bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6363: The biparatopic antibody KA-3005 against MET is suitable for developing antibody-drug conjugates (ADCs) to treat MET-expressing cancers
Authors: Wu Guojin , Liang Jiabei , Peng Hao , Hao Feng , Liu Tongtong , Ning Jinying 
Published: March 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 6426: Identification of potential immune biomarkers for GSK-3 inhibitor elraglusib (9-ING-41) in patients with relapsed/refractory metastatic cancer
Authors: Weiskittel Taylor , Huntington Kelsey , Zhang Leiqing , Koukol Austin , Carneiro Benedito A. , Li Hu , Ugolkov Andrey , El-Deiry Wafik , Mazar Andrew 
Published: March 2024

Abstract
Cytokines mediate strong immunomodulatory effects in cancer. Elraglusib (9-ING-41), an inhibitor of GSK-3, is a potent antitumor and immune-modulatory agent in phase 2 clinical trials for the treatment of various cancers. Here, we examined the immune environment of elraglusib-treated cancer patients by measuring peripheral blood protein levels to explore whether the expression level of cytokines/chemokines/soluble cell receptors/growth factors (CCSG) is correlated with clinical outcome. Using a customized Luminex platform, the expression of forty CCSG hypothesized to be linked to GSK-3 activity was assessed in pre-dose plasma samples obtained from 45 cancer patients with relapsed/refractory metastatic disease (NCT03678883; the 1801 trial). All patients in the 1801 trial were treated with elraglusib (dose range: 1-15 mg/kg) either as a single agent (Part 1; n=21) or in combination with chemotherapy (Part 2; n=24). Pre-dose peripheral blood protein levels were examined as binary predictors of clinical outcome using optimal cutoff points determined by maximally selected rank statistics. In the aggregate Part 1 and 2 populations (n=45), we identified 13 CCSG that significantly stratified the cohort by overall survival (OS). High pre-dose levels of CD95 and TNFRSF10C were associated with better OS. CD95 was a better prognostic of OS than TNFRSF10C (HR: 2.27, 95% CI: 1.10-4.67, p-value: 0.023). Low pre-dose levels of 11 CCSG were also significantly associated with favorable OS, with IL-8 being the most predictive (HR: 0.137, 95% CI: 0.0545-0.346, p-value: &lt;0.0001). Part 1 and 2 predose samples were also analyzed separately, and many of the biomarkers identified in the aggregate analysis retained significance in the separated analysis. In Part 1, CXCL5, IFN-alpha, and IL-18 emerged as unique markers, and in Part 2, CCL22 was the single unique marker.The results of our exploratory study identified several putative biomarkers of elraglusib clinical benefit and demonstrated potential immunomodulatory mechanisms of elraglusib that will be used to inform the further clinical development of elraglusib for the treatment of metastatic cancer.
Citation Format: Taylor Weiskittel, Kelsey Huntington, Leiqing Zhang, Austin Koukol, Benedito A. Carneiro, Hu Li, Andrey Ugolkov, Wafik El-Deiry, Andrew Mazar. Identification of potential immune biomarkers for GSK-3 inhibitor elraglusib (9-ING-41) in patients with relapsed/refractory metastatic 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 6426.
Abstract 644: PKC-iota specific inhibitor ICA-1S causes the degradation of mutant p53 in ovarian cancer cell lines
Authors: Marzan Mahfuza , Oishee Nuzhat Nowshin , Olatunji Abigail , Acevedo-Duncan Mildred 
Published: March 2024

Abstract
Ovarian cancer is the most lethal malignant disease of female. Treatment options for ovarian cancer are mostly the use of chemotherapeutics, surgery, or radiotherapy. However, due to resistance to drugs, relapse occurs and thus 5 years survival rate is only 47%. The tumor suppressor protein p53 works as a transcription factor to transcribe several proteins such as p21, p16 and PUMA that lead to halt cell cycle and also induce apoptosis when there is a damage in DNA. Mutation in several regions of p53 (mutp53) is quite common in cancers and can lead to the accumulation of p53 with loss of functions or sometimes gain of oncogenic functions. Thus there is a search for drugs that can degrade the mut53 and can restore the functions of normal p53. In this research, it was observed that the treatment of ovarian cancer cell lines (ES-2, HEY and OVCAR3) with atypical protein kinase C-iota (aPKCɩ) specific inhibitors ICA-1S can cause the degradation of mutp53 (53.6%, N=6 trials). Treatment with ICA-1S also lowered the level of phosphorylated p53 (ser15, 87%, N=3 trials). However, the level of MDM2 protein (murine double minute 2), a known p53 E3 ligase was not significantly (98%, N=2 trials) affected by ICA-1S in ES-2 cell line with mut p53 as well as p21 was also not affected. However level of PUMA was decreased both in ES-2 and HEY cell lines. Immunoprecipitation (IP) with aPKCɩ specific beads showed the aPKCɩ is associated with p53, though reverse IP with p53 beads was not able to show the association. Application of proteasome inhibitor MG-132 at a single dose of 0.5µM could not completely inhibit the degradation of mut53 and WTp53 in ICA-1S treated ES-2 cell line and HEY cell line, respectively, indicating the drug may be affecting the transcription of p53 as well. It is therefore postulated that aPKCɩ can phosphorylate p53, stabilizing it and may be affecting the transcription of p53 as well in those cell lines. Further research (kinase activity assay, immunoprecipitation, immunofluorescence) is going on to reveal the mode of this degradation.
Citation Format: Mahfuza Marzan, Nuzhat Nowshin Oishee, Abigail Olatunji, Mildred Acevedo-Duncan. PKC-iota specific inhibitor ICA-1S causes the degradation of mutant p53 in ovarian cancer cell lines [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 644.
Abstract 6462: Somatic mutational profile in MUTYH- associated colorectal cancers (MUTYH-CRCs)
Authors: Kaldas David , de Castria Tiago Biachi 
Published: March 2024

Abstract
Background: Biallelic inactivation of MUTYH leads to hereditary predisposition to colorectal polyposis and CRC. Herein we evaluated co-alterations in somatic next-generation sequencing (NGS) in patients with MUTYH-CRC, mainly KRAS G12C, high tumor mutational burden and microsatellite instability (MSI-H)/mismatch repair deficiency (dMMR).
Methods: Data was collected on patients with MUTYH-CRC in the period between 2015 and 2023 at Moffitt Cancer Center (Tampa, Florida, United States). All patients with MUTYH-CRC were included regardless disease stage. Different germline panels were used to detect MUTYH and Foundation One, Caris and Moffitt STAR (in house NGS) were used to detect somatic co-alterations.
Results: A total of 36 patients were identified with MUTYH- CRC, the median age at diagnosis was 44-year-old, 55% were men. All patients had a somatic NGS available, 18 patients (50%) had KRAS mutation, and specifically KRAS G12C was detected in 9 patients (24%), 6 patients (17%) had MSI-H/dMMR, 5 patients (14%) had BRAF mutation and 4 patients (11%) with BRCA2 mutation.
Conclusion: MUTYH-CRC is associated with a high incidence of targetable alterations including KRAS G12C and BRAF. Considering unique characteristics in MUTYH-CRC tumor microenvironment, including T cell infiltrate, trials combining KRAS G12C/BRAF inhibitors and immune checkpoint inhibitors are warranted.
Citation Format: David Kaldas, Tiago Biachi de Castria. Somatic mutational profile in MUTYH- associated colorectal cancers (MUTYH-CRCs) [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 6462.
Abstract 6479: Metastases in uveal melanoma patients: Trends and risk factors
Authors: Beneke Alice A. , Taneja Kamil , Ladehoff Lauren , Root Kevin , Toloza Eric 
Published: March 2024

Abstract
Purpose: Uveal melanoma has a high tendency to metastasize. Due to its rarity, there has not been large population studies that have demonstrated the effect of demographic variables on a patient’s risk to have metastases.
Methods: The Nationwide Emergency Department Sample was queried from the last quarter of 2015 to 2019 to identify patients with a diagnosis of uveal melanoma. Multivariable logistic regression, with patient- and hospital-level characteristics as covariates, was used to identify factors associated with a higher chance of developing a metastasis and specific metastasis locations.
Results: From the last quarter of 2015 to 2019, there were 7,561 ED encounters with a diagnosis of uveal melanoma. Of these patients, 5.8% had at least one metastasis. Most patients with a metastasis were at least 65 years of age (47.1%), male (54.4%), a Medicare beneficiary (45.2%), and belonged to a family in the highest income quartile (29.7%). The median age of these patients was 61 years (IQR: 32-74). Most patients presented to hospitals in the South (40.7%), with a Trauma Level I designation (56.1%), and to a metropolitan teaching hospital (72.9%). The most common sites of metastasis were liver (17.0%), brain (5.3%), and bone (2.0%). Multivariable logistic regression identified the following factors to be associated with increased risk of developing a metastasis: private insurance (odds ratio [OR]=1.62; p=0.012), highest income quartile (OR=2.30; p&lt;0.001), and 2nd highest income quartile (OR=1.78; p=0.002). The following factors were associated with higher odds of developing a liver metastasis specifically: no-charge/charity work (OR=15.8; p=0.012), highest income quartile (OR=1.99; p=0.003), and second highest income quartile (OR=1.66; p=0.035). Presenting to a Trauma Level I hospital was associated with decreased risk of developing a liver metastasis (OR=0.57; p=0.016). Belonging to the highest income quartile was associated with a higher chance of developing a brain metastasis (OR=2.13; p=0.023) or a bone metastasis (OR=2.74; p=0.045). Among patients with a metastasis, the in-hospital mortality rate was 8.3%.
Conclusion: Metastasis is an important complication to monitor in uveal melanoma patients. In this study, we have demonstrated that income and insurance status are factors that are associated with higher rates of metastases. Physicians should place special attention to these groups to ensure that metastases are minimized.
Citation Format: Alice A. Beneke, Kamil Taneja, Lauren Ladehoff, Kevin Root, Eric Toloza. Metastases in uveal melanoma patients: Trends and risk factors [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 6479.
Abstract 6512: BPI-501836: A highly potent small molecule inhibitor targeting KRASG12D mutation
Authors: Yang Xiang , Lu Yuan , Xu Renqi , Kong Xiaoqiang , Sun Yongqing , Zhu Xingjie , Liu Xiaoyun , Zou Zhengyao , Chen Haibo , Liu Yanju , Sun Jialing , Han Han , Yang Cheng , Guo Jing , Lan Hong , Zhou Quan , Ding Lieming , Wu Hao , Wang Jiabing 
Published: March 2024

Abstract
As one of the most notorious un-druggable oncogenes, mutant KRAS impairs the transition of RAS from its active GTP-binding form to the inactive GDP-binding form, leading to sustained activation of downstream MAPK pathway and ultimately tumorigenesis. The recent approved KRASG12C inhibitors have demonstrated clinical benefits in KARSG12C mutant patients. However, the other prevalent KRAS mutations, such as KRASG12D, remain a huge unmet medical challenge. There’s no approved KRASG12D specific inhibitors yet. Here we present BPI-501836, a highly potent and selective small molecular inhibitor for KRASG12D. In vitro, BPI-501836 exhibited very high potency by disrupting the KRASG12D and cRAF interaction in a cell-free assay. In cell-based assays, BPI-501836 inhibited proliferation of KRASG12D mutant cell lines with sub-nanomolar IC50 values, without affecting wide type or non-G12D KRAS mutant cell lines. Moreover, it also attenuated ERK phosphorylation in KRASG12D mutant cells. In vivo, tumor regression was observed following the administration of 6 mg/kg (iv, QW) BPI-501836 in KRASG12D human pancreatic Panc04.03 xenograft mouse models, or in the KRASG12D human pancreatic PK-59 xenograft mouse models with an intraperitoneal injection of 20 mg/kg per week. Noteworthy was the prolonged half-life of BPI-501836 observed across various species, coupled with its high distribution in tumor tissues. Moreover, sustained suppression of ERK phosphorylation in tumor tissues persisted for up to 144 hours after the last dose of BPI-501836 in both xenograft mouse models. This extended pharmacodynamic effect supports the feasibility of a once-weekly dosing schedule in clinical applications. Safety assessments conducted through a 4-week repeated infusion (intravenous, twice weekly) of BPI-501836 in beagle dog demonstrated favorable safety profiles. In conclusion, BPI-501836 emerges as a highly potent and selective KRASG12D inhibitor, exhibiting promising pharmacokinetics, pharmacodynamics, and safety profiles in pre-clinicalstudies. BPI-501836 is currently in IND-enabling stage and holds potential for further development as a therapeutic agent.
Citation Format: Xiang Yang, Yuan Lu, Renqi Xu, Xiaoqiang Kong, Yongqing Sun, Xingjie Zhu, Xiaoyun Liu, Zhengyao Zou, Haibo Chen, Yanju Liu, Jialing Sun, Han Han, Cheng Yang, Jing Guo, Hong Lan, Quan Zhou, Lieming Ding, Hao Wu, Jiabing Wang. BPI-501836: A highly potent small molecule inhibitor targeting KRASG12D mutation [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 6512.
Abstract 6539: RNAi mediated silencing of STAT3 in tumor-associated immune cells induces robust anti-tumor effects in immunotherapy resistant tumors
Authors: Ganesh Shanthi , Kim Minju , Lee Jenny , Feng Xudong , Krishnan Harini Sivagurunatha , Rijnbrand Rene , Beaudry Amber , Lockridge Jennifer A. , Uttamsingh Vinita , Hanrahan John 
Published: March 2024

Abstract
Malignant tumors are often associated with an immunosuppressive tumor microenvironment (TME), rendering most of them resistant to standard-of-care immune checkpoint inhibitors (CPIs). Signal transducer and activator of transcription 3 (STAT3), a ubiquitously expressed transcription factor, has well-defined immunosuppressive functions in several leukocyte populations within the TME. Since the STAT3 protein has been challenging to target using conventional pharmaceutical modalities, we investigated the feasibility of applying systemically delivered RNA interference (RNAi) agents to silence its mRNA directly in tumor-associated immune cells. In preclinical murine tumor models, chemically stabilized acetylated small-interfering RNAs (siRNAs) selectively silenced Stat3 mRNA in multiple relevant cell types in TME and tumor-draining lymph nodes (TDLN), reduced STAT3 protein levels, and increased cytotoxic T-cell infiltration. In murine models of CPI-resistant tumors, RNAi-mediated Stat3 silencing resulted in tumor growth inhibition, which was further enhanced and resulted in tumor regressions in combination with CPIs. Our findings suggest that targeting STAT3 directly and reducing STAT3 protein in the suppressive immune cell populations in the TME and TDLN may overcome some of the current limitations of immunotherapy and be of therapeutic benefit especially for cancer patients who failed to respond to standard immunotherapy treatments alone. A human active STAT3 conjugate is currently in Phase 1 clinical trial for treatment of immunotherapy refractory cancer types (NCT06098651).
Citation Format: Shanthi Ganesh, Minju Kim, Jenny Lee, Xudong Feng, Harini Sivagurunatha Krishnan, Rene Rijnbrand, Amber Beaudry, Jennifer A. Lockridge, Vinita Uttamsingh, John Hanrahan. RNAi mediated silencing of STAT3 in tumor-associated immune cells induces robust anti-tumor effects in immunotherapy resistant tumors [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 6539.
Abstract 6573: Targeting DLK1, a Notch ligand, with an antibody-drug conjugate in adrenocortical carcinoma
Authors: Sun Nai-Yun , Kumar Suresh , Weiner Amber , Kim Yoo Sun , Mendoza Arnulfo , Nguyen Rosa , Okada Reona , Pommier Yves , Martinez Dan , Pogoriler Jennifer , Diskin Sharon , Maris John , Del Rivero Jaydira , Roper Nitin 
Published: March 2024

Abstract
Adrenocortical carcinoma (ACC) is an aggressive and rare endocrine malignancy with poor prognosis. First-line therapy (adrenolytic agent mitotane in combination with chemotherapy) for recurrent and metastatic ACC has limited efficacy and there are no approved second-line therapies. Antibody-drug conjugates (ADCs) are an emerging immunotherapeutic class in which a cytotoxic payload is directed to tumor cells via antibodies to cell surface proteins. As Notch ligands, such as DLL3, are ADC targets in neuroendocrine cancers, we screened for expression of Notch ligands in ACC. Among Notch ligands (DLL1, DLL3, DLK1, JAG1, JAG2), DLK1 (delta-like non-canonical Notch ligand 1) was the most highly expressed. Moreover, ACC had the near highest expression of DLK1 across all TCGA tumors likely because this ligand is of adrenal origin (with limited expression in other normal tissues apart from the pituitary gland and ovaries). By immunohistochemistry, we verified DLK1 to be expressed, at variable levels, in 97% of ACC tumors (n=30/31). We then tested a DLK1-directed antibody-drug conjugate (ADCT-701; DLK1-PBD), consisting of a humanized anti-DLK1 monoclonal antibody coupled to DNA damaging pyrrolobenzodiazepine (PBD) dimers (SG3199; drug-to-antibody ratio~1.8) via a cleavable linker in ACC pre-clinical models. ADCT-701 exhibited potent, nanomolar cytotoxicity in DLK1-expressing ACC cell lines and ACC patient-derived short-term organoid cultures. ADCT-701 cytotoxicity was dependent on DLK1 expression as DLK1 knockout and DLK1 overexpression abrogated and facilitated cytotoxicity, respectively. Mechanistically, ADCT-701 induced cytotoxicity through DLK1 dependent receptor-mediated internalization and DNA damage (γH2AX) as well as apoptosis (annexin V/PI positive cells, cleaved PARP, and cleaved caspase-3). In vivo studies showed that ADCT-701 was highly effective against DLK1-positive ACC xenografts and PDX models with durable anti-tumor activity. Our pre-clinical data demonstrate DLK1 as an important therapeutic target in ACC and support an upcoming phase I clinical trial of ADCT-701 in patients with neuroendocrine tumors including ACC (NCT06041516).
Citation Format: Nai-Yun Sun, Suresh Kumar, Amber Weiner, Yoo Sun Kim, Arnulfo Mendoza, Rosa Nguyen, Reona Okada, Yves Pommier, Dan Martinez, Jennifer Pogoriler, Sharon Diskin, John Maris, Jaydira Del Rivero, Nitin Roper. Targeting DLK1, a Notch ligand, with an antibody-drug conjugate in adrenocortical 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 6573.