer (NSCLC), both in vitro and in vivo. In vitro proliferation assays were conducted on KAT6A-expressing or overexpressing cell lines: VCAP (prostate cancer), OAW28 (ovarian cancer, KAT6A-amplified), OVCAR3 (ovarian cancer), and LCLC-97TM1 (NSCLC). In vivo efficacy was evaluated in xenograft models using OVCAR3 and LCLC-97TM1 cells in immunocompromised mice.OP-3136 inhibited proliferation across all tested prostate cancer, ovarian cancer and NSCLC cell lines. In the OVCAR3 xenograft ovarian cancer model, oral administration of OP-3136 as monotherapy at 0.5 and 1 mg/kg resulted in tumor regression with tumor growth inhibition (TGI) of 104.5% and 105.4%, respectively. In the LCLC-97TM1 NSCLC xenograft model, monotherapy with OP-3136 at 1 mg/kg achieved a TGI of 62%. These findings highlight the potential of OP-3136 monotherapy to treat prostate, ovarian, and NSCLC tumors and strongly support expanding the clinical investigation of KAT6 inhibitors beyond ER+/HER2- breast cancer. Citation Format: Gopinath S. Palanisamy, Susanna A. Barratt, Chelsea Hope, Srinivasan Jayaraman, Brandon Robello, Guadalupe Peña, Raymond A. Ng, David C. Myles. OP-3136, a selective KAT6 inhibitor, demonstrates anti-tumor activity in prostate, ovarian, and non-small cell lung cancer preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB166.
Abstract LB037: CD28 drives CAR T cell responses in multiple myeloma
Authors: Mackenzie M. Lieberman, Jason H. Tong, Nkechi U. Odukwe, Colin A. Chavel, Kimberly M. Crasti, Terrence J. Purdon, Craig M. Brackett, Spencer R. Rosario, A.J. Robert McGray, Jonathan L. Bramson, Renier J. Brentjens, Ehsan Malek, Kelvin P. Lee, Scott H. Olejniczak
Journal: Cancer Research (2025)

Abstract FDA approval of chimeric antigen receptor (CAR) T cell therapy for multiple myeloma (MM) has reshaped the therapeutic landscape for this incurable disease. In pivotal clinical trials CAR T cells outperformed standard-of-care chemotherapy, yet most patients experienced MM relapse within two years, underscoring the need to improve CAR T cell therapy for MM. In the current study, we set out to determine if inhibition of MM survival signaling through CD28 could increase sensitivity to CAR T cell therapy. Contrary to expectations, we found that blocking CD28 interaction with its ligands CD86/CD80 using abatacept (CTLA4-Ig) accelerated MM relapse following CAR T therapy in preclinical models. Knockout studies determined that endogenous CD28 expressed on 4-1BB co-stimulated (BBζ) CAR T cells sustained in vivo anti-MM activity. Mechanistically, endogenous CD28 reprogrammed BBζ CAR T cell mitochondrial metabolism to maintain redox balance, stimulated proliferation, and increased inflammatory cytokine production in the MM bone marrow microenvironment (BME). In agreement, higher grade cytokine-mediated toxicities were associated with CD86 expression on CD138+ cells from CAR T cell treated MM patients and short-term abatacept exposure decreased inflammatory cytokine levels in the MM BME of CAR T cell treated mice without affecting their long-term survival. Overall, data directly demonstrate that CD28 signaling sustains in vivo function of BBζ CAR T cells and indicate that transient CD28 inhibition could reduce cytokine release and associated toxicities in MM patients. Citation Format: Mackenzie M. Lieberman, Jason H. Tong, Nkechi U. Odukwe, Colin A. Chavel, Kimberly M. Crasti, Terrence J. Purdon, Craig M. Brackett, Spencer R. Rosario, A.J. Robert McGray, Jonathan L. Bramson, Renier J. Brentjens, Ehsan Malek, Kelvin P. Lee, Scott H. Olejniczak. CD28 drives CAR T cell responses in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB037.
Abstract LB019: LINC00152-regulated PDE4D mediates drug resistance and metastasis in highly aggressive breast cancer
Authors: Ozge Saatci, Rashedul Alam, Kim-Tuyen Huynh-Dam, Aynur Isik, Meral Uner, Nevin Belder, Pelin Ersan, Unal M. Tokat, Burge Ulukan, Metin Cetin, Kubra Calisir, Mustafa E. Gedik, Hilal Bal, Ozlem Sener Sahin, Yasser Riazalhosseini, Denis Thieffry, Daniel Gautheret, Besim Ogretmen, Sercan Aksoy, Aysegul Uner, Aytekin Akyol, Ozgur Sahin
Journal: Cancer Research (2025)

Abstract Phosphodiesterase 4D (PDE4D) is a member of the phosphodiesterase family of enzymes, catalyzing the hydrolysis of cAMP second messenger and inhibiting cAMP signaling. Targeting PDE4D raises the intracellular cAMP levels, leading to apoptosis and cell cycle arrest in different tumor types. However, its contribution to drug resistance and metastasis is still elusive. lncRNAs are more than 200 nucleotides in length and carry out diverse functions including transcriptional regulation, and regulation of proteins or RNA molecules by direct binding and stabilization. LINC00152 is an oncogenic lncRNA that promotes survival, proliferation, epithelial-mesenchymal transition (EMT) and invasiveness in cancer cells. Despite being a driver in several key oncogenic processes, whether LINC00152 is an upstream regulator of PDE4D to drive endocrine resistance and metastasis in ER+ breast cancer remains to be elucidated. Here we showed that LINC00152 stabilizes PDE4D mRNA, thus driving tamoxifen resistance upon deactivation of the cAMP/PKA/CREB axis. Overexpressing PDE4D rescues LINC00152-mediated tamoxifen resistance by blocking tamoxifen-induced ferroptosis. In addition, we demonstrated that inhibiting LINC00152 or PDE4D reduces the migration of endocrine resistant cells upon PKA-mediated blockage of TGF-β signaling. Targeting PDE4D using the clinically-tested PDE4D selective inhibitor, BPN14770 significantly reduces spontaneous metastasis in the highly aggressive, endocrine resistant-mimicking MMTV-PyMT model in vivo. Importantly, we showed that high levels of PDE4D mRNA is associated with worse metastasis-free survival in endocrine-treated ER+ breast cancer patients. Overall, we identified the highly oncogenic lncRNA, LINC00152 as an upstream regulator of PDE4D, which drives endocrine resistance and metastasis in the highly aggressive ER+ breast cancer. Citation Format: Ozge Saatci, Rashedul Alam, Kim-Tuyen Huynh-Dam, Aynur Isik, Meral Uner, Nevin Belder, Pelin Ersan, Unal M. Tokat, Burge Ulukan, Metin Cetin, Kubra Calisir, Mustafa E. Gedik, Hilal Bal, Ozlem Sener Sahin, Yasser Riazalhosseini, Denis Thieffry, Daniel Gautheret, Besim Ogretmen, Sercan Aksoy, Aysegul Uner, Aytekin Akyol, Ozgur Sahin. LINC00152-regulated PDE4D mediates drug resistance and metastasis in highly aggressive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB019.
Abstract LB038: Advancing immunotherapy with the development of a novel STING mRNA analog
Authors: Yong Ho Heo, Youngjin Han, Seung-Hyun Shin, Chang Gyu Lim, Ji Hee Lee, Hocheol Shin, Jooyun Byun, Daejin Kim, In Young Choi
Journal: Cancer Research (2025)

Abstract Stimulator of IFN genes (STING), encoded by the STING1 gene, plays a crucial role in initiating immune responses against viral and bacterial pathogens, as well as cancer. Cyclic GMP-AMP synthase (cGAS) detects aberrant cytosolic DNA and produces cyclic GMP-AMP (cGAMP) that binds to and activates STING. Activation of the cGAS-STING pathway induces type I interferon production and NF-κB signaling pathway, leading to the secretion of inflammatory cytokines. These inflammatory cytokines strengthen anti-tumor immunity and contribute to the capacity of immune systems to suppress tumor progression. STING is regulated by various post-translational modifications (PTMs) at different domains, including phosphorylation, ubiquitination, SUMOylation, palmitoylation, alkylation and glycosylation. We engineered an mRNA-based therapeutic encoding a constitutively-active STING variant to activate anti-tumor immune responses. To further enhance the anti-tumor efficacy of the engineered STING variant mRNA, we optimized CDN binding domain associated with STING activity. Using human (HEK-blue ISG) and mouse (B16-blue ISG) reporter cell lines, we evaluated the activation capacity of our different STING mRNA analogs on the STING/TBK1/IRF3 pathway. Increased secretion of IFN-β was confirmed via ELISA, and the expression of inflammatory cytokines downstream of the type I interferon and NF-κB signaling pathways was detected using qRT-PCR. To further validate efficacy, we tested our STING mRNA analog in syngeneic tumor models. Administration of our mRNA analog effectively suppressed tumor growth. Previous approaches utilizing STING agonist as anti-cancer immunotherapies have faced challenges including poor metabolic stability, inefficient cytosolic delivery, and reduced efficacy due to downregulated STING expression in human tumors. Here, we evaluated the anti-cancer potency of an mRNA-encoded constitutively-active STING analog. Our findings propose a novel strategy leveraging mRNA technology to overcome these limitations and robustly trigger STING-mediated anti-tumor immunity. Citation Format: Yong Ho Heo, Youngjin Han, Seung-Hyun Shin, Chang Gyu Lim, Ji Hee Lee, Hocheol Shin, Jooyun Byun, Daejin Kim, In Young Choi. Advancing immunotherapy with the development of a novel STING mRNA analog [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB038.
Abstract LB192: Design and validation of PD-L1 transferrin receptor targeting chimera (TransTAC) protein degraders
Authors: George Morcos, Lawrence Shue, Dingjingyu Zhou, Johely Duque-Jimenez, Xin Zhou
Journal: Cancer Research (2025)

Abstract Background: Immune checkpoint blockade (ICB), the blocking of immune checkpoint molecules using therapeutic antibodies, has transformed cancer care for over a decade. But while highly efficacious for several malignancies, challenges remain for the widespread adoption of ICB therapy including primary and acquired resistance and immune-related adverse events. Targeted protein degradation represents an alternative therapeutic modality in which immune checkpoint molecules can be degraded from cell surfaces in a targeted manner, thereby preventing their activation and downstream regulatory effects on T-cells. Recently, the Zhou lab has developed transferrin receptor targeting chimeras (TransTACs); bispecific antibodies which take advantage of the overexpression and exceptionally fast endocytosis of transferrin receptors (TfRs) in cancer cells to simultaneously degrade surface proteins. Aim: The aim of this study was to investigate the molecular determinants of TransTAC design and evaluating their efficacy in PDL1 internalization, degradation, and overall TransTAC function. Methods: Using standard protein engineering techniques, several TransTACs targeting the immune checkpoint PDL1 were designed, and their internalization and degradation efficacies were evaluated using flow cytometry and immunoblotting respectively. Bispecific T-cell engager (BiTE) assays were also conducted to determine the functional effect of TransTAC-mediated PDL1 degradation on T-cell activation. Results &amp; Discussion: Internalization and degradation assays of several TransTAC variants demonstrated that increased affinity to PDL1 is positively correlated with degradation efficiency and that a cleavable linker may not be required for PDL1 degradation. Furthermore, the BiTE assay recapitulated the expected increase in T-cell activation following PDL1 internalization from the cell surface of Raji cancer cells. Finally, a degradation screening identified one variant containing a mutated TfR1 binder with greater degradation efficiency than comparable constructs. Conclusion: Our findings demonstrate three key molecular determinants of TransTAC design- affinity to the protein of interest, the presence or absence of a cleavable linker, and TfR1 binding - which may potentially affect the therapeutic efficacy of TransTAC technology. Citation Format: George Morcos, Lawrence Shue, Dingjingyu Zhou, Johely Duque-Jimenez, Xin Zhou. Design and validation of PD-L1 transferrin receptor targeting chimera (TransTAC) protein degraders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB192.
Abstract LB184: CF10 displays improved activity relative to 5-FU in a mouse CRLM model under conditions of physiological folate
Authors: William H. Gmeiner, Charles Okechukwu, Xue Ma, Wencheng Li, Ralph D'Agostino, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth
Journal: Cancer Research (2025)

Abstract At least 25% of colorectal cancer (CRC) patients develop liver metastases (CRLM) and chemotherapeutic regimens based on the fluoropyrimidine (FP) drug 5-fluorouracil (5-FU) are widely used for CRLM treatment. While 5-FU-based regimens provide a survival advantage in CRLM treatment, long-term survival is uncommon. The primary molecular target of FPs is thymidylate synthase (TS). We demonstrated that a nanoscale FP polymer, CF10, displayed greater potency than expected based on FP content in part through more direct conversion to the TS-inhibitory metabolite, FdUMP. CF10 has shown encouraging pre-clinical efficacy in multiple CRC models. In this study, we tested CF10 for potency advantages relative to 5-FU and trifluorothymidine (TFT, the FP component of TAS-102), in CRC cell lines in the Broad Institute PRISM screen and in CRC cells cultured under conditions of human-like folate levels. We confirm a general potency advantage for CF10 relative to 5-FU and TFT and demonstrate that this potency advantage is retained in CRC cells cultured with human-like folate levels and is enhanced by LV co-treatment to a similar extent as 5-FU. Our results confirm CF10 development proceeding as a CF10/LV combination. Mechanistically, CF10 cytotoxicity closely correlates with poisons of DNA topoisomerase 1 (Top1) in the PRISM screen relative to 5-FU and TFT. A TS/Top1 dual targeting cytotoxic mechanism for CF10/LV was confirmed by TS activity assay, and immunofluorescence detection of Top1cc. CF10/LV activated the ATR/Chk1 pathway consistent with enhanced replication stress and induced apoptosis. In vivo studies confirm CF10/LV is well-tolerated in mice adapted to human-like folate levels. CF10 and CF10/LV eradicated liver metastasis in a CRLM model without scarring or weight loss displaying therapeutic advantages relative to legacy FPs. Our pre-clinical data support an early-phase clinical trial for CF10 for treating liver-metastatic CRC. Citation Format: William H. Gmeiner, Charles Okechukwu, Xue Ma, Wencheng Li, Ralph D'Agostino, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth. CF10 displays improved activity relative to 5-FU in a mouse CRLM model under conditions of physiological folate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB184.
Abstract LB190: Unlocking multi-omic cancer insights with QIAseq xHYB CGP Panel for comprehensive genomic profiling
Authors: Qiong Jiang, Peter Hahn, Helene Bauby, Krishna Amin
Journal: Cancer Research (2025)

Abstract Comprehensive genomic profiling assays are increasingly being adopted to assess the genomic landscape of cancer. The QIAseq xHYB CGP Panel represents a significant advancement in comprehensive genomic profiling, designed to accelerate cancer research and diagnostic development through its multimodal analysis capabilities. This panel targets over 720 genes, providing full coverage of coding regions and microsatellite instability (MSI) markers, which are essential for detailed tumor profiling and biomarker discovery. The automation-friendly workflow employs the QIAseq Multimodal DNA/RNA Library Kit followed by hybrid capture using the QIAseq xHYB CGP Panel, offering compatibility with various sample types, including FFPE, cell-free DNA (cfDNA), and tissue samples. The QIAseq xHYB CGP Panel enables comprehensive detection of DNA biomarkers (such as SNVs, CNVs, InDels) alongside RNA biomarkers (fusions, exon-skipping events) from a single tissue sample, allowing for a deeper exploration of cancer biology through both modalities. Furthermore, the customization option meets the growing need of modifying panel content as new discoveries and guidelines continue to grow. In summary, the QIAseq xHYB CGP Panel is a powerful new tool for advancing oncology research, enabling multiomic comprehensive genomic profiling. Citation Format: Qiong Jiang, Peter Hahn, Helene Bauby, Krishna Amin. Unlocking multi-omic cancer insights with QIAseq xHYB CGP Panel for comprehensive genomic profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB190.