tbuckley/cabot-search huggingface dataset:
Abstract 4264: A novel, potent DNA polymerase theta inhibitor, QX-001280, demonstrates anti-tumor activity in combination with a PARP1 inhibitor
Authors: Dafydd Thomas, James Duan, Xianhai Huang, Vijay Reddy, Wayne Tang
Journal: Cancer Research (2025)

Abstract Microhomology-mediated end joining (MMEJ) is a repair mechanism that resolves double strand DNA breaks. It is considered a secondary double strand break repair mechanism behind homologous recombination (HR) but is often utilized by tumors that have lost the ability to perform HR. Critical to this process is DNA polymerase theta (Pol θ). Pol θ is a heterobifunctional protein that consists of an N-terminal helicase domain, a disorder central region and a C-terminal polymerase domain. Following DNA resection by the MRE11-RAD50-NBS-1 (MRN) complex Pol θ is recruited to the site of the double strand break where it adds the missing bases. The bases are then ligated to resolve the double strand break. The central role of Pol θ in MMEJ is highlighted by the fact that inhibition of Pol θ can be synthetic lethal with BRCA mutation and PARP-1 inhibitor treatment, with loss of BRCA1 or 2 resulting in non-functional HR. This loss was exploited with the development of the novel Pol θ inhibitor, QX-001280, and combining with a PARP inhibitor to elicit anti-tumor effect. QX-001280 is a potent inhibitor which binds to the Pol θ Helicase domain. In vitro, QX-001280 had an IC50 for the inhibition of Polθ of 0.84 nM, indicating potent inhibition of the helicase domain of Pol θ. Potent inhibition was also observed in DLD-1 BRCA2 null cells with an IC50 of 1.03 nM. Combination with a PARP inhibitor, Olaparib, led to significant increase in phosphorylated H2AX indicating that double strand breaks are not being resolved inferring that Pol θ and MMEJ are being inhibited. In addition, cell viability was significantly reduced in DLD-1 BRCA2 null cells treated with increasing doses of PARP inhibitor in combination Pol θ inhibitor, with a reduction in IC50. In vivo, single agent PARP inhibitor or Pol θ inhibitor had a modest effect on tumor growth. However, when Olaparib and QX-001280 are combined robust tumor regressions were observed. QX-001280 was well tolerated in all the dose groups. In conclusion, QX-001280 is a potent and specific inhibitor of Polθ which exhibits anti-tumor activity both in vitro and in vivo. It is a high-quality candidate for clinical investigation in combination therapy with PARP inhibitors for cancer treatment. Citation Format: Dafydd Thomas, James Duan, Xianhai Huang, Vijay Reddy, Wayne Tang. A novel, potent DNA polymerase theta inhibitor, QX-001280, demonstrates anti-tumor activity in combination with a PARP1 inhibitor [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 4264.
Abstract 3024: The novel selective CDK9 Inhibitor ORI-15412 reduces PD-L1 expression and drives the efficacy in combination therapies for melanoma and triple-negative breast cancer
Authors: Gergana Galabova, Michael Almstetter, Nicole Brusis, Christiane Gilch, Roland Koestler, Julie Kondrotas, Jan Kubitzki, Henrik Kuhn, Hendrik Liebers, Federico Medda, Patricia Perez-Galan, Jean Tassel, Nadine Traube, Andreas Treml, David Wifling, Nasser Yehia, Peter Zegar, Michael Thormann
Journal: Cancer Research (2025)

Aggressive cancers like melanoma and triple-negative breast cancer (TNBC) are challenging to treat due to limited therapeutic options and high relapse rates. Advances in combination therapies offer promise by targeting multiple cancer progression and resistance pathways. This study explores ORI-15412, Origenis' novel, oral CDK9 inhibitor, as monotherapy and in combination therapies in syngeneic melanoma (B16F10) and TNBC (4T1) murine models. ORI-15412, developed with Origenis' proprietary MOREsystem®, MolMind®, BRAINstorm™, and Cippix® technologies, shows unhindered brain penetration, high selectivity, and potency. Its CDK9 inhibition effectively targets the pTEFb complex and downstream pathways, including phospho-RNA Pol II, MCL-1, and c-MYC, inducing apoptosis and inhibiting osteoclast differentiation in cancer cell models (L363, MV4-11, and huPBMCs). ORI-15412 also dose-dependently reduces PD-L1 expression, highlighting its potential to modulate immune responses. In vivo, ORI-15412 monotherapy showed significant tumor growth inhibition (TGI) in B16F10 melanoma and 4T1 TNBC models. Combined with anti-PD-1 antibody, Vemurafenib, or Trametinib, it enhanced anti-tumor activity, achieving 72-84% TGI in the B16F10 model. In the 4T1 TNBC model, combining ORI-15412 with anti-PD-1 antibody achieved a 63% TGI, outperforming monotherapies or controls. ORI-15412 was non-toxic at effective doses in mono and combination therapies. These findings highlight ORI-15412 as a pivotal component in combination therapy for hard-to-treat cancers. Its effects on tumor growth inhibition and immune checkpoint modulation support its selection as a clinical candidate for melanoma, TNBC, and other malignancies. Citation Format: Gergana Galabova, Michael Almstetter, Nicole Brusis, Christiane Gilch, Roland Koestler, Julie Kondrotas, Jan Kubitzki, Henrik Kuhn, Hendrik Liebers, Federico Medda, Patricia Perez-Galan, Jean Tassel, Nadine Traube, Andreas Treml, David Wifling, Nasser Yehia, Peter Zegar, Michael Thormann. The novel selective CDK9 Inhibitor ORI-15412 reduces PD-L1 expression and drives the efficacy in combination therapies for melanoma and triple-negative breast 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 3024.
Abstract 3021: Discovery of a novel and selective CDK2 inhibitor for targeted cancer therapy
Authors: Douglas D. Fang, Yueqin Liu, Yang Liu, Wei Sha, Charles Z. Ding
Journal: Cancer Research (2025)

Targeted inhibition of CDK2 presents a promising therapeutic strategy for breast cancer patients who experience disease progression following CDK4/6-based therapies. In addition, CDK2 hyperactivity or CCNE1 amplification drives the progression of many cancer types, making it an attractive target. However, developing CDK inhibitors is often complicated by toxicities resulting from off-target inhibition of other CDK family members, particularly CDK1 and CDK9, which are essential for normal cell proliferation and survival. Achieving selectivity for CDK2 is therefore crucial to maximize therapeutic efficacy while minimizing adverse effects, enabling a broader therapeutic window in clinical applications. Here, we present VB18214 as a novel and selective CDK2 inhibitor. In biochemical assays, VB18214 demonstrated potent inhibition of the CDK2/cyclin E1 complex (IC50 = 0.6 nM) and exhibited 200-fold selectivity over CDK1/cyclin B1. Intracellular NanoBRET assays confirmed its high affinity for CDK2/cyclin E1 (IC50 = 3.8 nM), along with exceptional selectivity—124-fold over CDK1/cyclin B1, 12-fold over CDK4/cyclin D1, 94-fold over CDK6/cyclin D3, 334-fold over CDK7/cyclin H, and 1348-fold over CDK9/cyclin T1. In CCNE1-amplified OVCAR3 ovarian cancer cells, VB18214 effectively inhibited cell proliferation (IC50 = 18.5 nM). Compared to the clinically advanced CDK2 inhibitor PF-07104091, VB18214 demonstrated 5-fold greater potency in inhibiting CDK2 kinase activity, 16-fold higher affinity for CDK2 in NanoBRET assays, 2-fold greater selectivity over CDK1 in both biochemical and intracellular assays, and 9-fold higher antiproliferative activity in OVCAR3 cells.These findings position VB18214 as a potent and selective CDK2 inhibitor with significant potential for clinical development in cancers driven by CDK2/cyclin E dysregulation, as well as CDK4/6 treatment progressed mBC. More characterization data for VB18214 will be updated at the meeting. Citation Format: Douglas D. Fang, Yueqin Liu, Yang Liu, Wei Sha, Charles Z. Ding. Discovery of a novel and selective CDK2 inhibitor for targeted cancer therapy [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 3021.
Abstract 4278: Targeting tumor pericyte-specific transcription factor heterodimer for anti-metastasis cancer therapy
Authors: Junqiu Zhang, Wenqian Yin, Minfeng Chen, Yi Xue, Wencai Ye, Dongmei Zhang
Journal: Cancer Research (2025)

Abstract Pericytes, mural cells that envelop capillaries, play a critical role in tumor metastasis. While current therapies targeting tumor pericytes (TPCs) effectively suppress tumor angiogenesis and growth, they paradoxically promote metastasis, highlighting the need for improved TPC-based strategies. In this study, we identified a TPC-specific transcription factor heterodimer, TCF21-TCF3, which is positively associated with hematogenous metastasis. TCF3 is essential for TCF21-mediated collagen hydroxylation, facilitating extracellular matrix deposition and accelerating tumor metastasis. Using hydrogen-deuterium exchange mass spectrometry (HDX-MS), transverse relaxation-optimized spectroscopy (TROSY) NMR, and mutational analysis, we characterized the interacting residues of the TCF21-TCF3 heterodimer. A peptide designed to disrupt the TCF21-TCF3 interaction inhibited the formation of the heterodimer, downregulated TCF21/TCF3-dependent gene expression, and suppressed malignant behaviors, effectively reducing metastasis. This study proposes that targeting TPC-specific transcription factor heterodimers offers a promising therapeutic approach to combat tumor metastasis. Citation Format: Junqiu Zhang, Wenqian Yin, Minfeng Chen, Yi Xue, Wencai Ye, Dongmei Zhang. Targeting tumor pericyte-specific transcription factor heterodimer for anti-metastasis cancer therapy [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 4278.
Abstract 4263: QX-001352 is a novel and specific inhibitor of PARG with potentially BIC in vitro and in vivo anti-tumor efficacy
Authors: Dafydd Thomas, Xianhai Huang, Vijay Reddy, Wayne Tang
Journal: Cancer Research (2025)

Abstract When DNA is damaged one of the critical steps is the addition of Poly-ADP-ribose (PAR) chains to target proteins. Poly ADP-ribose polymerase 1 (PARP1) is an enzyme that adds PAR chains to target DNA repair proteins including itself. This serves as a recruitment signal for other DNA repair enzymes to localize to the site of DNA damage. Poly ADP-ribose glycohydrolase (PARG) has a crucial role in DNA repair. This role is by virtue of its intrinsic enzymatic activity to catalyze the removal of PAR chains from target proteins. This removal leads to the resolution of DNA strand breaks. When PARG is inhibited or its expression is abrogated, PAR chains go unresolved and therefore DNA lesions also. This leads to genomic instability and cell death. Therefore, there is a critical balance of PAR chains which is reciprocally regulated by PARP1 and PARG and perturbing this balance may negatively affect tumor cell growth. This makes PARG a rational drug target in oncology, against which the compound QX-001352 has been developed as a potentially best in class (BIC) inhibitor. QX-001352 is a potent inhibitor of PARG. QX-001352 was shown to inhibit the removal of PAR chains from PARylated PARP1 with an IC50 of 0.2 nM in a biochemical assay. This suggests QX1352 is a potent inhibitor of PARG.QX-001352 was able to inhibit the growth of two ovarian tumor cell lines as well as a breast and gastric tumor cell line. The IC50’s ranged from 1.5 nM to 11.9 nM indicating potent cell growth inhibition which represents around 10 folds more potent activity than a benchmark compound in the clinic. QX-001352 blocked the removal of PAR chains in Kuramochi cells in dose dependent manner with an IC50 of 0.1 nM indicating excellent target engagement. In vivo in a Kuramochi cell xenograft model, QX-001352 caused robust tumor regression. Both low and high doses of QX-001352 were fully efficacious whereas no effect was seen with vehicle treated animals. QX-001352 was well tolerated in all the treated groups. In conclusion, QX-001352 is a potent and specific inhibitor of PARG. This inhibition leads to PAR chain accumulation and prevents tumor cell growth both in vitro and in vivo. QX-001352 possesses highly desirable physicochemical properties and demonstrated favorable off-target profiles. Thus QX-001352 may be an effective PARG inhibitor in the clinic. Citation Format: Dafydd Thomas, Xianhai Huang, Vijay Reddy, Wayne Tang. QX-001352 is a novel and specific inhibitor of PARG with potentially BIC in vitro and in vivo anti-tumor efficacy [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 4263.
Abstract 2651: Nuclear prothymosin α suppresses TGF-β-induced EMT by stabilizing smad7: implications for lung cancer progression and metastasis
Authors: Bing-Hua Su, Li-Hsin Cheng
Journal: Cancer Research (2025)

Elevated expression of prothymosin α (ProTα), a 12.5-kDa acidic protein encoded by the PTMA gene, is frequently observed in cancers, including lung cancer, where it correlates with poor prognosis. Although ProTα is primarily localized to the nucleus, advanced-stage tumors exhibit its translocation to the cytoplasm, indicating a potential involvement in disease progression. In this study, we aim to elucidate the molecular mechanisms by which nuclear ProTα regulates epithelial-to-mesenchymal transition (EMT) and metastasis in lung cancer. Our findings demonstrate that nuclear ProTα suppresses TGF-β-induced EMT by enhancing Smad7 acetylation and stability. This acetylation disrupts the binding of Smad2 to the promoters of EMT transcription factors SNAI1, TWIST1, and ZEB1, thereby reducing their expression. Conversely, the loss of nuclear ProTα resulting from caspase-3-mediated cleavage of its nuclear localization signal (NLS) enables cytoplasmic translocation, associated with increased metastatic potential. Moreover, the use of mutant Smad7 constructs confirmed that the inhibitory effect of ProTα on EMT is dependent on Smad7 acetylation. Our clinical analyses of lung cancer specimens demonstrate that high nuclear ProTα levels are prevalent in early-stage tumors, while metastatic cases exhibit significant nuclear ProTα loss. These observations identify nuclear ProTα as a potential biomarker for tumor progression and a suppressor of lung cancer metastasis through TGF-β signaling interruption. In conclusion, this study underscores the importance of nuclear ProTα in lung cancer progression and highlights its potential as a prognostic indicator and therapeutic target for metastasis prevention. Further research into ProTα-targeted therapies could open new avenues in cancer treatment. Citation Format: Bing-Hua Su, Li-Hsin Cheng. Nuclear prothymosin α suppresses TGF-β-induced EMT by stabilizing smad7: implications for lung cancer progression and metastasis [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 2651.
Abstract 4266: Discovery and characterization of a novel LRRC15-targeting antibody drug conjugate (ADC) for the treatment of solid tumors
Authors: Shanshan Yan, Bing Wan, Donghui Li, Yue Ge, Wilson Peng, Jiaqing Yi, Ziruo Wen, Xinchuan Dai, Leo Xu, Lina Wang, Qiuping Ye, Peter Huang, Linda N. Liu
Journal: Cancer Research (2025)

Abstract Leucine-rich repeat-containing protein 15 (LRRC15) is a type I transmembrane protein involved in cell-cell and cell-extracellular matrix (ECM) interactions. It is overexpressed in various mesenchymal tumors such as sarcoma, glioblastoma and melanoma, where it promotes tumor metastasis. Additionally, LRRC15 is upregulated in cancer-associated fibroblasts (CAFs) across various cancer types, contributing to immune-excluded and immune-suppressive tumor microenvironment (TME). This makes LRRC15 an appealing target for cancer therapy. ZL-6201 is an innovative antibody-drug conjugate (ADC) targeting LRRC15, developed using the TME-activable linker-payload (TMALIN®) platform. This ADC comprises a humanized anti-LRRC15 antibody, a protease-cleavable linker, and a novel camptothecin derivative payload. It achieves a high drug-to-antibody ratio (DAR 8) with homogeneously conjugated, hydrophilic linker-payload combinations. ZL-6201 demonstrated strong and specific binding to human and cynomolgus LRRC15 without cross-reactivity to other LRRC family members. Its high affinity and specificity for LRRC15 on the cell surface led to target-mediated internalization and subsequent cytotoxicity in tumor cells upon payload release. Additionally, it exhibited potent bystander killing of LRRC15 negative tumor cells in an in vitro co-culture system. In in vivo efficacy studies, ZL-6201 was well-tolerated and effectively suppressed the growth of established human tumors in a dose-dependent manner in both tumor cell line-derived (CDX) and sarcoma patient sample-derived xenograft (PDX) models. In a human chondrosarcoma SA4109 PDX model, a significantly higher concentration of payload and ADC were detected in the tumors compared to mouse serum, indicating targeted delivery of the ADC. Collectively, these findings support advancing ZL-6201 into IND-enabling studies as a potential treatment for patients with sarcoma and other LRRC15-positive solid tumors. Citation Format: Shanshan Yan, Bing Wan, Donghui Li, Yue Ge, Wilson Peng, Jiaqing Yi, Ziruo Wen, Xinchuan Dai, Leo Xu, Lina Wang, Qiuping Ye, Peter Huang, Linda N. Liu. Discovery and characterization of a novel LRRC15-targeting antibody drug conjugate (ADC) for the treatment of solid 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 4266.
Abstract 3552: An mRNA-encoded adjuvant-enzyme activates STING to enhance the immunogenicity of vaccines targeting human papillomavirus positive cancers
Authors: Jonathan Chow, Kelsey Finn, Anastasia Nikiforov, Dahlia Alkekhia, Stephan Matissek, Saisha Nalawade, Angela O'Neil, Carolyn MacFarlane, Philip Coblentz, Milap Chokshi, Colin Kelly, Brenna Sherbanee, Nicolina Lamberti, Evan Kennedy, Andrew Cornforth, Sivan Elloul, Jonathan C. Kagan
Journal: Cancer Research (2025)

Despite the clinical success of prophylactic vaccines against human papillomavirus (HPV), vaccines administered post-infection are unable to prevent HPV-associated cancers. Therapeutic HPV vaccines that can treat pre-malignant and established oropharyngeal and anogenital tumors therefore represent an unmet clinical need. Using a novel mRNA-encoded catalytic vaccine adjuvant, Corner Therapeutics is developing a therapeutic vaccine against HPV.The cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) signaling pathway is a robust inducer of inflammation and protective immunity. No effective means to activate this pathway in the context of mRNA-based vaccines is known. Towards this end, we engineered an mRNA construct encoding a self-DNA reactive form of the enzyme cGAS (hereafter cGASΔN) to use as a catalytic vaccine adjuvant. Herein we show that cGASΔN mRNA was successfully formulated into lipid nanoparticles (LNPs) of a size and consistency matching LNPs used clinically, and that the cGASΔN mRNA is translated into a functional protein allowing for downstream STING signaling in primary human dendritic cells. When treated with cGASΔN mRNA-LNPs, human dendritic cells produced cytokines, chemokines and interferons, and expressed cell surface activation markers associated with T cell co-stimulation. The immunostimulatory activities of cGASΔN-LNPs resulted in robust ability of DCs to activate HPV-specific human T cells in in vitro cocultures. In contrast, DCs stimulated with LNPs encoding non-stimulatory proteins (akin to those used clinically), were ineffective inducers of T cell activation. In murine vaccination studies, intramuscular injection of LNPs encoding cGASΔN and HPV16 E6 and E7 antigens enhanced antigen-specific T cell responses to both viral proteins. These results establish cGASΔN mRNA-LNPs as a potent adjuvant to enhance the immunogenicity of mRNA-based HPV antigens, and that this promising approach could be utilized to develop therapeutic cancer vaccines. Citation Format: Jonathan Chow, Kelsey Finn, Anastasia Nikiforov, Dahlia Alkekhia, Stephan Matissek, Saisha Nalawade, Angela O'Neil, Carolyn MacFarlane, Philip Coblentz, Milap Chokshi, Colin Kelly, Brenna Sherbanee, Nicolina Lamberti, Evan Kennedy, Andrew Cornforth, Sivan Elloul, Jonathan C. Kagan. An mRNA-encoded adjuvant-enzyme activates STING to enhance the immunogenicity of vaccines targeting human papillomavirus positive 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 3552.