tbuckley/cabot-search huggingface dataset:
Abstract 4489: Developing dual FLT3/MNK inhibitors to overcome sorafenib resistance in FLT3-ITD AML cells
Authors: Linxiang Zhao, Shuwei Zuo, Kun Xing, Xiaoshuang Yue, Huimin Zhang, Jingyi Zhang, Samuel Waxman, Yongkui Jing
Journal: Cancer Research (2024)

Abstract Acute myeloid leukemia (AML) patients with FLT3-ITD mutations are associated with poor prognosis. FLT3-ITD inhibitors developed only result in transient disease remission with disease relapse and resistance. Agents overcoming FLT3-ITD inhibitor resistance need to be developed. Sorafenib is one of FLT3-ITD inhibitors used in clinic. Using FLT3-ITD AML MOLM-13 cell line, we established a sorafenib resistant subclone MOLM-13/Sor, explored the resistance mechanism and revealed the overactivated mTOR signaling. MNK as one of the alternative mTOR signaling pathways is activated. MNK inhibitor eFT508 could overcome sorafenib resistance. Previously we developed a dual pyrido[3,2-d]pyrimidine MNK/PIM inhibitor 21o. Through optimization of 21o we obtained two new compounds H104 (IC50 values: MNK1 19 nM; MNK2 8 nM; FLT3-ITD 46 nM; PIM1 1388 nM) and H118 (IC50 values: MNK1 35 nM; MNK2 21 nM; FLT3-ITD 25 nM; PIM1 518 nM) with selective inhibition of MNK and FLT3 and losing PIM inhibition ability. H104 and H118 show better antiproliferative efficacy in FLT3-ITD MOLM-13 cells (GI50: 1.07±0.04 μM and 0.99±0.08 μM) than non-FLT3-ITD HL-60 cells (GI50: 7.04±0.15 μM and 4.78±0.31 μM). More intriguingly H104 and H118 exhibit superior antiproliferative effects in sorafenib resistant MOLM-13/Sor cells (GI50: 0.44±0.05 μM and 0.24±0.06 μM). H104 and H118 decreased the levels of p-eIF4E, c-myc and Mcl-1, the downstream substrates of FLT3-ITD and MNK. Our data indicate that the activated MNK is one mechanism of FLT3-ITD resistance and the dual MNK/FLT3 inhibitors have advantage for FLT3-ITD AML treatment. Citation Format: Linxiang Zhao, Shuwei Zuo, Kun Xing, Xiaoshuang Yue, Huimin Zhang, Jingyi Zhang, Samuel Waxman, Yongkui Jing. Developing dual FLT3/MNK inhibitors to overcome sorafenib resistance in FLT3-ITD AML cells [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 4489.
Abstract 3294: The GSPT1 molecular glue degrader MRT-2359 is active against prostate cancer
Authors: Ralph Tiedt, Martin Schillo, Arnaud Osmont, Débora Bonenfant, Rajiv Narayan, Owen Wallace, Markus Warmuth
Journal: Cancer Research (2024)

Abstract We have previously described our GSPT1 molecular glue degrader MRT-2359, which was optimized to achieve preferential antiproliferative activity in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) expressing high N-MYC or L-MYC mRNA. A clinical trial with this new drug candidate is ongoing (NCT05546268). Here, we present pre-clinical profiling of MRT-2359 across hundreds of cancer cell lines representing multiple cancer types, aiming at identifying other cancers where preferential sensitivity is associated with high expression of a MYC family member. These studies showed that prostate cancer cell lines clearly segregate into groups that are either sensitive or insensitive. Sensitive prostate cancer cell lines could be further divided into two subgroups: (1) androgen receptor positive cell lines displaying higher c-MYC mRNA expression levels than the other prostate cancer cell lines, (2) neuroendocrine prostate cancer cell lines with or without high N-MYC. The latter is in line with our previous observation that the neuroendocrine phenotype is generally associated with heightened sensitivity to MRT-2359 independently of MYC status. The insensitive cell lines were androgen receptor and neuroendocrine negative and displayed lower c-MYC mRNA levels. GSPT1 degradation in androgen receptor-positive cell lines led to rapid and deep loss of c-MYC protein as well as reduction of androgen receptor, including the splice variant AR-V7 that is associated with resistance to agents targeting androgen signaling. In androgen receptor-negative cell lines, the levels of c-MYC protein decreased only modestly upon GSPT1 degradation. Finally, in immunocompromised mice, xenografts of the AR-V7-positive cell line 22RV1 and the neuroendocrine prostate cell line NCI-H660, both of which are sensitive to MRT-2359 in vitro, were treated with several MRT-2359 dose regimens including continuous as well as intermittent (5 days on/9 days off) dosing. Most regimens led to marked tumor regression. Tumors of both models fully regressed after a 4-week course of 10 mg/kg MRT-2359 once daily, and no tumor regrowth could be detected after cessation of treatment. No significant in vivo response was observed for xenografts of the insensitive cell line PC-3. These data support the clinical investigation of MRT-2359 in prostate cancer. Citation Format: Ralph Tiedt, Martin Schillo, Arnaud Osmont, Débora Bonenfant, Rajiv Narayan, Owen Wallace, Markus Warmuth. The GSPT1 molecular glue degrader MRT-2359 is active against prostate 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 3294.
Abstract 7229: In situ trans-differentiation therapy effectively terminates the growth and recurrence of glioblastoma
Authors: Huihui Zhao, Zhaozhong Li, Xiaohui Zhang, Congjian Zhao, Zhao Zhu, Yueguang Liu
Journal: Cancer Research (2024)

Abstract Background: Glioblastoma (GBM) is the most common and malignant brain tumor in adults, and remains almost invariably lethal due to its aggressive and invasive nature. The standard first-line treatment for GBM is surgical resection, postoperative radiotherapy and chemotherapy with temozolomide (TMZ), but it exhibits short-term effects due to a high recurrence rate of GBM is its (up to almost one hundred percent). This long-existing clinical challenge has demanded development of novel and effective therapeutic strategies. In situ cell trans-differentiation therapy which direct reprograms tumor cells into terminally differentiated benign cells represents a novel therapeutic strategy for tumors. We further explored the application of in situ trans-differentiation therapy for glioblastoma. Results: In the present study, we have conducted a large-scale screen for transcription factors which can reprogram glioblastoma cells into terminally differentiated postmitotic cells. Over-expression of a combo of selected trans-differentiation factors that possess the highest trans-differentiation rate effectively reprogramed human glioma cells into neuronal-like cells with characteristic neuronal morphology and expression of neuronal genes in culture, as a result substantially reducing glioblastoma cell proliferation and tumor development after orthotopic transplantation. With replicable recombinant oncolytic virus vectors, product candidate can specifically replicate in glioma cells, therefore transcription factors can be specifically delivered to all tumor cells rather than normal cells. In either cell line-derived or patient-derived tumor tissue xenograft models, intra-tumoral injection product candidate inhibited glioblastoma cells growth at an exceptionally high efficiency. Remarkably product candidate combination with TMZ resulted in a complete regression of tumor and no recurrence was observed in animal model cases. Conclusion: In summary, our findings have established a novel therapeutic approach for treating glioblastoma by terminating sustained proliferation of glioma cells via transcription factors-induced in situ cell trans-differentiation and supported further clinic investigations in patients. Citation Format: Huihui Zhao, Zhaozhong Li, Xiaohui Zhang, Congjian Zhao, Zhao Zhu, Yueguang Liu. In situ trans-differentiation therapy effectively terminates the growth and recurrence of glioblastoma [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 7229.
Abstract 6091: Multi-cancer early cancer detection and cancer-type identification with high sensitivity non-invasive using urine: Pancreatic lung cancer early detection
Authors: Eric Di Luccio, Takaaki Hirotsu
Journal: Cancer Research (2024)

Abstract N-NOSE, a breakthrough cancer detection test from HIROTSU BIO SCIENCE, utilizes the unique chemotactic behavior of the nematode C. elegans. This nematode is drawn to the urine of individuals with 15 different types of cancers (including stomach, colon-rectum, lung, breast, pancreas, liver, prostate, uterus, esophagus, gallbladder, bile duct, kidney, urinary bladder, ovary, oropharynx) while avoiding urine from healthy persons, making N-NOSE a comprehensive primary screening tool. It has a high accuracy rate, with 87.5% sensitivity and 90.2% specificity for early-stage cancers. Being non-invasive and reasonably priced, N-NOSE has been a significant success in Japan since its 2020 launch, with over 500,000 screenings.This presentation delves into the technology aspect of N-NOSE in Japan, comparing its clinical research and key findings with competitors to underscore its effectiveness in early cancer detection. Furthermore, N-NOSE now advances to not only detect cancer but also identify its type in a noninvasive way, using urine and with high PPV.With pancreatic cancer being particularly lethal, we outline “N-NOSE plus pancreas,” the world’s first pancreatic cancer detection test at an early stage. This involves genetically modifying C. elegans to react specifically to early-stage pancreatic cancer urine samples, a development centered on the newly identified cr-4 GPCR in AWC neurons. Next, we profile our newest liver-cancer-specific test, “N-NOSE plus liver,” which offers early liver cancer detection with high sensitivity and specificity using urine.Finally, we highlight how N-NOSE bridges the gap in cancer screening and type identification, offering a complete, non-invasive solution. Citation Format: Eric Di Luccio, Takaaki Hirotsu. Multi-cancer early cancer detection and cancer-type identification with high sensitivity non-invasive using urine: Pancreatic lung cancer early detection [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 6091.
Abstract 2049: Novel preclinical models for PROTAC evaluation: And beyond
Authors: yuzhou xu, Jichuan Zhang, Ye Tian, Ziyu Chen, Amy Wang, Ting Ma, Qikuan Chen, Yinfei Yin
Journal: Cancer Research (2024)

Abstract Proteolysis-targeting chimeras (PROTACs) are a novel class of small molecules that induce the degradation of target proteins. Unlike conventional inhibitors that disable target proteins by direct binding, PROTACs are event-driven, meaning that a single PROTAC molecule can induce the degradation of multiple target protein molecules. This catalytic mechanism allows PROTACs to achieve complete inhibition of target proteins at lower concentrations compared to conventional inhibitors, making them a promising therapeutic approach for previously considered "undruggable" targets.Despite their promise, the development of PROTACs faces several challenges. The large molecular weight of PROTACs can lead to poor cell permeability and bioavailability. Additionally, the lack of high-throughput, quantitative assays for evaluating PROTAC efficacy hinders structure-activity relationship (SAR) studies. The formation of the Protein-PROTAC-E3 ternary complex is crucial for PROTAC function, and reliable methods for assessing this interaction are essential for PROTAC development.In this poster, ChemPartner showcases a comprehensive suite of preclinical models for PROTAC evaluation, encompassing both in vitro and in vivo approaches. Using low-cost, high-throughput biochemical assays, we can provide valuable insights into PROTAC efficacy, facilitating SAR studies and elucidating the relationship between molecular structure and activity. Followed by in cell and in vivo function assays, we can test PROTAC PK/PD, toxicity, and efficacy. This suite of assays provides a powerful tool to speed up PROTAC development and reduce the fail rate. Citation Format: yuzhou xu, Jichuan Zhang, Ye Tian, Ziyu Chen, Amy Wang, Ting Ma, Qikuan Chen, Yinfei Yin. Novel preclinical models for PROTAC evaluation: And beyond [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 2049.
Abstract 3320: <i>In vivo</i> and <i>in vitro</i> experience with novel direct Pan-RAS inhibitors
Authors: Tariq Arshad, Howard Donninger, Goeff Clarke, Joe Burlison, Rob Monsen, Mike Sabo
Journal: Cancer Research (2024)

Abstract RAS oncogenes are frequently activated by mutations in human cancer, where they act as driving elements of the disease. Mutation rates can range from ~25% of Non Small Cell Lung cancers to over 90% of pancreatic cancers. RAS proteins can also be hyper-activated to drive cancer at a significant frequency in the absence of RAS gene mutations when their protein regulatory systems are damaged. Thus, RAS may be the most frequently activated oncoprotein in cancer. We have developed a series of novel, direct, RAS inhibitors with a unique binding site on RAS. The binding of the agents alters the structure of the RAS effector loop and blocks the association with RAS downstream effectors. We used in silico library screening followed by Medicinal Chemistry optimization to develop the compounds. We have validated the agents using Microscale Thermophoresis and NMR to quantify binding to recombinant RAS protein. We have used mutant and wild type RAS driven tumor cell lines in 3D growth and protein-based RAS signaling assays to quantify and characterize the action of the family of inhibitors. We have used xenograft assays to demonstrate compound anti-tumor activity in RAS driven cell lines and pdx systems. We have identified compounds that can bind mutant and wild type K, H, N and M-RAS. We can suppress the association of mutant and wild type RAS protein with its effector RAF-1 in treated cells. The compounds can suppress 3D growth of mutant or wild type RAS driven tumor cell lines and repress tumor development in vivo. The compound family bind to a different site than either clinical agent AMG-510 (K-RAS G12C specific) or MRTX-1133 (K-RAS G12D specific). They exhibit distinct RAS signal inhibition patterns compared to these agents. They can also co-operate with the clinical agents and reduce drug resistance effects. Citation Format: Tariq Arshad, Howard Donninger, Goeff Clarke, Joe Burlison, Rob Monsen, Mike Sabo. In vivo and in vitro experience with novel direct Pan-RAS inhibitors [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 3320.
Abstract 2069: High content imaging without sacrificing coverage, resolution or speed: Functional validation through multiple assays
Authors: Matthew Boisvert, Josh Kieler, Dan DiSepio, Don Weldon
Journal: Cancer Research (2024)

Abstract Traditionally, high content screening (HCS) required compromise: sacrificing resolution, sample coverage or speed. This has limited high content screening’s utility as a high throughput tool, as speed is essential to cancer research at scale. Using a new approach, Araceli Endeavor® offers a solution to this compromise. This system images 96, 384 or 1536 -well high content microplates in under 10 minutes with full well coverage and sub-micron resolution, enabling high content screening at high throughput speeds without compromising resolution or coverage. Paired with the Clairvoyance™ analysis software, plates are analyzed at similar speeds, going from images to object-level data in 5-25 minutes. As with any new technology, validation is needed. Here we validate Endeavor and Clairvoyance at the level of the bioassay, using a range of common high content assays across different modalities. Assays are chosen to quantifiably demonstrate sensitivity, breadth, and broad applicability. Performance was benchmarked by using well-characterized compounds, matching published EC50/IC50 values when possible. We examined submicron-level nuclear spot counting, measuring histone yH2Ax and micronuclei formation after genotoxic insult. Intensity-based assays include cellular positivity, here live/dead, and subcellular translocation with transcription factor NFΚB after induction with cytokines Il1b and TNFα. Looking at cytosolic vesicle aggregation, we measured autophagic flux with two distinct modalities, comparative imaging and analysis of live cell dye and immunohistochemistry-based detection yielded consistent EC50 values between methods. Overall, these assays yield consistent, robust results corresponding to literature values, showing the importance of full well coverage and resolution. We demonstrate how assays that formerly took hours can be effectively imaged and analyzed without sacrificing quality in 10-30 minutes. Citation Format: Matthew Boisvert, Josh Kieler, Dan DiSepio, Don Weldon. High content imaging without sacrificing coverage, resolution or speed: Functional validation through multiple assays [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 2069.
Abstract 2381: The bispecific antibody KA-3001, targeting PSMA and CD28, specifically enhances T cell activation within prostate tumors
Authors: Jiabei Liang, Chen Su, Hao Peng, Feng Hao, Tongtong Liu, Jinying Ning, Guojin Wu
Journal: Cancer Research (2024)

Abstract Immunotherapy, which involves blocking PD-1 signaling, has revolutionized the treatment paradigm for advanced solid tumors. However, prostate cancer exhibits a low response ratio to anti-PD-1 therapy. In this study, we have developed a bispecific antibody (BsAb), KA-3001, targeting PSMA and human CD28, aiming to enhance T cell activation in the tumor microenvironment. KA-3001, in a regular IgG1 format, features an identical light chain and was designed using our common light chain bispecific antibody discovery platform with knob-into-hole technology. Mutations in the Fc domain were introduced to eliminate ADCC, ADCP, and CDC activity. KA-3001's two Fabs demonstrate high affinity for PSMA and relatively low affinity for CD28. In comparison to REGN5678, KA-3001 exhibits significantly stronger binding to PSMA-expressing prostate tumor cells, along with relatively lower CD28 activation, minimizing toxicity while maintaining anti-tumor efficacy. In PBMC humanized immunodeficient mouse tumor models, KA-3001 effectively suppresses the growth of 22Rv1 tumors with or without PD-1 antagonist antibody. Furthermore, KA-3001 has a half-life of more than five days in the blood of Balb/c mice. Finally, we assessed the developability of this antibody through various treatments such as high concentration, low pH, repeated freezing and thawing, and high temperature. The BsAb demonstrates neither aggregation nor degradation. In conclusion, the BsAb KA-3001, developed using our common light chain antibody discovery platform, stands out as a promising pre-clinical candidate drug for the treatment of prostate cancer. Citation Format: Jiabei Liang, Chen Su, Hao Peng, Feng Hao, Tongtong Liu, Jinying Ning, Guojin Wu. The bispecific antibody KA-3001, targeting PSMA and CD28, specifically enhances T cell activation 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 2381.
Abstract 3299: Harnessing PIKfyve as a therapeutic vulnerability in neuroendocrine prostate cancer
Authors: Yang Zheng, Kyle Garcia Rogers, Arya Gopal Kamat, Sarah Nicole Yee, Rahul Mannan, Xia Jiang, Rowena Kannaiyan, Xuhong Cao, Yuzhuo Wang, Yuanyuan Qiao, Arul M. Chinnaiyan
Journal: Cancer Research (2024)

Abstract Neuroendocrine prostate cancer (NEPC) represents an aggressive subtype characterized by the independence on androgen receptor (AR) signaling and the acquisition of neuroendocrine features. Despite its rarity among prostate cancer cases, NEPC carries a particularly poor prognosis with limited treatment options. Our prior investigation demonstrated the heightened efficacy of targeting PIKfyve with ESK981 in AR- prostate cancer models, prompting further exploration. In this study, we expanded our investigation to assess the efficacy of ESK981 monotherapy across five NEPC models, encompassing one cell line xenograft and four patient-derived xenografts (PDXs). Our findings revealed consistent tumor inhibition and notable regression in select models. Comparative analysis highlighted the superior effectiveness of ESK981 in NEPC compared to AR+ prostate cancer, as evident through percent tumor growth inhibition (%TGI) assessments. Early evaluations post five days of treatment (PD5) unveiled that PIKfyve inhibition induced apoptotic cell death specifically in NEPC models, confirmed through immunoblotting and TUNEL staining in a time-dependent manner. Intriguingly, PD5 TUNEL positivity correlated with endpoint %TGI, suggesting its potential as a predictor for long-term efficacy. To further delineate the role of PIKfyve in NEPC, we successfully established two novel ex vivo NEPC cell lines from these PDXs, overcoming the constraint of limited publicly accessible NEPC cell lines, and confirmed their NEPC characteristics. Employing a doxycycline-inducible PIKfyve knockdown system in these cells demonstrated significant tumor inhibition in xenograft models, albeit with a lower %TGI compared to ESK981 monotherapy. In conclusion, our results illuminate the preferential cytotoxicity of PIKfyve inhibition in NEPC tumors compared to AR+ prostate cancer, advocating PIKfyve as a compelling therapeutic target. This study provides a strong rationale for advancing ESK981 into clinical trials for NEPC patients, underscoring its potential in addressing this challenging malignancy. Citation Format: Yang Zheng, Kyle Garcia Rogers, Arya Gopal Kamat, Sarah Nicole Yee, Rahul Mannan, Xia Jiang, Rowena Kannaiyan, Xuhong Cao, Yuzhuo Wang, Yuanyuan Qiao, Arul M. Chinnaiyan. Harnessing PIKfyve as a therapeutic vulnerability in neuroendocrine prostate 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 3299.