tbuckley/cabot-search huggingface dataset:
Abstract ND12: Discovery of PF-07220060, a potent and selective CDK4 inhibitor
Authors: Lars Anders, Gary Gallego
Journal: Cancer Research (2024)

Abstract PF-07220060 was developed based on the clinical need to improve efficacy and safety outcomes in patients treated with currently approved dual CDK4/6 inhibitors, including Palbociclib. Although all dual CDK4/6 inhibitors increase response rates and prolong disease control, they show common dose-limiting hematologic toxicities, foremost neutropenia. This poses challenges to provide these agents at doses necessary to extinguish cell cycling in tumors. Human ER+ breast cancer cells are highly dependent on CDK4 but not CDK6. By contrast, CDK4 is dispensable for human bone marrow derived cells, or cells enriched for neutrophil precursors or hematopoietic stem cells. This is primarily due to the compensatory role of CDK6 in these compartments. These observations prompted us to develop PF-07220060, an aminopyrimidine-based inhibitor, endowed with 20-fold and 4-fold increased selectivity for CDK4 over CDK6 when compared to Palbociclib and Abemaciclib/Ribociclib, respectively. CDK4-over-CDK6 selectivity is explained by G-loop conformational differences between the two kinases, with the G-loop of CDK4 being more flexible, assuming a more open conformation when bound to CDK4 selective versus non-selective inhibitors. PF-07220060 reduces dose-limiting neutropenia in beagle dogs by 15-fold when compared with Palbociclib, consistent with early clinical data obtained with PF-07220060. Higher tolerated plasma concentrations of PF-07220060 versus dual CDK4/6 inhibitors enable increased inhibition of CDK4 kinase activity in tumors. This translates to improved tumor growth inhibition across CDK4-driven models of human breast and prostate cancer at clinically relevant doses. Our work establishes proof-of-concept for CDK4 selective inhibition and introduces a best-in-class CDK4 inhibitor for treatment of HR+ HER2- breast cancer and other CDK4 dependent tumor types. Citation Format: Lars Anders, Gary Gallego. Discovery of PF-07220060, a potent and selective CDK4 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr ND12.
Enhanced Electrochemical Characterization of the Immune Checkpoint Protein PD‐L1 using Aptamer‐Functionalized Magnetic Metal‐Organic Frameworks (Adv. Healthcare Mater. 9/2024)
Authors: Ying Ma, Maoqiang Wu, Fayin Mo, Zuanguang Chen, Jing Lu, Duanping Sun
Journal: Advanced Healthcare Materials (2024)
Abstract CT083: A first-in-human phase 1/2a study of a novel anti-PAUF monoclonal antibody PBP1510 in patients with advanced/metastatic pancreatic cancer
Authors: Jaime Feliu Batlle, Daniel A. King, Jamie Kim, Sumita Pradhan, Yun-Yong Park, Kedar Diwakar Mandakhalikar, Wei Qi Loh
Journal: Cancer Research (2024)

Abstract Background Pancreatic Adenocarcinoma Up-regulated Factor (PAUF) is a protein overexpressed in pancreatic cancer but not in non-cancerous tissues and plays an important role in carcinogenesis and metastasis. PBP1510 is a first-in-class, anti-PAUF humanized immunoglobulin G1 monoclonal antibody developed for treatment of pancreatic cancer. PBP1510 demonstrated promising pancreatic cancer growth inhibition efficacies in in vivo patient-derived xenograft studies and is being evaluated in humans for the first time in the ongoing PAUF-I study. Methods PAUF-I (NCT05141149) is an open-label, multi-center, Phase 1/2a study in advanced/metastatic pancreatic cancer patients. Eligible patients must have a tumor that has progressed on standard chemotherapy, with at least 1 measurable lesion per RECIST v1.1 criteria, an ECOG performance status score of 0 or 1, a life expectancy of ≥ 3 months, and adequate baseline organ function to enroll. PBP1510 is administered as a 90-minute intravenous infusion in 28-day cycles and tumor assessments are performed every 8 weeks from the first dose. Phase 1 uses a 3 + 3 dose-escalation design to assess the safety, tolerability, pharmacokinetics (PK), and immunogenicity of ascending doses of PBP1510 as a single agent or in combination with gemcitabine (Table 1). The observation period for dose-limiting toxicities (DLT) is 28 days. ORR and pre- and post-treatment PAUF levels in tumor tissue will be explored in the analyses. A recommended phase 2 dose (RP2D) will be selected based on PK, safety, and efficacy data from Phase 1. Phase 2a is the dose expansion phase which aims to evaluate the safety, tolerability, PK, immunogenicity, and efficacy of PBP1510 administered at RP2D in combination with gemcitabine. As of January 2024, 6 patients have been enrolled. The 1M cohort (1 mg/kg) was completed without any report of DLT. Dose escalation is in progress and DLT evaluation is ongoing for the 2nd and 3rd patients in the 2M cohort. TABLE 1: NAND Dose escalation and cohorts (Phase 1) Monotherapy Combination Cohort PBP1510 Dose (mg/kg) Gemcitabine Dose (mg/m2) Cohort PBP1510 Dose (mg/kg) Gemcitabine Dose (mg/m2) 1M 1 - 1C 1 1000 2M 3 - 2C 3 1000 3M 6 - 3C 6 1000 4M 10 - 4C 10 1000 5M 15 - 5C 15 1000 Citation Format: Jaime Feliu Batlle, Daniel A. King, Jamie Kim, Sumita Pradhan, Yun-Yong Park, Kedar Diwakar Mandakhalikar, Wei Qi Loh. A first-in-human phase 1/2a study of a novel anti-PAUF monoclonal antibody PBP1510 in patients with advanced/metastatic pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT083.
Abstract PL04-03: Metastasis aggressiveness: A function of metabolite signaling
Authors: Sarah-Maria Fendt
Journal: Cancer Research (2024)

Abstract Metastasis formation is the leading cause of death in cancer patients. Yet, the molecular mechanisms responsible for the aggressiveness of metastases remain largely unknown. We used experimental metastasis mouse models and samples from patients with breast cancer to study metastases aggressiveness. We discovered that the aggressiveness of cancer cells in lung metastases was driven by an alternative translational program that was regulated by metabolite signaling. Strikingly, the identified molecular mechanism could be disrupted by repurposing a clinical approved inhibitor, which resulted in reduced metastasis formation in mouse models. Thus, this research highlights that dissecting and targeting cancer cell aggressiveness may provide therapeutic options against metastasis formation. Citation Format: Sarah-Maria Fendt. Metastasis aggressiveness: A function of metabolite signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr PL04-03.
Abstract LB034: First-in-class compounds targeting the MIEN1 signaling pathway: A breakthrough approach for breast and prostate cancer therapy
Authors: Amit Kumar Tripathi, Jamboor K. Vishwanatha
Journal: Cancer Research (2024)

Abstract We report the identification and complete characterization of first-in-class molecules targeting the MIEN1 signaling pathway in cancer. Migration and invasion enhancer 1 (MIEN1) overexpression characterizes several cancers and facilitates cancer cell migration and invasion. Leveraging conserved ITAM and prenylation motifs within MIEN1, we identified potent anti-cancer peptides. Among them, bioactive peptides LA3IK and RP-7 induced pronounced transcriptomic and protein expression changes at sub-IC50 concentrations. The peptides effectively inhibited genes and proteins driving cancer cell migration, invasion, and EMT pathways, concurrently suppressing EGF-induced NF-kB nuclear translocation in metastatic breast cancer cells. Specifically, peptides targeted the same signal transduction pathway initiated by MIEN1. Molecular docking and circular dichroism spectroscopy indicated the formation of MIEN1-peptide complexes. The third-positioned isoleucine in LA3IK and CVIL motif in RP-7 were crucial for inhibiting breast cancer cell migration. This is evident from the limited migration inhibition observed when MDA-MB-231 cells were treated with scrambled peptides LA3IK-SCR and RP-7-SCR. Additionally, LA3IK and RP-7 effectively suppressed tumor growth in an orthotopic breast cancer model. Notably, mice tolerated high peptide doses of up to 90 mg/Kg well, surpassing significantly lower doses of 5 mg/Kg intravenously (iv) and 30 mg/Kg intraperitoneally (ip) used in both in vivo pharmacokinetic studies and orthotopic mouse model assays. D-isomers of LA3IK and RP-7 showed enhanced anti-cancer activity compared to their L-isomers. D-LA3IK remained stable in mouse plasma for 24 h with 75% remaining, exhibiting superior pharmacokinetic properties over D/L-RP-7. In summary, our findings mark the first report of short peptides based on MIEN1 protein sequence capable of inhibiting cancer signaling pathways, effectively impeding cancer progression both in vitro and in vivo. Citation Format: Amit Kumar Tripathi, Jamboor K. Vishwanatha. First-in-class compounds targeting the MIEN1 signaling pathway: A breakthrough approach for breast and prostate cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB034.
Abstract LB114: STING licensing of type I dendritic cells potentiates antitumor immunity
Authors: Jian Wang, Suxin Li, Maggie Wang, Xu Wang, Shuqing Chen, Zhichen Sun, Xiubao Ren, Gang Huang, Baran D. Sumer, Nan Yan, Yang-Xin Fu, Jinming Gao
Journal: Cancer Research (2024)

Abstract Stimulator of interferon genes (STING) is an immune adaptor protein that senses cyclic GMP-AMP (cGAMP) in response to self or microbial cytosolic DNA as a danger signal. STING is ubiquitously expressed in diverse cell populations including cancer cells with distinct cellular functions such as activation of type I interferons, autophagy induction, or triggering apoptosis. It is not well understood whether and which subsets of immune cells, stromal cells, or cancer cells are particularly important for STING-mediated antitumor immunity. Here using a polymeric STING-activating nanoparticle (PolySTING) with a “shock-and-lock” dual activation mechanism, we show type 1 conventional dendritic cell (cDC1) is essential for STING-mediated rejection of multiple established and metastatic murine tumors. STING status in the host but not in the cancer cells (Tmem173− / − ) is important for antitumor efficacy. Specific depletion of cDC1 (Batf3− / − ) or STING deficiency in cDC1 (XCR1creSTINGfl/fl ) abolished PolySTING efficacy, whereas depletion of other myeloid cells had little effect. Adoptive transfer of wildtype cDC1 in Batf3− / − mice restored antitumor efficacy while transfer of cDC1 with STING or IRF3 deficiency failed to rescue. PolySTING induced a specific chemokine signature in wildtype but not Batf3− / − mice. Multiplexed immunohistochemistry analysis of STING-activating cDC1s in resected tumors correlates with patient survival while also showing increased expressions after neoadjuvant pembrolizumab therapy in non-small cell lung cancer patients. Therefore, we have defined that a subset of myeloid cells is essential for STING-mediated antitumor immunity with associated biomarkers for prognosis. Citation Format: Jian Wang, Suxin Li, Maggie Wang, Xu Wang, Shuqing Chen, Zhichen Sun, Xiubao Ren, Gang Huang, Baran D. Sumer, Nan Yan, Yang-Xin Fu, Jinming Gao. STING licensing of type I dendritic cells potentiates antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB114.
Abstract LB320: Runx2 as a key transcription factor regulating contractility and extracellular matrix remodeling in abnormally activated fibroblasts: Implications for tumorigenesis and keloid pathogenesis
Authors: Keun-Woo Lee, Insuk Sohn, Seok-Hyung Kim, So-Young Yeo
Journal: Cancer Research (2024)

Abstract Cancer associated fibroblasts (CAFs) express a variety of cytokines and factors that activate and contribute to pathways that favor tumorigenesis. CAFs disrupt normal cellular functions, such as cell cycle regulation and cell death including apoptosis, or signal certain types of cells to abnormally activate pro-tumor activities. In addition, when it is abnormally activated, it is characterized by increased collagen deposition and more contractility. Likewise, This pattern of abnormal activation is often observed in keloid disease. Keloid constitutes an abnormal fibroproliferative wound healing response with excessive collagen deposition causing abnormal wound healing. To better understand the CAF subtypes with abnormal activation and cancer-promoting properties and the subtypes of keloid fibroblasts with similar activation properties, it is essential to find the master transcription factors (TFs) that determine their identity. To identify functionally important TFs in abnormal CAFs and keloid fibroblasts, we analyzed H3K27ac ChIP-seq of CAFs and keloid fibroblasts and observed that Runx2 significantly enriched the two types of abnormal fibroblasts.To investigate the biological function of Runx2 , we established CAFs from colon cancer patients and performed ShRNA-mediated knockdown of the RUNX2 gene. We confirmed that knockdown of RUNX2 in CAFs suppressed the migration or invasion of cancer cells. Additionally, using a gel contraction assay, we confirmed that fibroblast contractility was significantly reduced by RUNX2 knockdown. Similarly, in keloid fibroblasts, it was confirmed that the migration and gel contraception abilities of fibroblasts were significantly reduced following knockdown of RUNX2 [A1] gene. Last but not least, expression of ECM elements, such as collagens and fibronectin, were significantly as a result of the knockdown of the RUNX2 gene in both abnormally activated fibroblasts. To conclude, we believe that Runx2 acts as a key TF that maintains the contractility and ECM remodeling ability of abnormally activated fibroblasts. Our findings indicate that Runx2 is a attractive therapeutic target not only for pro-tumorigenesis in the cancer microenvironment, but also for keloid fibroblasts. Citation Format: Keun-Woo Lee, Insuk Sohn, Seok-Hyung Kim, So-Young Yeo. Runx2 as a key transcription factor regulating contractility and extracellular matrix remodeling in abnormally activated fibroblasts: Implications for tumorigenesis and keloid pathogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB320.
Abstract LB286: Extrachromosomal DNA in lung cancer from never smokers
Authors: Azhar Khandekar, Tongwu Zhang, Marcos Diaz-Gay, Jens Luebeck, Ludmil Alexandrov, Maria Landi
Journal: Cancer Research (2024)

Abstract Extrachromosomal DNA (ecDNA), circular DNA that resides outside of the linear chromosome, is a potent form of oncogene amplification in cancer. The structure and properties of ecDNA are markedly different from those of linear DNA, characterized by features like non-Mendelian inheritance and an altered epigenetic landscape. A prior pan-cancer analysis ​​indicated patients with cancers harboring ecDNA have statistically worse overall survival when compared to cancer patients with other types of focal amplification. Moreover, its unique characteristics also make it a promising target for therapy. Recently, efforts have intensified to profile ecDNA across many cancer types, yet comprehensive studies of ecDNA in lung cancer in never smokers (LCINS) is lacking. Given that LCINS is partially driven by somatic copy number alterations, we hypothesized that ecDNA-driven focal amplifications significantly influence LCINS tumor evolution. As part of the Sherlock-Lung project (current data freeze, 1217 samples), we comprehensively profiled 871 treatment-naive samples using a robust computational pipeline that refined copy number segmentation by accounting for tumor purity and ploidy. ecDNA was present in 151 (17.3%) of tumor samples, with a third of ecDNA-positive samples harboring more than one distinct ecDNA amplicon. Consistent with prior reports, no ecDNA was found in bulk sequenced blood or matched normal lung tissues. These ecDNA often included genes (84%), frequently overlapping with known oncogenes like MDM2, TERT, and MYC, which showed higher expression levels compared to non-amplified or other amplified genes. Notably, most MDM2 amplifications (36/45) were on ecDNA. ecDNA was significantly associated with whole genome doubling, tumor stage, and several endogenous mutational signatures, including APOBEC (SBS2 and SBS13), and clock-like signature (SBS1). Intriguingly, ecDNA-positive tumors were associated with significantly worse survival compared to tumors without any focal amplifications, though tumors with other amplification types (e.g. breakage-fusion-bridge, linear amplification, or complex events) had similar survival impacts. The unprecedented size of our cohort and the integration of clinical, epidemiologic, and multi-omics data allowed us to perform the first in-depth characterization of ecDNA in LCINS. We reconstructed the genomic regions involved in ecDNA and revealed the full spectrum of simple and complex ecDNAs across cancer histologies as well as the clinical and functional impact of ecDNA on LCINS. Citation Format: Azhar Khandekar, Tongwu Zhang, Marcos Diaz-Gay, Jens Luebeck, Ludmil Alexandrov, Maria Landi. Extrachromosomal DNA in lung cancer from never smokers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB286.
Abstract LB322: ARC2-001, a CAF-targeting drug exhibits strong anticancer effect in in vivo setting
Authors: So-Young Yeo, Mohamed Farh, InSuk Sohn, Seok-Hyung Kim, Keun-Woo Lee
Journal: Cancer Research (2024)

Abstract For more effective tumor growth suppression, a combinatorial treatment of CAF-targeting agent and other well-validated therapies such as chemotherapy, radiotherapy, and immune checkpoint therapy should be considered. Thus, we hypothesized that co-administration of the CAF-targeting drug, ARC2-001 (the in vitro-approved CAF-targeting candidate) and clinically practiced anticancer drugs could be useful strategy for treating under clinical settings. However, it is essentially important to evaluate this using well-established pre-clinical models. We thoroughly verified the anticancer effect of ARC-001 using two in vivo model systems. ( 2nd- in vivo systems for CAF targeted drugs Research). 1. (Subcutaneous model) Immune-deficient mice (NOD/SCID): in which human colon cancer cell line HCT116 was co-injected with human CAF (CAFs were obtained from stage IV CRC patients) followed by administration of ARC2-001 alone or in combination with 5-fluorouracil (5FU). 2. (Subcutaneous and Orthotopic model) Wild-type mice (C57BL/6): in which mouse colon cancer cells was co-injected with mouse colon CAFs (both cancer cells and CAFs were obtained from chemically-induced colorectal cancer model with rich desmoplastic stroma) followed by administration of ARC2-001 alone or in combination with aPD-1. We observed a magnificent inhibition of tumor growth and metastasis in the combined treatment group over singular treatment groups in both models. This denotes that ARC2-001 largely augments the anti-cancer effect of widely employed anticancer drugs, such as 5FU, and thus can be exploited as an adjuvant for enhanced colorectal cancer chemotherapy.Collectively, our results evidenced the necessity of considering CAF-targeting agents for a more regulated therapeutic strategy to treat desmoplastic cancers. Citation Format: So-Young Yeo, Mohamed Farh, InSuk Sohn, Seok-Hyung Kim, Keun-Woo Lee. ARC2-001, a CAF-targeting drug exhibits strong anticancer effect in in vivo setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB322.
Abstract CT088: EVT801, a novel selective VEGFR-3 inhibitor targeting tumor angiogenesis, is pursuing dose escalation stage of phase I first-in-human study
Authors: Carlos Gomez-Roca, Philippe Cassier, Michael Fitzgerald, Lise Davenne, Cristina Costantin, Philippe Rochaix, Jean-Pierre Delord, John Friend, Andrea Nizzardo, Alessia Tagliavini, Marco Pergher, Pierre Fons, Marie Mandron
Journal: Cancer Research (2024)

Abstract Background: EVT801 is a highly selective, orally available VEGFR3 inhibitor that modulates tumor angiogenesis without inducing hypoxia, one of the main causes of cancer-associated immunosuppression. EVT801 has shown compelling efficacy as single agent in multiple in vivo models. In addition, combination of EVT801 and Immune Checkpoint Therapy (ICT) agents shows additive effects and thus holds promises for combination treatment without induction of hypoxia-induced immunosuppression. Clinical trial design: A phase I clinical study (NCT05114668) is underway to evaluate safety, tolerability, pharmacokinetics of EVT801 and explore patient characterization which is key for further development. The phase I trial consists in two sequential stages. During the first stage, currently ongoing, EVT801 is orally administered to patients with advanced solid tumors in a multiple ascending dose study using an accelerated 3+3 design (1 patient per dose until grade 2 toxicities are observed) in up to 48 patients in 8 dose levels. The primary objective is to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Stage 2 will focus on validation of this RP2D in two 6-patient cohorts diagnosed with 2 indications. In addition to conventional measures of safety, tolerability, efficacy, and pharmacokinetics, the phase I study employs a rich suite of biomarkers analysis using histology, transcriptomics and immunomonitoring to provide early insights into the pharmacological activity of EVT801. At end of September 2023, 20 patients have been treated in five different cohorts for EVT801 doses ranging from 50mg QD to 400mg BID. At this date, only 1 dose limiting toxicity was declared at the higher dose. Conclusion: Collection of safety data on these first enrolled patients showed no safety alert which allows further dose escalation and reinforces the good safety profile of EVT801 observed during the preclinical toxicology studies. Citation Format: Carlos Gomez-Roca, Philippe Cassier, Michael Fitzgerald, Lise Davenne, Cristina Costantin, Philippe Rochaix, Jean-Pierre Delord, John Friend, Andrea Nizzardo, Alessia Tagliavini, Marco Pergher, Pierre Fons, Marie Mandron. EVT801, a novel selective VEGFR-3 inhibitor targeting tumor angiogenesis, is pursuing dose escalation stage of phase I first-in-human study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT088.