tbuckley/cabot-search huggingface dataset:
Abstract 5322: Discovery of CRD1601, a potent and selective HPK1 inhibitor with robust <i>in vivo</i> anti-cancer activity
Authors: Monali Banerjee, Ritesh Shrivastava, David Pryde, Sandip Middya, Sabyasachi Debnath, Anindita Middya, Dharmendra Yadav, Nidhi Rawat, Rajib Ghosh, Manisha Padaliya, Sourav Basu, Arjun Surya
Journal: Cancer Research (2024)

Abstract Background: Haematopoietic Progenitor Kinase (HPK-1, MAP4K1) is a member of the STE20 family of serine/threonine kinases, expressed predominantly in hematopoietic cells. HPK-1 functions as a negative regulator of T-cell and B-cell receptor activation by triggering proteasomal degradation and disrupting signalosome complexes downstream of TCR and BCR. HPK1 inhibition is a novel IO strategy that could combine with existing chemotherapies and immunotherapies. Methods: Curadev used a pharmacophore based approach to discover novel small molecule HPK-1 inhibitors using in vitro enzymatic and phenotypic cellular screens using primary cells. CRD1601, the clinical candidate was selected based on its ability to enhance human T-cell proliferation through the induction of IL2 and IFNγ. Syngeneic tumor models were used to assess anti-tumor activity of selected compounds as a monotherapy or combination therapy. Results: CRD1601 is a potent HPK1 inhibitor with a single digit nanomolar IC50 value in enzymatic assay and potent cellular activity in the SLP76 assay. A single dose of CRD1601 in mice treated with an anti-CD3 antibody caused systemic enhancement of pro-inflammatory cytokines such as IL2, IFN gamma and reduced pSLP76 levels in the spleen. Further, CRD1601 reversed the immunosuppressive effect of PGE2 and NECA. CRD1601 demonstrated significant single agent activity in murine tumor models while also synergizing with chemotherapy and immunotherapy. Conclusions: Inhibition of HPK-1 is a promising therapeutic modality that could augment the effects of existing anti-cancer treatments including immunotherapy. CRD1601 is a potent and selective HPK-1 inhibitor with favorable drug like properties that has been selected from a rich portfolio of active compounds and shows promising in vivo activity in tumor models. Citation Format: Monali Banerjee, Ritesh Shrivastava, David Pryde, Sandip Middya, Sabyasachi Debnath, Anindita Middya, Dharmendra Yadav, Nidhi Rawat, Rajib Ghosh, Manisha Padaliya, Sourav Basu, Arjun Surya. Discovery of CRD1601, a potent and selective HPK1 inhibitor with robust in vivo anti-cancer activity [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 5322.
Abstract 6266: Neurotensin receptor 1 regulates dimerization of HER2-HER4 and proliferation of non-small cell lung cancer cells
Authors: Terry W. Moody, Irene Ramos-Alvarez, Robert T. Jensen
Journal: Cancer Research (2024)

Abstract The neurotensin receptor 1 (NTSR1) is a 418 amino acid type A G protein-coupled receptor which causes phosphatidylinositol turnover and proliferation of non-small cell lung cancer (NSCLC) cells (Moody et al., Peptides 2021; 137: 710480). Adding the agonist NTS to NSCLC cells increases transactivation of the receptor tyrosine kinases (RTK) EGFR, HER2 and HER3 (Moody et al., Biology 2023 12: 957). The RTK tyrosine phosphorylation and growth caused by NTS is impaired by SR48692, a small molecule NTSR1 antagonist. The effects of NTS were investigated on HER4 using NSCLC cells. By Western blot, cell lines NCI-H522 and H661 had high levels of NTSR1, HER 4 and neuregulin 1 (NRG1), a ligand for HER4 but not NTSR2, HER3 or NRG2. By RT-PCT, high levels of HER4 and its isoforms JM-a, CYT1 and CYT2 were present in NCI-H522 and H661 cells. Adding NTS (0.1 μM) or NRG1 (0.01 μg/ml) to NCI-H522 or H661 cells increased P-Tyr1284-HER4 and P-ERK 3-fold. Using immunoprecipitation techniques, adding NTS to NSCLC cells increased formation of HER4-HER2 heterodimers which leads to cancer proliferation (Lucas et al., Pharmacol Rev 2022; 74:18). The increase in PY1284-HER4 caused by NTS was impaired by SR48692, HER4 siRNA, NRG1 siRNA or ibrutinib (TKI). The NTSR1 regulation of HER4 transactivation is impaired by GM6001 (MMP inhibitor]), PP2 (Src inhibitor) or N-acetylcysteine (antioxidant). The clonal growth of NSCLC cells is increased by NTS or NRG1 but decreased by SR48692 or ibrutinib. The results indicate that NTS increases the formation of HER2/HER4 heterodimers leading to the proliferation of NSCLC cells. Citation Format: Terry W. Moody, Irene Ramos-Alvarez, Robert T. Jensen. Neurotensin receptor 1 regulates dimerization of HER2-HER4 and proliferation of non-small cell lung cancer 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 6266.
Abstract 4479: Design, synthesis, and evaluation of amino acid conjugated niclosamide prodrugs as a PepT1 substrate
Authors: Alaina C. McDonough, Jeffery Y. Cheng, Shabber Mohammed, Pui-Kai Li, Yangzom Bhutia
Journal: Cancer Research (2024)

Abstract The anthelmintic drug, Niclosamide, has a multitude of promising anticancer properties including inhibition of key signaling pathways involved in tumorigenesis, disruption of mitochondrial function, degradation of the overexpressed androgen receptor, and more. However, a key limitation of the clinical use of Niclosamide in cancer treatment is its low solubility and cellular uptake, which result in poor pharmacokinetic properties and dose-limiting GI toxicities at concentrations lower than the therapeutic threshold of the drug. To overcome this, we hypothesized that we could use amino acid conjugated niclosamide prodrugs to improve cellular uptake by creating a substrate of the PepT1 transport protein. The overexpression of the PepT1 transport protein that is involved in many hormonal cancers is being used to our advantage. Our study involved first synthesizing a group of niclosamide and niclosamide analogs conjugated with polar or nonpolar amino acids. Next, we conducted a Glycine-Sarcosine assay measuring changes in the uptake of the dipeptide glycyl-sarcosine (Gly-Sar). Our initial step was to examine if our conjugates could disrupt the absorption of Gly-Sar. The active conjugate will be tested whether they are substrates or inhibitors of the transporter. For the future, we have plans to determine the half-maximal inhibitory concentration (IC50) of niclosamide conjugates in various cancer cell lines and to quantify cleavage of the prodrugs intracellularly. Citation Format: Alaina C. McDonough, Jeffery Y. Cheng, Shabber Mohammed, Pui-Kai Li, Yangzom Bhutia. Design, synthesis, and evaluation of amino acid conjugated niclosamide prodrugs as a PepT1 substrate [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 4479.
Abstract 3446: Associations of non-steroidal anti-inflammatory drug use and circulating inflammatory proteins with gallbladder dysplasia
Authors: Lorena Rosa, Paz Cook, Ruth M. Pfeiffer, Troy J. Kemp, Allan Hildesheim, Burcin Pehlivanoglu, Volkan Adsay, Enrique Bellolio, Juan Carlos Araya, Ligia Pinto, Catterina Ferreccio, Gloria Aguayo, Eduardo Viñuela, Jill Koshiol
Journal: Cancer Research (2024)

Abstract Background: Most gallbladder cancer (GBC) cases arise from the metaplasia-dysplasia-GBC sequence, and chronic inflammation has been associated with its development. The use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced risk of GBC; however, little is known about these associations with preneoplastic lesions. We thus aimed to study the associations of the use of NSAIDs and inflammatory proteins with gallbladder dysplasia, a precursor to GBC. Methods: Associations of NSAIDs and gallbladder dysplasia were evaluated in 1,925 Chilean cholecystectomy patients, 82 with dysplasia and 1,843 with gallstones but not dysplasia. In addition, we measured 33 circulating inflammatory proteins in a subsample of 68 dysplasia cases diagnosed at the time of sample selection and 136 gallstone controls. Age- and sex-adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated, and associations of inflammatory proteins and gallbladder dysplasia were analyzed. Results: NSAID use was inversely associated with gallbladder dysplasia (OR: 0.48, 95% CI: 0.26-0.83). Comparing the highest versus lowest category of each immune-related protein, eight proteins were inversely associated with dysplasia with ORs ranging from 0.30 (95%CI: 0.12-0.77) for IL-33 to 0.76 (95%CI: 0.59-0.99) for MIP-1B. Of those, GRO remained associated with dysplasia (OR: 0.64, 95%CI: 0.45-0.91) and BCA-1 was borderline-associated (OR: 0.74, 95%CI: 0.54-1.01) in the multivariable logistic regression model additionally adjusted for sex, age and NSAID use. Conclusion: NSAID users were less likely to have gallbladder dysplasia, suggesting that NSAIDs might be beneficial for gallstones patients. Prospective studies are needed to understand the inverse association of immune-related markers and dysplasia, and to evaluate the biological effect of NSAIDs in GBC. Research supported by general funds from the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, and the Office of Research on Women’s Health, National Institutes of Health. Citation Format: Lorena Rosa, Paz Cook, Ruth M. Pfeiffer, Troy J. Kemp, Allan Hildesheim, Burcin Pehlivanoglu, Volkan Adsay, Enrique Bellolio, Juan Carlos Araya, Ligia Pinto, Catterina Ferreccio, Gloria Aguayo, Eduardo Viñuela, Jill Koshiol. Associations of non-steroidal anti-inflammatory drug use and circulating inflammatory proteins with gallbladder dysplasia [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 3446.
Abstract 60: Functional mapping of glioblastoma recurrence reveals targetable dependencies in an axonal guidance pathway in highly invasive brain cancers
Authors: Sheila Kumari Singh, Chirayu Chokshi, Vaseem Shaikh, Benjamin Brakel, Alisha Anand, Chitra Venugopal, Thomas Kislinger, Kevin Henry, Martin Rossotti, Kevin Brown, John Lazo, Jason Moffat
Journal: Cancer Research (2024)

Abstract Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. Here, we explore the functional drivers of post-treatment recurrent GBM. By conducting genome-wide CRISPR-Cas9 screens in patient-derived GBM models, we uncover distinct genetic dependencies in recurrent tumor cells that were absent in their patient-matched primary predecessors, accompanied by increased mutational burden and differential transcript and protein expression. These analyses map a multilayered genetic response to drive tumor recurrence, identifying protein tyrosine phosphatase 4A2 (PTP4A2) as a novel modulator of self-renewal, proliferation and tumorigenicity at GBM recurrence. Genetic perturbation or small molecule inhibition of PTP4A2 represses axon guidance activity through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1), exploiting a functional dependency on ROBO signaling. Importantly, engineered anti-ROBO1 single-domain antibodies also mimic effects of PTP4A2 inhibition. Since a pan-PTP4A inhibitor was limited by poor penetrance across the blood brain barrier (BBB) in vivo, a second-generation chimeric antigen receptor (CAR)-T cell therapy was engineered against ROBO1 that elicits specific and potent anti-tumor responses in vivo. A single dose of anti-ROBO1 CAR-T cells doubles median survival in patient-derived xenograft (PDX) models of recurrent glioblastoma, and also eradicates tumors in around 50% of mice engrafted with PDX models of lung-to-brain metastases and pediatric relapsed medulloblastoma. We conclude that functional reprogramming drives tumorigenicity and dependence on a multi-targetable PTP4A-ROBO1 signaling axis at GBM recurrence, with potential in other malignant brain tumors. Citation Format: Sheila Kumari Singh, Chirayu Chokshi, Vaseem Shaikh, Benjamin Brakel, Alisha Anand, Chitra Venugopal, Thomas Kislinger, Kevin Henry, Martin Rossotti, Kevin Brown, John Lazo, Jason Moffat. Functional mapping of glioblastoma recurrence reveals targetable dependencies in an axonal guidance pathway in highly invasive brain 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 60.
Abstract 3070: CDK12 is a novel therapeutic target in glioblastoma
Authors: Jeong-Yeon Mun, Chang Shu, Qiuqiang Gao, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D. Siegelin
Journal: Cancer Research (2024)

Abstract Glioblastoma (GBM), the most common primary brain tumor in adults carries a highly unfavorable prognosis of only one to two years despite treatment with the standard of care, involving surgery, temozolomide and radiation. Patient-derived xenograft (PDX) GBM cultures were assessed for their susceptibility to loss of CDK12 function, which was either mediated genetically (shRNA) or by the novel inhibitor, SR-4835. GBM metabolism was measured by utilizing extracellular flux analysis as well as LC/MS based carbon tracing analyses. In vivo efficacy was determined by orthotopic GBM models in mice. Based on Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) and shRNA library screens in multiple GBM cell cultures we identified CDK12 as essential for the growth of GBM. Consistently, loss of function of CDK12 (genetically and pharmacologically) led to a reduction of growth of GBM patient-derived xenograft (PDX) lines in vitro. Notably, SR-4835 reduced GBM growth in the low nanomolar range and synergistically enhanced the potency of temozolomide. Extracellular flux analysis and metabolite screening analyses, including carbon tracing (U13C-Glucose, U13C-Glutamine) suggested that loss of function of CDK12 elicited a substantial inhibition of cellular respiration, causing energy deprivation with subsequent cell death with apoptotic features. On the molecular level, loss of function of CDK12 increased ATF4 along with pro-apoptotic Noxa, whereas anti-apoptotic Mcl-1 decreased. In turn, adenoviral mediated ectopic expression of Mcl-1 inhibited cell death mediated by loss of function of CDK12 in GBM cells. In an orthotopic murine PDX model of GBM animals receiving treatment with SR-4835 had a significantly longer overall survival without induction of toxicity as compared to mice treated with vehicle. In summary, these findings suggest that CDK12 is a novel treatment target for GBM and that CDK12 is an important driver of energy metabolism in GBM to partially mediate apoptotic resistance. Moreover, SR-4835 enhanced the potency of temozolomide in GBM models. Therefore, the novel CDK12 inhibitor, SR-4835 should be tested in a clinical trial in patients suffering from GBM. Citation Format: Jeong-Yeon Mun, Chang Shu, Qiuqiang Gao, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D. Siegelin. CDK12 is a novel therapeutic target in 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 3070.
Abstract 1739: Detection of regulatory T cells, a comparison of flow cytometry and epigenetic qPCR immunophenotyping using healthy donor and oncology patient whole blood
Authors: Udo Baron, Laura Lozza, Angelina Bisconte, Eva Raschke, Deborah Phippard, Sven Olek
Journal: Cancer Research (2024)

Abstract Human regulatory T cells (Tregs) are part of the adaptive immune response and play a pivotal role in suppressing both the immune and anti-tumor responses. Infiltration of Tregs into the tumor microenvironment has been associated with poor clinical prognosis. In addition, increased peripheral Treg frequency is associated with disease progression. Monitoring Tregs in both the blood and in the tumor of patients is being used to evaluate clinical prognosis and response to treatment in immuno-oncology studies. The key challenge is the ability to detect Tregs with high accuracy and precision. Here, we have used epigenetic qPCR (Epiontis ID®) as a method to detect and quantify Tregs in peripheral whole blood and compared it with flow cytometry. Flow cytometry is the current gold standard for immunophenotyping. For method comparison, we analyzed 113 whole blood samples from healthy donors. We have demonstrated equivalence and shown a strong correlation between epigenetic qPCR and flow cytometry-based data, indicating that Epiontis ID® is a robust and sensitive DNA-based method for Treg quantification. This epigenetic qPCR method does not require fresh samples or intact cells, since DNA can be extracted from frozen blood. We then evaluated Treg levels in blood samples from solid tumor cancer patients by epigenetic qPCR to demonstrate the clinical application and relevance for immune monitoring. Here, Treg frequencies were reported as relative (%) and absolute counts (cells/µL) values. Epigenetic qPCR for immune monitoring mitigates the operational and technical challenges of monitoring Tregs in the periphery for immuno-oncology studies which traditionally been performed by flow cytometry. This Epiontis ID® method provides the sensitivity and accuracy needed for determining patient response in progressive disease. Citation Format: Udo Baron, Laura Lozza, Angelina Bisconte, Eva Raschke, Deborah Phippard, Sven Olek. Detection of regulatory T cells, a comparison of flow cytometry and epigenetic qPCR immunophenotyping using healthy donor and oncology patient whole blood [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 1739.
Abstract 5955: <i>In vivo</i> precision therapy for glioblastoma using a nanodrug targeting microRNA-10b
Authors: Bryan Doyun Kim, Elizabeth Kenyon, Ming Chen, Sujan Mondal, Ana de Carvalho, Anna Moore
Journal: Cancer Research (2024)

Abstract Glioblastoma multiforme (GBM) is the most common and aggressive primary brain malignancy, which accounts for about half of all brain tumors. Notably, GBM has been shown to express high levels of microRNA-10b (miR-10b) compared to normal brain tissue, which expresses virtually no miR-10b. Importantly, the mounting body of evidence suggests that suppressing miR-10b in glioblastoma cells disrupts various pathways involved in tumor formation, ultimately leading to the suppression of tumor growth and an increase in apoptosis. We have recently reported that our experimental nanodrug targeting miR-10b (MN-anti-miR10b) effectively suppresses miR-10b expression, inhibits tumor cell migration and invasion, and decreases GBM cell viability in vitro. MN-anti-miR10b consists of an iron oxide core with cross-linked dextran, which acts as the delivery vehicle, and is further conjugated with Cy5.5 fluorophores and therapeutic anti-miR-10b locked-nucleic acid antagomirs. The iron oxide core provides MR imaging contrast while Cy5.5 enables optical imaging modalities in vivo. In this study, U251, human GBM cells, were orthotopically implanted in nude, athymic mice and injected via tail vein with PBS, scrambled antagomir vehicle control (MN-Scr), or MN-anti-miR10b (10 and 20 mg Fe/kg), beginning on day 7 post-implantation. Mice were injected with respective treatments once a week for 6 weeks before assessing changes in survival and expression of miR-10b. In one trial, we assessed the differences in survival between treatment groups after completion of the injection regimen and found that MN-anti-miR10b can increase survival compared to control groups. In another trial, mice were euthanized one week after the last injection and GBM tissues were assessed for miR-10b expression by qRT-PCR. RNA samples extracted from this trial have been submitted for RNA sequencing and differential gene expression analysis will be performed. Here, we demonstrated in vivo that MN-anti-miR10b can efficiently decrease miR-10b expression (57%) and increase median survival (MN-anti-miR10b: 54.5 days vs MN-Scr: 44 days vs PBS: 44 days) compared to PBS and MN-Scr treatment groups. These studies suggest the use of MN-anti-miR10b can be effective in the treatment of GBM in vivo. Citation Format: Bryan Doyun Kim, Elizabeth Kenyon, Ming Chen, Sujan Mondal, Ana de Carvalho, Anna Moore. In vivo precision therapy for glioblastoma using a nanodrug targeting microRNA-10b [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 5955.
Abstract 7591: Tumor Treating Fields (TTFields) show efficacy in Triple-Negative breast cancer (TNBC) cells alone and in combination with PARP inhibitor Talazoparib
Authors: Maryam Ghandali, Praveen Srinivasan, Yutong Xia, Eric T. Wong, Robert W. Sobol, Lanlan zhou, Benedito A. Carneiro, Stephanie L. Graff, Wafik S. El-Deiry
Journal: Cancer Research (2024)

Abstract Breast cancer is the most common cancer in women worldwide, and the fifth leading cause of cancer-related deaths globally. Triple-negative breast cancer (TNBC), the most aggressive form of breast cancer, is usually treated with surgery, chemotherapy, and radiation. Tumor Treating Fields therapy are FDA-approved for the treatment of glioblastoma (GBM) and malignant pleural mesothelioma (MPM).TT Fields use alternating electric fields to inhibit tumor growth through mitotic disruption, cellular damage, integrated stress response activation, and immune mechanisms and inhibit cell proliferation, induce cell death, and cause cell cycle arrest.TT Fields can induce BRCAness and when combined with PARP inhibition, this combination may result in synthetic lethality. We explored the effect of TTFields on two TNBC cell lines MDA-MB436 (BRCA1-mutant, p53-null) and MDA-MB468 (BRCA1 wild-type, p53-mutant) treated with TTFields (150 kHz) for 24 hours. Western blot analysis showed elevation of p21 independent of p53 mutational status. We examined the combination of PARP inhibitor (Talazoparib) with TTFields in MDA-MB468 cells to determine the effect of the combination in BRCA wild-type cancer cells. Western blot analysis showed p21 upregulation after 24 hours in combination without an increase in p53. p21 acts as a G1-checkpoint protein and loss of p21 expression has been observed in a high percentage of human breast cancer cells. Our results suggest a rational and potentially effective therapy that could be further developed and used for the treatment of breast cancer. Our ongoing studies are exploring potential mechanisms of synergy between PARP inhibitor Talazoparib and TTFields using various TNBC models, and the effect of the combination on cell cycle arrest in cell culture and in vivo. Citation Format: Maryam Ghandali, Praveen Srinivasan, Yutong Xia, Eric T. Wong, Robert W. Sobol, Lanlan zhou, Benedito A. Carneiro, Stephanie L. Graff, Wafik S. El-Deiry. Tumor Treating Fields (TTFields) show efficacy in Triple-Negative breast cancer (TNBC) cells alone and in combination with PARP inhibitor Talazoparib [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 7591.