tbuckley/cabot-search huggingface dataset:
Abstract 5933: Identifying MC4R-targeted small molecule to investigate MC4R impact on cachexia progression
Authors: Julia Stokes, Dhanir Tailor, Marie Foss, Benedikt Grau, Sanjay Malhotra
Journal: Cancer Research (2024)

Abstract Background: The melanocortin system participates in energy homeostasis and appetiteregulation. This metabolic system is primarily located in the central nervous system,specifically in the hypothalamus and brainstem region. Within the melanocortin system,there are five established melanocortin receptors (MCR). MCRs are g-protein-coupledreceptors (GPCRs) and when these receptors are activated, they can increase neuronexcitation, regulate neurotransmitter release, regulate synaptic input, and alterconnection and strength. When Melanocortin-4 Receptor (MC4R) plays a critical role inthe progression of multiple metabolic diseases including cachexia. Cachexia is definedas the reduction of fat and lean mass, which is caused not just by lack of appetite, but byinflammatory impact. Cachexia is a symptom seen in numerous chronic diseases fromcancer to mitochondrial dysfunction to autoimmune inflictions. This makes MC4R apotentially strong therapeutic target. Method: In-silico and high-throughput methods were used to identify small moleculesthat target and inhibit MC4R. For high-throughput screen, Hek293 cells withconstitutively active MC4R tagged with a nanoluciferase were used to identify molecules,specifically with inhibitory qualities. cAMP accumulation and β-arrestin recruitmentassay were used to determine the impact on MC4R functionality. Results: 4738 small molecules were screened using high-throughput methods. Using a60% cutoff, 21 small molecules were identified as potential MC4R inhibitors. 17 arecurrently under investigation to confirm high-throughput results and identify functionalimpact. Several of these molecules have shown promising potential in vitro and will likelymove forward into in vivo studies. Conclusion: This study identifies prospective small molecule inhibitors that targetMC4R and may be used as a probe to explore MC4R biology. Citation Format: Julia Stokes, Dhanir Tailor, Marie Foss, Benedikt Grau, Sanjay Malhotra. Identifying MC4R-targeted small molecule to investigate MC4R impact on cachexia progression [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 5933.
Abstract 5910: Developing a novel humanized anti-FABP4 antibody for breast cancer treatment
Authors: Jiaqing Hao, Matthew Yorek, Jian yu, Anthony Avellino, Bing Li
Journal: Cancer Research (2024)

Abstract Circulating levels of adipocyte fatty acid binding protein (A-FABP, also known as FABP4) are linked with metabolic dysregulation. Our previous study demonstrated that high serum levels of FABP4 increased the risk of breast cancer, indicating that circulating FABP4 could be a potential therapeutic target for this disease. In this study, we generated mouse monoclonal antibodies (mAb) against FABP4 by immunizing C57BL/6 mice with recombinant human FABP4. After screening over 1300 hybridoma clones, we identified an FABP4 neutralizing mAb, named 12G2, which inhibited breast cancer growth in various mouse models. To facilitate clinical application, we engineered chimeric and humanized variants of the 12G2 mAb. Notably, the humanized variant, 12G2-variant 9 (12G2-vt9), effectively inhibited mammary tumor growth and progression by reducing the activity of FABP4/ALDH1 in different breast cancer mouse models. Our findings suggest that 12G2-Vt9 is a promising neutralizing mAb targeting FABP4-mediated cancer stemness through ALDH1 signaling, offering potential as a targeted therapeutic antibody for the clinical treatment of breast cancer. Citation Format: Jiaqing Hao, Matthew Yorek, Jian yu, Anthony Avellino, Bing Li. Developing a novel humanized anti-FABP4 antibody for breast cancer treatment [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 5910.
Abstract 4514: Discovery of potent and orally bioavailable degraders of HPK1 based on a novel HPK1 binder
Authors: Zhimin Zhang, Mengqiang Wu, Ling Wang, Xi Yang, Zhiping Zhang, Liubin Guo, Hao Pan, Mengting Zhao, Linli Wang, Sirui Liu, Zhao Dong, Chunhua Jiang, Haowen Zheng, Dongzhou Liu
Journal: Cancer Research (2024)

Abstract Background: Proteolysis targeting chimeras (PROTACs) are novel structures designed to target a protein of interest (POI) for ubiquitination and degradation, leading to the selective reduction in the expression levels of the POI. Hematopoietic progenitor kinase 1 (HPK1) is considered a promising target for tumor immunotherapy. PROTAC-involved disruption of HPK1 protein activity enhanced the treatment efficacy of CAR-T-cell-based immunotherapies in different solid tumors and mouse models. Thus, targeting HPK1 by PROTAC to restore T-cell activity is an attractive approach to induce a greater immune responses in cancer. Results: We designed and synthesized a series of HPK1 degraders by tethering our previously discovered novel HPK1 inhibitor with CRBN binder through various linkage. The most potent PROTAC effectively degrades HPK1 proteins in the Ramous cell in a dose-dependent manner and achieves DC50 value &amp;lt;50 nM. The maximum degradation (D max ) values achieved are &amp;gt;90%. Our PROTAC showed EC50 value &amp;lt;100 nM for IL-2 and IFNγ production. PK studies revealed a low clearance, high plasma exposure and oral bioavailability in mice and rats. Furthermore, our PROTAC is shown to induce robust and statistically significant tumor growth inhibition in the MC38 and CT26 syngeneic model with increased T cell signatures observed within the tumor. The PROTAC in combination with anti-PD1 also resulted in robust anti-tumor activity with TGI &amp;gt; 90%. The 14 days DRF experiment shows that the compound has a great safety window(&amp;gt;200 folds). Conclusion: We show here that a potent oral HPK1 degrader demonstrates strong immune cell activation and robust anti-tumor activity in mouse syngeneic tumor models, as a single agent and in combination with anti-PD1. Further evaluation of these potent degraders in additional in vivo studies will continue to build upon our mechanistic understanding of HPK1 degradation as a novel immunomodulatory approach for anti-tumor immunity. Citation Format: Zhimin Zhang, Mengqiang Wu, Ling Wang, Xi Yang, Zhiping Zhang, Liubin Guo, Hao Pan, Mengting Zhao, Linli Wang, Sirui Liu, Zhao Dong, Chunhua Jiang, Haowen Zheng, Dongzhou Liu. Discovery of potent and orally bioavailable degraders of HPK1 based on a novel HPK1 binder [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 4514.
Abstract 5907: Pre-clinical evaluation of a novel antibody drug conjugate (ADC) LM-317 targeting NaPi2b
Authors: Wentao Huang, Zhifang Liu, Yifan Li, Heng Pan, Xia Qin, Da Fei, Runsheng Li
Journal: Cancer Research (2024)

Abstract Introduction: NaPi2b is a multi-transmembrane type II sodium-dependent phosphate transporters that regulates phosphate homeostasis in normal physiological condition [1]. It is highly expressed in ovarian cancer (OC), non-small-cell lung cancer (NSCLC), and papillary thyroid cancer, with limited expression in normal tissue, making it a promising target for antibody-drug conjugates (ADCs) [2,3]. LM-317 is a novel NaPi2b targeted humanized monoclonal antibody LM-117 conjugated to the next-generation topoisomerase I inhibitor LDX2 via a cleavable linker, with antibody-drug ratio of 8. Here, we present the preclinical in vivo and in vitro results of LM-317. Results: LM-317 is highly specific cross-reactive with rhesus monkeys, cynomolgus monkeys, mouse, and rat NaPi2b. Concentration-dependent cell binding and internalization effects of LM-317 were observed in human NaPi2b-expressing cells, and OC and NSCLC cells expressing NaPi2b, with EC-50 of 0.92 - 9.7 nM and 1.51 - 4.76 nM, respectively. The cytotoxicity effect of LM-317 in NaPi2b -positive tumor cells was superior to LM-117-DXD, with IC-50 of 0.002 - 0.52nM. The in vivo studies showed that 1 mg/kg of LM-317 almost completely eradicated tumors in the OVCAR-3 xenograft mice model of OC, and similar antitumor activity was observed in the NCI-H175-xenograft mice model of NSCLC at the dose of 3 mg/kg. Single dose of 6 mg/kg of LM-317 showed sustained tumor eradication in the NSCLC xenograft -mouse model. LM-317 also exhibited potent tumor regression in the PDX model of OC and NSCLC. The tumor growth inhibition (TGI) value was 80%-100% in OC and NSCLC PDX models with different expression degree of NaPi2b after treatment with LM-317. The antitumor activity of LM-317 in cell line- and PDX models of OC and NSLCL was comparable to those of LM-117-DXD. Conclusion: The novel ADC LM-317 targeting NaPi2b showed robust antitumor activity in vitro, and in the OC and NSCLC cell line derived models and PDX models. LM-317 could potentially provide therapeutic benefit to treat NaPi2b-positive tumors including OC and NSCLC in the future. Reference: 1.S. Banerjee et al. Cancer Treatment Reviews 112 (2023) 1024892.Finstad CL, Lloyd KO, Federici MG, et al. Clin. Cancer Res. 1997;3(8):1433-14423.Zhang et al. Tumor Biology July 2017: 1-7. Citation Format: Wentao Huang, Zhifang Liu, Yifan Li, Heng Pan, Xia Qin, Da Fei, Runsheng Li. Pre-clinical evaluation of a novel antibody drug conjugate (ADC) LM-317 targeting NaPi2b [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 5907.
Abstract 6778: New microplate platform with cryopreserved 3D tumor spheroids for faster and convenient pre-clinical testing
Authors: Nils Goedecke, Simon Stroebel, Simon Hutter, Tala Issa, Irina Agarkova, Laure-Anne Ligeon, Olivier Frey
Journal: Cancer Research (2024)

Abstract Drug discovery and safety testing depend on predictive in vitro models, including multicellular tissues with organotypic functions. While traditional 2D tumor cell cultures have been extensively used in early drug screening due to their user-friendly nature, automation compatibility, and high throughput, they fall short in representing the intricate 3-dimensional structure, physiology, and complex multicellular nature of actual tumors. However, generating such 3D tissues for each test campaign is labor intensive. In addition, not all researchers have the resources to establish these 3D models. To pave the way, we developed a new platform that offers a range of cryopreserved 3D tumor models in micro plate format allowing for high-content screening. It enables users to start testing compounds within a 3-to-5 days simply by thawing an ARCTis™ plate (Always Ready Cryo Tissues) and following clear instructions. Another advantage of these cryopreserved 3D models derives from the fact that they are made in larger batches which means the start point for compound testing is always the same. This improves data quality, maximizes the test window length, and makes the data comparable across work groups. Currently, our growing portfolio consists of 25 tumor cell lines from ATCC representing the most common solid tumors. Their functionality has been determined based on efficacy tests for each cell line with the apoptotic agent Staurosporine. Various cell lines exhibited compact spheroids with a round morphology, less compact aggregates with non-spherical morphology, or loose cell-cell interaction aggregates, which can correlate with their tumor site of origin. Upon treatment with Staurosporine the dose-response profiles indicated growth inhibition, tumor shrinkage, or tumor cell killing effects based on size assessment and cell metabolic analysis (ATP). Moreover, we demonstrated the robust performance of these assays from plates stored for up to 6 months at -80°C.In conclusion, this groundbreaking approach addresses the limitations of traditional 2D cell cultures by providing a high-throughput, in-plate frozen, 3D cell culture platform. By offering a combination of a more physiologically relevant representation of tumors with a robust frozen-storage and time flexible assay platform our method holds great promise for advancing cancer drug discovery by easing the exploration of complex drug testing screens in vitro. Citation Format: Nils Goedecke, Simon Stroebel, Simon Hutter, Tala Issa, Irina Agarkova, Laure-Anne Ligeon, Olivier Frey. New microplate platform with cryopreserved 3D tumor spheroids for faster and convenient pre-clinical testing [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 6778.
Abstract 6351: MUC1*-ADCs are effective against heterogeneous solid tumor cancers
Authors: Cynthia Carol Bamdad, Benoit S. Smagghe, Scott T. Moe, Mark G. Carter, Trevor J. Grant, Kevin R. Yi, Michael J. Nash, Jacy P. Marquez, Natalie K. Miller, Jac-Leen S. Nash, Dan S. Miller, Danica M. Walkley, Andrew K. Stewart
Journal: Cancer Research (2024)

Abstract Purpose: To develop a MUC1*-ADC for the treatment of over 75% of solid tumor cancers. Methods: MUC1* (muk 1 star) is a growth factor receptor created after cleavage and release of the N-terminal portion of MUC1. The targeting antibody, huMNC2, has already demonstrated safety and cancer selectivity in a 1st-in-human CAR-T clinical trial for treatment of metastatic breast cancers. MNC2 is an IgG1 antibody that only recognizes the conformational epitope created when MUC1 is cleaved by specific tumor-associated enzymes. Confocal microscopy and pHlourin2 were employed to measure antibody internalization as a function of time. We conjugated MNC2 to MMAE, MMAF, Dxd and exatecan via several different linkers. MUC1*-ADCs with DARs ranging from 4-8 were tested in vitro and in vivo for efficacy against a panel of solid tumor cancers. Heterogenous MUC1* tumors were made by mixing different ratios of mCherry wild-type cancer cells with GFP MUC1* overexpressed cancer cells. Resulting H scores ranged from 10-280 (max 300). Results: Cancer cells internalized the MUC1* MNC2 antibody within 2 hours. In vitro, MUC1*-ADC IC50s ranged from 1.3nM to 20.0nM, depending on the linker-payload and cancer subtype, wherein the majority had an IC50 of about 10nM. In general, efficacy in animals was seen across multiple cancer sub-types treated with multiple MUC1*-ADCs. Efficacy in animals xenografted with heterogeneous MUC1* tumors showed a dependence on antigen density. Greatest efficacy was observed for breast cancer xenografts with an H Score &amp;gt;10 treated with MNC2-Deruxtecan. However, only pancreatic tumors with higher H Scores were completely eliminated by MNC2-MMAE, MNC2-Deruxtecan and MNC2-exatecan. MNC2-ADC and MNC2-CAR share the same antibody. No off-tumor toxicity was observed in animals treated with MNC2-ADC, which mimicked lack of off-target toxicities for MNC2-CAR T cells in humans. Conclusions: These data, combined with MNC2-CAR T data from our 1st-in-human trial for metastatic breast cancer, supports a conclusion that the MUC1* antibody MNC2 is safe and could have high therapeutic value as a MUC1*-ADC for multiple solid tumors with both high and low antigen density. Citation Format: Cynthia Carol Bamdad, Benoit S. Smagghe, Scott T. Moe, Mark G. Carter, Trevor J. Grant, Kevin R. Yi, Michael J. Nash, Jacy P. Marquez, Natalie K. Miller, Jac-Leen S. Nash, Dan S. Miller, Danica M. Walkley, Andrew K. Stewart. MUC1*-ADCs are effective against heterogeneous solid tumor 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 6351.
Abstract 4513: Exploration degradation of intrinsically disordered protein YAP induced by PROTACs
Authors: Chen Zhou, Chunbao Sun, Liya Pi, Chenglong Li
Journal: Cancer Research (2024)

Abstract Yes-associated protein (YAP), a potent oncogene and a key player in the Hippo tumor suppression pathway, has long been considered challenging to target due to its partially intrinsically disordered nature. However, recent advancements in High-throughput Screening (HTS) have yielded a breakthrough, as several YAP binders have been identified, igniting new possibilities in the quest to combat YAP-driven malignancies. Building upon this progress, a novel approach utilizing Proteolysis-Targeting Chimera (PROTAC) technology was employed to design and synthesize a series of YAP degraders. Here, our degraders were created by linking NSC682769, a previously reported YAP binder, with either VHL ligand 2 or pomalidomide using various linkers of different lengths and types. Among these degraders, YZ-6 emerges as the most promising, inducing rapid and sustained YAP degradation via promoting its ubiquitination-proteasome-dependent proteolysis. This process effectively suppressed YAP/TEAD-led transcription in both YAP-dependent NCI-H226 and Huh7 cancer cell lines. In addition to its degradation capabilities, YZ-6 also exhibited antiproliferative activity in both cell lines. Importantly, YZ-6 efficiently suppressed tumor development in the Huh7 xenograft mouse model, accompanied by a remarkable decrease in YAP levels, without adverse effects on the mice. These findings highlight the potential of PROTAC-mediated degradation as a viable strategy for reducing oncogenic YAP levels and attenuating downstream signaling in cancer cells. Moreover, the development of PROTACs based on NSC672869 holds promise for treating YAP-driven malignancies, opening new avenues for cancer therapy. Citation Format: Chen Zhou, Chunbao Sun, Liya Pi, Chenglong Li. Exploration degradation of intrinsically disordered protein YAP induced by PROTACs [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 4513.
Abstract 6256: Prevalence of BRCA1 and BRCA2 proteins in breast cancer in a nigerian population and their relationship with different breast cancer morphological variants
Authors: Solomon Raphael, Abdul Oluwasesan
Journal: Cancer Research (2024)

Abstract Background: Breast cancer is the commonest site specific cancer in women and a leading cause of cancer death among women in Nigeria and globally. The trend in Nigeria and Africa is that breast cancers are seen in younger age groups, are of higher grades and follow an aggressive course. It has been suggested that this may largely be due to mutation in BRCA genes with the attendant alteration in function of its proteins. This study aimed at determining the prevalence of BRCA1 and BRCA2 proteins in breast cancers seen in our environment as well as to see any association between these proteins and different morphological variants. Materials and Methods: A descriptive study using tissue blocks of all histologically diagnosed breast cancer in our department between 2013 and 2017. Fresh sections were recut for histological grading and immunohistochemistry. Proteintech BRCA1 and BRCA2 polyclonal antibodies and detection kit were used. Results: One hundred and thirty (130) cases met the inclusion criteria for this study. The mean (SD) age of the patients was 44.8 (10.3) years with ages ranging from 26 to 79 years. There were more cases of breast cancer (73.1%) seen before 50 years. Two (2) Male Breast Cancer (MBC) cases were seen, giving the female to male ratio of 64:1. The commonest morphological variant encountered was Invasive Carcinoma, No Special Type at 84.6% of cases. This was followed by invasive medullary (7.8%). The least common variant was papillary cancer at 0.8%. The tumors seen were mostly grade 3 (71.2%), followed by grade 2 at 22.7% and the least was grade 1 at 6.1%. Positivity for BRCA1 and BRCA2 proteins was seen in 27.7% and 30.0% of cases respectively. One of the MBC showed reactivity for BRCA1 protein. No significant relationship was seen between BRCA 1/2 proteins expression and age or breast cancer histotypes. Conclusion: BRCA 1 and 2 proteins are an important risk factor for breast cancers seen in this environment. However, there is no association with age distribution and morphological variants of the breast cancer in our population. Citation Format: Solomon Raphael, Abdul Oluwasesan. Prevalence of BRCA1 and BRCA2 proteins in breast cancer in a nigerian population and their relationship with different breast cancer morphological variants [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 6256.
Abstract 6362: The bispecific antibody KA-3002, targeting PSMA and 4-1BB, specifically enhances T cell activity within prostate tumors
Authors: Guojin Wu, Jiabei Liang, Hao Peng, Feng Hao, Tongtong Liu, Jinying Ning
Journal: Cancer Research (2024)

Abstract Cancer immunotherapy with 4-1BB agonists has faced limitations in further clinical development due to dose-limiting toxicity. PSMA, highly expressed in normal prostate tissue and prostate cancer, is a clinically validated target for prostate cancer treatment. In this study, we developed a bispecific antibody (BsAb), KA-3002, targeting PSMA and human 4-1BB, with the aim of restricting 4-1BB stimulation to the interior of tumors. KA-3002 was developed based on our nanobody antibody discovery platform. KA-3002, in IgG1 format, features mutations in the Fc domain to eliminate ADCC, ADCP, and CDC activity. It contains two identical nanobodies at the C-terminal against 4-1BB to stimulate 4-1BB signaling in T cells and binds to PSMA with two Fabs at the N-terminal. KA-3002 exhibits high avidity binding to prostate tumor cells expressing PSMA (EC50&amp;lt;1nM) and also binds to 4-1BB expressed on 293T cells and activated human T cells. In the presence of a low concentration of CD3 antibody to stimulate T cell activation, co-culture of tumor cells expressing PSMA with primary T cells isolated from human PBMC enhances T cell activation and proliferation. In PBMC humanized immunodeficient mouse tumor models, KA-3002 effectively suppresses the growth of 22Rv1 tumors, which highly express PSMA. The antibody also demonstrates a half-life of more than five days in the blood of Balb/c mice. Finally, we assessed the developability of this antibody with different treatments such as high concentration, low pH, repeated freezing and thawing, and high temperature. KA-3002 shows neither aggregation nor degradation. In conclusion, the BsAb KA-3002, developed with our nanobody antibody discovery platform, emerges as a promising pre-clinical candidate drug for the treatment of prostate cancer. Citation Format: Guojin Wu, Jiabei Liang, Hao Peng, Feng Hao, Tongtong Liu, Jinying Ning. The bispecific antibody KA-3002, targeting PSMA and 4-1BB, specifically enhances T cell activity within prostate 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 6362.