tbuckley/cabot-search huggingface dataset:
Abstract 720: Combining zelasudil, a small molecule ROCK2 inhibitor, with chemotherapy or immunotherapy improves response in preclinical models of pancreatic cancer
Authors: Marina Pajic, Benjamin McLean, Diego Chacon Fajardo, Sean Porazinski, Dannielle H. Upton, Diana Schuhmacher, Aji Istadi, Thomas Cox, Paul Timpson, Daniel J. Wilcock, Katie J. Anderson, Helen Mason, Nicolas E. Guisot, Clifford D. Jones, Caroline Phillips, Richard Armer
Journal: Cancer Research (2024)

Abstract Zelasudil (RXC007) is an orally available, highly selective small molecule inhibitor of Rho-associated coiled-coil containing protein kinase 2 (ROCK2), which has demonstrated pre-clinical anti-fibrotic efficacy and is currently being tested in a Phase 2a clinical trial for the treatment of idiopathic pulmonary fibrosis (IPF) (NCT05570058). Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and therapeutically challenging disease with a dense and highly fibrotic tumor microenvironment which may limit efficacy of conventional therapies. Here, we investigate the benefit of combining an anti-fibrotic, RXC007, with either standard of care chemotherapy or immunotherapy in mouse models of PDAC.In a fibrotic patient-derived metastatic PDAC orthotopic model, RXC007 (10mg/kg, 50mg/kg and 100mg/kg BID 5d on/2d off PO) in combination with SoC chemotherapy Gemcitabine (100mg/kg IP QW)/Abraxane (30 mg/kg IP QW) improved survival in a dose-dependent manner (all P&amp;lt;0.0001) compared to Gemcitabine/Abraxane alone.In the immunocompetent orthotopic LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) model of metastatic PDAC, survival was significantly increased (P&amp;lt;0.0001) upon treatment with a combination of RXC007 (50 mg/kg BID 5d on/2d off PO) and anti-PD1 (200 ug BIW) compared to anti-PD1 alone. ROCK2 inhibition elicited positive immunomodulatory effects in KPC pancreatic tumors, with increase of CD8+ (P=0.0031) and CD4+ (P=0.008) T cell infiltrate into the tumor cortex and reduction in immunosuppressive FOXP3+ regulatory T cells at the tumor border. Furthermore, RXC007 monotherapy exhibited anti-fibrotic effects, via a decrease in collagen content and organization, effects associated with CAF reprogramming and reduced intra-tumoral aSMA+ PDPN+ myofibroblast-like CAFs (myCAFs; P=0.0406).This data highlights the potential for treating highly fibrotic tumours with RXC007 in combination with SoC chemotherapy or immunotherapy in order to improve patient outcomes in this aggressive and treatment-refractory cancer. Citation Format: Marina Pajic, Benjamin McLean, Diego Chacon Fajardo, Sean Porazinski, Dannielle H. Upton, Diana Schuhmacher, Aji Istadi, Thomas Cox, Paul Timpson, Daniel J. Wilcock, Katie J. Anderson, Helen Mason, Nicolas E. Guisot, Clifford D. Jones, Caroline Phillips, Richard Armer. Combining zelasudil, a small molecule ROCK2 inhibitor, with chemotherapy or immunotherapy improves response in preclinical models of pancreatic cancer [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 720.
Abstract 5961: NRF2-responsive kinases in esophageal squamous cell carcinoma
Authors: Boopathi Subramaniyan, Zhaohui Xiong, Chorlada Paiboonrungruang, Yahui Li, M Ben Major, Xiaoxin Chen
Journal: Cancer Research (2024)

Abstract Esophageal squamous cell carcinoma (ESCC) ranks as the 7th most frequently diagnosed cancer and the 6th leading cause of cancer-related death worldwide. NRF2 is identified as a therapeutic target for human ESCC, with a mutation rate of approximately 10-22%. Hyperactive NRF2 promotes proliferation, metastasis, and resistance to radiation and chemotherapy in ESCC. Although some evidence suggest NRF2 regulates kinases which contribute to these phenotypes, it remains unclear which kinases are responsive to hyperactive NRF2. Using NRF2 ChIP-seq analysis, we have enrichment of 42 kinases including Akt2 and Pkm and 31 phosphatases including Pten and Dusp16 enriched in the Keap1-/- mouse esophagus in comparison with the wild-type esophagus. We further confirmed the binding of NRF2 to the promoter regions of mouse Akt2 and Pten. mRNA expression profiling revealed enrichement of the PI3K/AKT, RAS, ERK, and GSK3 pathways in the Keap1-/- esophagus as compared to the Nrf2-/-;Keap1-/- esophagus. Immunohistochemical staining showed that pAKT, p-mTOR, pS6, PKM2 were overexpressed in the Keap1-/- esophagus, as well as in the adult NRF2-hyperactive esophagus (Sox2CreER;LSL-Nrf2E79Q/+). Using PhosphoExplorer array and PamChip array to analyze NRF2W24C-KYSE70 cells (in comparison with NRF2null-KYSE70 cells) and Sox2CreER;LSL-Nrf2E79Q/+ mouse esophageal epithelium in comparison with wild-type mouse tissue, we further identified multiple kinases including PI3K as potential NRF2-responsive kinases. These findings suggest a potential role for kinases such as PI3K in NRF2-driven ESCC, and support the idea of targeting both NRF2 and NRF2-responsive kinases as a therapeutic strategy for ESCC. Citation Format: Boopathi Subramaniyan, Zhaohui Xiong, Chorlada Paiboonrungruang, Yahui Li, M Ben Major, Xiaoxin Chen. NRF2-responsive kinases in esophageal squamous cell 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 5961.
Abstract 5931: Investigating the therapeutic potential of STK17A inhibition in GBM
Authors: Jesus R. Castro
Journal: Cancer Research (2024)

Abstract For decades, the survival rate for glioblastoma (GBM) has remained nearly stagnant, and currently the 5-year survival rate is only 5%. There is an unmet medical need for therapeutic development, as GBM is the most common primary brain tumor, yet only four FDA approved drugs have been developed for GBM over the last century. GBM is notoriously heterogeneous, and this has posed a challenge for researchers seeking to find therapeutic targets. However, by taking advantage of RNA sequencing, a potential biomarker and target for GBM has been identified: the kinase STK17A (Serine/Threonine Kinase 17A), also known as DRAK1. We confirmed that STK17A is overexpressed in brain cancers by analyzing public databases and single-cell RNA sequencing data from GBM patients, and further associated it with poor patient outcome. Little is known about STK17A, but it has been found to be involved with cell proliferation, tumorigenesis, and tumor metastasis. The role of STK17A in GBM pathophysiology and its therapeutic potential as a drug target remains a critical knowledge gap.In order to better understand STK17A’s role in GBM pathophysiology, we first knocked down STK17A in GBM cell lines and determined that STK17A had functional roles in proliferation and morphology. Similar conclusions were drawn after knocking down STK17A in vivo in GBM xenograft mouse models. These findings supported STK17A as a viable therapeutic target. We then designed and optimized novel brain-penetrant STK17A inhibitors with IC50 values of &amp;lt;20nM in enzyme assays and &amp;lt;1μM in cell-based targeting engagement and proliferative assays. The designed and prepared novel STK17A inhibitors were further evaluated through kinase enzymatic assays and biological assays as well as in vitro proliferation and toxicity assays. We further characterized the inhibitors by showing Drug Metabolism and Pharmacokinetics (DMPK) properties in vivo in mouse models at 10 mg/kg via oral administration. We then used these potent, selective, and highly brain penetrant STK17A inhibitors to investigate the anti-tumor effects of STK17A inhibition in GBM in vivo and demonstrate the efficacy of our novel STK17A inhibitors.In conclusion, this work seeks to contribute to the field of targeted therapies for GBM by optimizing and examining the first iterations of novel brain penetrant STK17A inhibitors, initiating studies for the treatment of GBM in vitro and in vivo, and providing proof of efficacy for further studies in GBM patients. Ultimately, the results from our findings will lead to novel strategies for targeted drug development and more robust therapeutic options for GBM patients. Citation Format: Jesus R. Castro. Investigating the therapeutic potential of STK17A inhibition in GBM [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 5931.
Abstract 4512: Discovery of highly potent, selective, and orally bioavailable IKZF2 degrader and its anti-tumor activity in syngeneic mouse models
Authors: Seulki Park, Jeong Hee Moon, Gaseul Lee, Hyun Jin Kim, Jeong-Hoon Kim, Jong Yeon Hwang
Journal: Cancer Research (2024)

Abstract Molecular glue degraders (MGDs) are emerging as innovative therapeutic modalities, owing to their efficacy in targeting previously undruggable targets. MGDs induce close proximity between the target protein and E3 ligase, resulting in the degradation of the target protein. In the wake of the remarkable success of PD-1/PD-L1 inhibitors, various approaches to modulate the activity of regulatory T cells (Tregs) activity have been explored. Tregs represent the primary immune suppressor and significantly impede antitumor immune responses. IKZF2, a marker of stable suppressive Treg, is essential for maintaining the stable Treg cell phenotype. Depletion of IKZF2 can induce a transition from Treg to effector T cell (Teff) phenotypes, thereby enhancing anti-tumor responses. Leveraging an Immunomodulatory drug (IMiD), Novartis has developed the IKZF2 degrader DKY709, which is currently undergoing Phase I clinical trials, both as a monotherapy and in combination with a PD-1 immune checkpoint inhibitor. In this presentation, we present the preclinical results of the best-in-class IKZF2 degrader, PRT-101. PRT-101 elicits rapid and robust degradation of IKZF2, demonstrating subnanomolar DC50 and achieving 100% Dmax in a proteasome- and CRBN-dependent manner. However, PRT-101 does not induce the degradation of well-known neosubstrates, including IKZF1, IKZF3, SALL4, and CK1a. Global proteomic analysis reveals that PRT-101 exclusively facilitates IKZF2 degradation. The degradation of IKZF2 by PRT-101results in an increase in IL-2 secretion, a marker of T effector function. Furthermore, oral administration of PRT-101 exhibits excellent pharmacokinetics, concurrent with IKZF2 degradation, yielding superior anti-tumor effects compared to DKY709 in the MC38 mouse syngeneic model. In conclusion, our findings underscore the potential of the novel IKZF2 degrader as a promising immuno-oncology target for the treatment of solid tumors. Citation Format: Seulki Park, Jeong Hee Moon, Gaseul Lee, Hyun Jin Kim, Jeong-Hoon Kim, Jong Yeon Hwang. Discovery of highly potent, selective, and orally bioavailable IKZF2 degrader and its anti-tumor activity in syngeneic mouse models [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 4512.
Abstract 6363: The biparatopic antibody KA-3005 against MET is suitable for developing antibody-drug conjugates (ADCs) to treat MET-expressing cancers
Authors: Guojin Wu, Jiabei Liang, Hao Peng, Feng Hao, Tongtong Liu, Jinying Ning
Journal: Cancer Research (2024)

Abstract MET is overexpressed in a significant fraction of lung (25%-50%) and gastroesophageal cancers, making the targeting of MET with an antibody-drug conjugate (ADC) an attractive approach. Here, we developed a bispecific antibody (BsAb) named KA-3005, targeting two different epitopes within the extracellular domain of MET using our common light chain antibody discovery platform. KA-3005 has a regular antibody structure with an identical light chain, developed using knob-into-hole technology. This antibody exhibits significantly higher avidity to MET expressed on tumor cells, with an EC50 of less than 0.1nM compared to its parent antibodies. It also completely blocks the binding of HGF to MET and the MET downstream pathway at a concentration as low as 1nM. This biparatopic antibody demonstrates a faster internalization rate upon binding to the surface of tumor cells expressing MET than its parent antibodies. KA-3005 effectively suppressed the growth of HCC827-HGF tumors in a xenograft mouse model. Additionally, it has a half-life of more than five days in the blood of Balb/c mice. Finally, we assessed the developability of KA-3005 under different treatments such as high concentration, low pH, repeated freezing and thawing, and high temperature, and it showed neither aggregation nor degradation. In conclusion, this biparatopic antibody, KA-3005, developed with our common light chain antibody discovery platform, is stable and holds potential for the development of ADCs targeting MET. Citation Format: Guojin Wu, Jiabei Liang, Hao Peng, Feng Hao, Tongtong Liu, Jinying Ning. The biparatopic antibody KA-3005 against MET is suitable for developing antibody-drug conjugates (ADCs) to treat MET-expressing 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 6363.
Abstract 5111: Rational synergistic radiosensitization strategies for group 3 medulloblastoma
Authors: Julija Povilaikaite, Kaitlin Stitz, Nikhita Austin, Vijay Ramaswamy
Journal: Cancer Research (2024)

Abstract Medulloblastoma (MB) is the most common malignant pediatric brain tumor. MB is comprised of 4 groups, termed Wnt, Shh, Group 3 and Group 4, each characterized by distinct molecular and clinical profiles. MYC-amplified Group 3 MB is associated imminent fatal metastatic relapse following standard treatment approaches, which currently include surgery, craniospinal irradiation and chemotherapy, highlighting an urgent need for identification of therapeutic vulnerabilities for these tumours. As such, using 4 novel patient-derived models of Group 3 MB that faithfully recapitulate the molecular and histological tumor characteristics, we characterised response to radiation of Group 3 MB in vitro to show that these tumors do not possess intrinsic radiation resistance. Furthermore, cumulative radiation experiments do not increase bulk radiation resistance in MB cells, highlighting the contribution of dynamic cell states to radiation response. In contrast, exposure to radiation leads to changes in cell clonogenic capacity as measured by limited dilution assays. Furthermore, RNA-seq data uncovered altered transcriptomic programs in response to cumulative radiation treatment. In particular, we observe differential regulation of genes encoding potassium ion channels and their regulators as well as genes encoding ECM and cell adhesion proteins. As part of our goal to evaluate the current multimodal treatment strategy of MB, we also show that a set of standard chemotherapeutic agents (etoposide, thiotepa and lomustine) currently used in the clinic do not produce a potent response at optimal doses in vitro, potentially accounting for abysmal survival outcomes seen in chemotherapy treated MB patients. As such, we conducted a screen of 144 FDA approved cancer drugs and identified therapeutics that selectively target Group 3 MB cells in contrast to normal tissue controls (foetal neural stem cells) in the low nanomolar dose range. In particular, topoisomerase inhibitor topotecan produces a potent response specific to MYC-amplified Group 3 MB, and sensitizes 2 patient-derived MB models to gamma irradiation. Altogether, our data characterizes Group 3 MB molecular and cellular responses to current treatment modalities and provides rationale for new clinical strategies to sensitize patients to radiation that will potentially allow to reduce the required radiation doses to treat these aggressive tumors, reduce the incidence of radiation treatment-related morbidity as well as improve cure rates. Citation Format: Julija Povilaikaite, Kaitlin Stitz, Nikhita Austin, Vijay Ramaswamy. Rational synergistic radiosensitization strategies for group 3 medulloblastoma [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 5111.
Abstract 2128: Surufatinib treatment in pancreatic cancer: unveiling the role of GPR34 in TAMs and enhancing immunotherapy efficacy
Authors: Xiaofan Guo, Yuxiao Liu, Yuning Song, Jing Huang, Wenbo Zhu, Peijun Xu, Jun Yu, Song Gao, Jihui Hao
Journal: Cancer Research (2024)

Abstract Background: Pancreatic cancer, often resistant due to its immunologically "cold" nature and tumor-associated macrophages (TAMs), presents challenges in chemotherapy and immunotherapy. This study uses single-cell transcriptomics to assess TAM subsets in response to surufatinib, an inhibitor targeting CSF-1R, FGFR1, and VEGFR1-3. Methods: Surufatinib-treated patient samples were analyzed using single-cell RNA sequencing to identify altered macrophage subsets. Additional techniques, such as flow cytometry, tissue microarrays, co-culture assays, and macrophage-specific knockout mice, were used for further study. Western blot and immunofluorescence clarified the molecular functions of TAMs, and the impact of targeting these TAMs on PD-1 therapy was evaluated in a pancreatic cancer mouse model. Results: Single-cell RNA sequencing revealed macrophage subsets with increased GPR34 expression following surufatinib treatment. The Gpr34fl/flLYZ2Cre mouse orthotopic-transplanted tumor model, treated with gemcitabine and albumin-bound paclitaxel, showed significantly reduced tumor growth compared to the control group, with notably lower percentages of exhausted T (Tex) cells and regulatory T (Treg) cells, and a significant increase in cytotoxic T cells in tumor tissue. LysoPS, produced by chronically injured pancreatic cancer cells, promotes the differentiation of bone marrow-derived monocytes (BMDM) into an immunosuppressive phenotype, an effect abolished after siGpr34 transfection. The LysoPS-GPR34 axis can significantly activate the NF-κB signaling pathway in BMDMs, potentially inducing the senescence-related secretory phenotype (SASP) and contributing to the macrophages' immunosuppressive phenotype. Combining a GPR34 antagonist with αPD-1 and PD-L1 inhibitors significantly curbed tumor growth and enhanced the immune environment in KPC mice. Conclusions: Elevated GPR34 in TAMs enhances immunosuppression via the NF-κB pathway, affecting T cell distribution. GPR34's role could be key in optimizing surufatinib treatment for pancreatic cancer, indicating new therapeutic avenues. Citation Format: Xiaofan Guo, Yuxiao Liu, Yuning Song, Jing Huang, Wenbo Zhu, Peijun Xu, Jun Yu, Song Gao, Jihui Hao. Surufatinib treatment in pancreatic cancer: unveiling the role of GPR34 in TAMs and enhancing immunotherapy efficacy [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 2128.
Abstract 6404: GRB2 stabilizes RAD51 at reversed replication forks restricting genomic instability and associated innate immune response
Authors: Zamal Ahmed, Zu Ye, Shengfeng Xu, Yin Shi, Xueqian Cheng, Yuan Zhang, Sunetra Roy, Sarita Namjoshi, Michael A. Longo, Todd Link, Katharina Schlacher, Guang Peng, Dihua Yu, Bin Wang, John Tainer
Journal: Cancer Research (2024)

Abstract Growth factor receptor-bound protein 2 (GRB2) is a cytoplasmic adapter for tyrosine kinase signaling and a nuclear adaptor for homology-directed-DNA repair. Here we find nuclear GRB2 protects DNA at stalled replication forks from MRE11-mediated degradation in the BRCA2 replication fork protection axis. Mechanistically, GRB2 binds and inhibits RAD51 ATPase activity to stabilize RAD51 on stalled replication forks. In GRB2-depleted cells, PARP inhibitor (PARPi) treatment releases DNA fragments from stalled forks into the cytoplasm that activate the cGAS-STING pathway to trigger pro-inflammatory cytokine production. Moreover in a syngeneic mouse metastatic ovarian cancer model, GRB2 depletion in the context of PARPi treatment reduced tumor burden and enabled high survival consistent with immune suppression of cancer growth. Collective findings unveil GRB2 function and mechanism for fork protection in the BRCA2-RAD51-MRE11 axis and suggest GRB2 as a potential therapeutic target and an enabling predictive biomarker for patient selection for PARPi and immunotherapy combination. Citation Format: Zamal Ahmed, Zu Ye, Shengfeng Xu, Yin Shi, Xueqian Cheng, Yuan Zhang, Sunetra Roy, Sarita Namjoshi, Michael A. Longo, Todd Link, Katharina Schlacher, Guang Peng, Dihua Yu, Bin Wang, John Tainer. GRB2 stabilizes RAD51 at reversed replication forks restricting genomic instability and associated innate immune response [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 6404.
Abstract 2460: Receptor antibody conjugated engager (RACE): A novel bispecific 4-1BB engager platform for enhanced immuno-oncology therapy
Authors: DaeHee Lee, Jihye Yoon, Jonggwan Jeong, Jeonghyeon Bak, KkaBi Son, Heechan Kim, Seil Jang, Minseok S. Kim
Journal: Cancer Research (2024)

Abstract Background: Traditional immuno-oncology strategies, such as checkpoint blockade therapy, are evolving to immune cell engagers as a smarter strategy. The early successes of Blincyto, a CD3 engager, demonstrated its capacity to activate host pan-T cells irrespective of their TCR-pMHC restriction status. However, this broad activation has been linked to off-target immunotoxicities, thus limiting its therapeutic applicability. In response, targeting immune co-stimulatory receptors like CD28 or 4-1BB has gained attention by their expression being induced on activated immune effector cells, presenting a more targeted approach to cancer therapy. Methods: We developed RACE, a novel bispecific 4-1BB engager. This platform fuses a 4-1BB ligand (4-1BBL) trimer with antibody F(ab’)2 fragments, excluding Fc domains. A Key and lock design on the 4-1BBL trimer interface facilitates asymmetric assembly of 4-1BBL dimer and monomer in the endoplasmic reticulum, achieving over 95% assembly efficiency in mammalian systems. Results: RACE differs from conventional 4-1BB agonistic antibodies in its ability to form natural hexagonal hyper-clusters of 4-1BB receptors, enhancing NF-κB signal transduction. Unlike first-generation 4-1BB antibodies, which incurred off-tumor hepatotoxicity, RACE selectively activates 4-1BB receptors only in the presence of tumor antigens. Enhanced cytotoxicity requires successful TCR signaling complex formation between T cells and cancer cells. In CT26 and MC38 tumor models, RACE not only induced strong anti-tumor effects without hepatic or systemic toxicities but showed synergistic efficacy with anti-PD-1 antibodies as well. Conclusion: The novel RACE platform represents a potent as well as safe immuno-oncology strategy, demonstrating significant potential for clinical application. Citation Format: DaeHee Lee, Jihye Yoon, Jonggwan Jeong, Jeonghyeon Bak, KkaBi Son, Heechan Kim, Seil Jang, Minseok S. Kim. Receptor antibody conjugated engager (RACE): A novel bispecific 4-1BB engager platform for enhanced immuno-oncology therapy [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 2460.