tbuckley/cabot-search huggingface dataset:
Abstract 3000: Evaluating the efficacy of a novel class of covalent microtubule stabilizers in taxane resistant ovarian cancer
Authors: Samantha S.M. Yee, Lin Du, April L. Risinger
Journal: Cancer Research (2020)

Abstract Ovarian cancer has few targeted therapies and high rates of metastasis. Taxane microtubule stabilizers, including paclitaxel, are a mainstay in the treatment of adult solid tumors as single agents and in combination with other cytotoxic chemotherapies, targeted therapies, and immunotherapies. The standard of care for ovarian cancer patients comprises of combination chemotherapy consisting of a taxane with a platinum agent administered intravenously or intraperitoneally. Although this approach is highly effective initially, up to 70% of ovarian cancer patients will acquire taxane resistance. Therefore, it is essential to identify drugs that retain efficacy in clinically relevant models of taxane resistance, including those with elevated P-glycoprotein (Pgp) expression. The development of a microtubule stabilizer that retains efficacy in taxane resistant ovarian cancer would be optimal since microtubule disruption is proven to be an effective target in this disease. The taccalonolides are a novel class of covalent and irreversible microtubule stabilizers that circumvent clinically relevant forms of taxane resistance in vitro and in vivo breast cancer models. However, the taccalonolides have a narrow therapeutic window and short serum half-life that would benefit from a more targeted delivery. We hypothesized that localized intraperitoneal delivery of the taccalonolides in ovarian cancer models may be an optimal strategy for the treatment of intraperitoneally disseminated disease. We have found that the taccalonolides are less susceptible than paclitaxel to Pgp-mediated drug resistance in a human ovarian cancer cell line model. Additional experiments have demonstrated that the taccalonolides retain long-term antiproliferative and cytotoxic efficacy following acute treatment of human and murine ovarian cancer cells, demonstrating superior cellular persistence as compared to other classes of microtubule stabilizing drugs. We are currently evaluating the efficacy of the taccalonolides in ovarian cancer models using localized, intraperitoneal administration in a syngeneic and orthotopic murine model, which may be optimal for delivery of this irreversible microtubule stabilizer. Citation Format: Samantha S.M. Yee, Lin Du, April L. Risinger. Evaluating the efficacy of a novel class of covalent microtubule stabilizers in taxane resistant ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3000.
Abstract 6575: A novel AI-driven spatial genomics platform enables tumor enrichment and analysis of heterogeneity
Authors: Bidhan Chaudhuri, Katie Konigsfeld, Marisa Sanchez, Jason Smith, Casey Laris, Claire Weston, John Butler
Journal: Cancer Research (2020)

Abstract Spatial genomics and digital pathology continue to advance at a rapid pace, generating large amounts of data. There is a critical unmet need for advanced tools to expedite spatial data generation, visualization, and analysis, to facilitate an improved understanding of health and disease, especially with the advancement of personalized cancer treatments. In this study we present a novel method for the extraction and analysis of genomic information from specific regions of interest (ROI) within a series of formalin-fixed paraffin embedded (FFPE) breast cancer adenocarcinoma tissue sections. An artificial intelligence-based tumor profiling algorithm first identified tumor, stroma, inflammatory, and necrotic regions within the tissue, and segmentation results were confirmed by a Board Certified Pathologist. Automated lysate extraction was then performed in the selected ROIs using ink-jet technology and novel ink chemistry. The process was performed directly on the tissue slide and the crude lysates generated were transferred to a standard collection tube for subsequent sequencing. DNA was extracted from the selected areas before being purified and analyzed using a multi-cancer panel. Library QC showed optimal coverage at an average of &amp;gt;95% uniformity. Sequencing results showed an average coverage of 95% at 250x across all amplicons of the panel. Variant calling was successfully performed. Sequencing data is presented to demonstrate the high coverage achieved using this workflow as well as the resulting tumor heterogeneity. This novel technology provides an efficient solution for the enrichment of tumor content with high sequencing coverage from FFPE tissue sections. Novel spatial data visualization and analysis techniques allowed a comprehensive assessment of tumor heterogeneity. Further studies on both DNA and RNA should be conducted to validate this approach for clinical molecular testing. Citation Format: Bidhan Chaudhuri, Katie Konigsfeld, Marisa Sanchez, Jason Smith, Casey Laris, Claire Weston, John Butler. A novel AI-driven spatial genomics platform enables tumor enrichment and analysis of heterogeneity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6575.
Abstract 2881: Injectable thermoresponsive hydrogel for the sustained delivery of triptolide in breast cancer treatment
Authors: Jingjing Li, Jinming Zhang, George Pak-Heng Leung
Journal: Cancer Research (2020)

Abstract To avoid the narrow therapeutic window and take advantage of the anticancer efficacy of triptolide (TP), a major active component of Tripterygium wilfordii Hook.F., a novel thermo-responsive nano-micelle hydrogel was fabricated in present study for the sustained release of TP in breast tumor tissue. Briefly, the amphiphilic poloxamer 188-g-poly (N-isopropylacrylamide-co-acrylic acid) copolymer was synthesized by atomic transfer radical polymerization reaction and self-assembled into micelles in aqueous solution with CMC value of 2.6×10-3 mg/mL. TP encapsulated nanogel (TP/F68-g-(PNIPAAm-co-AAC)) exhibited the sol-gel phase transition at 32°C with a narrow size distribution (about 50.16 nm) and sustained drug release in vitro. And then, the TP-loaded nanogel significantly inhibited the cell proliferation against human breast cancer MDA-MB-231 and MCF-7 cells, as well as the induction of cell apoptosis and cell cycle arrest activity. Moreover, we also found the superior anti-angiogenic activities of TP nanogel in both HUVEC and rat aortic ring model when compared to free TP. As expected, mediated by the 4T1 mouse breast cancer model, we demonstrated that a single injection of the TP-loaded nanogel system resulted in the long detention time in tumor tissue due to its thermo-responsive capacity. Moreover, the novel nanogel remarkably enhanced anticancer efficacy and reduced the side effects, when compared with the multiple injections of free TP. Therefore, the injectable thermo-responsive nanogel provided a potential strategy for the efficient delivery of TP with a sustained release manner in breast cancer treatment. Citation Format: Jingjing Li, Jinming Zhang, George Pak-Heng Leung. Injectable thermoresponsive hydrogel for the sustained delivery of triptolide in breast cancer treatment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2881.
Abstract 669: Combined inhibition of AKT &amp; TBK1 for the treatment of breast cancer
Authors: Hasem Habelhah, Laiqun Zhnag
Journal: Cancer Research (2020)

Abstract Breast cancer (BC) is the most frequently diagnosed malignancy and the second leading cause of cancer mortality in Western women. In ~80% of BC cases, the PI3K-AKT pathway is aberrantly activated, due to the alterations in genes encoding the pathway components, such as Ras, Her2, PTEN, PIK3C and AKT. This pathway regulates multiple cellular processes to promote BC development, growth, metastasis, and drug resistance. Consequently, over 100 clinical trials are currently underway worldwide to evaluate the therapeutic efficacy of PI3K and AKT inhibitors in BC; however, initial data reported so far revealed that inhibition of this pathway is either not effective or often results in development of resistance and relapse of the disease. Thus, identification of additional targets and therapeutic combinations are urgently needed. We previously mapped TRAF2 phosphorylation sites (Ser-11 and Ser-55), identified PKC and TBK1 are the relevant kinases, and reported that TRAF2 phosphorylation enhances NF-κB activation to promote cancer cell survival under conditions of cellular stresses. Recently, we discovered that inhibition of AKT leads to increased phosphorylation of TRAF2 at Ser-11 by TBK1 in 4 out of 6 commonly used BC cell lines. TBK1 (aka T2K for TRAF2-associated kinase) and its close homologue IKKϵ are serine/threonine kinases overexpressed in ~70% of BC and play critical roles in BC cell survival. Interestingly, all 4 BC cell lines that exhibited enhanced TRAF2 phosphorylation were completely resistant to AKT inhibition-induced apoptosis in vitro, and combined inhibition of both AKT and TBK1/IKKϵ synergistically induced apoptosis in these BC lines. Importantly, combined inhibition of AKT and TBK1/IKKϵ also significantly suppresses xenograft BC tumor growth in vivo. Mechanistically, AKT did not directly inhibit TBK1, IKKϵ or TRAF2; it seems that an unknown kinase suppressed by AKT in cancer cells in normal culture conditions enhances TBK1-mediated TRAF2 Ser-11 phosphorylation in BC cells upon AKT inhibition. Nevertheless, our data suggest that inhibition of the PI3K-AKT pathway derepresses the pro-survival TBK1-TRAF2 pathway, which in turn confers resistance to PI3K-AKT inhibition in BC, and that combined inhibition of AKT and TBK1 effectively suppresses BC tumor growth. These findings also provide strong rationales for PDX and clinical investigation of combined AKT and TBK1 inhibition for the treatment of human BCs. Citation Format: Hasem Habelhah, Laiqun Zhnag. Combined inhibition of AKT &amp; TBK1 for the treatment of breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 669.
Abstract 4228: PLAP (placental alkaline phosphatase)-CAR-T cells specifically target colorectal cancer
Authors: Vita M. Golubovskaya, Robert Berahovich, Hua Zhou, Xianghong Liu, Feng Li, Shirley Xu, Yuehua Wei, Djamila Ouaret, Walter Bodmer, Lijun Wu
Journal: Cancer Research (2020)

Abstract Placental alkaline phosphatase, PLAP encoded by ALPP gene in humans is mainly expressed in placenta and testis, and not expressed in any other normal tissues. PLAP is overexpressed in a proportion of colorectal cancers which makes it an attractive target for CAR (chimeric antigen receptor)-T cell therapy. PLAP mRNA expression was detected in 21.4% (25 out of 117) of colorectal cancer cell lines and this expression was confirmed by FACS at the protein level. In addition, IHC staining on primary colorectal cancer tumors demonstrated PLAP expression in &amp;gt;20% of colorectal cancer tumors. We generated mouse and humanized PLAP ScFv-CAR-T cells and demonstrated high specificity against PLAP-positive colon cancer cells using RTCA (real-time cytotoxicity assay) and IFN-gamma secretion. In addition, humanized-CAR-T cells significantly decreased Lovo xenograft tumor growth in vivo. The combination of hPLAP-CAR-T cells with PD-1, PDL-1 or LAG-3 checkpoint inhibitors significantly increased the activity of hPLAP-CAR-T cells. Significance: This study demonstrates ability of novel PLAP-CAR-T cells to kill colorectal cancers and that the extent of killing can be increased by combination with checkpoint inhibitors. These preclinical results suggest that PLAP-CAR-T cells combined with checkpoint inhibitors may be developed into an effective clinical therapy for PLAP expressing colorectal and other cancers. Citation Format: Vita M. Golubovskaya, Robert Berahovich, Hua Zhou, Xianghong Liu, Feng Li, Shirley Xu, Yuehua Wei, Djamila Ouaret, Walter Bodmer, Lijun Wu. PLAP (placental alkaline phosphatase)-CAR-T cells specifically target colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4228.
Abstract 1407: MicroRNA-18a targeting inhibits the tumor growth of cisplatin-resistant ovarian cancer
Authors: Blanca Iris Quiñones-Díaz, Jeyshka M. Reyes-González, Fatma Valiyeva, Pablo E. Vivas-Mejía
Journal: Cancer Research (2020)

Abstract Platinum-based therapy remains as the front-line treatment for ovarian cancer. However, despite initial response to treatment, most patients develop platinum resistance and eventually succumb to the malignancy. In an attempt to identify novel targets in cisplatin-resistant ovarian cancer, we studied the role of the microRNA-18a-5p (miR-18a) in cisplatin-resistant ovarian cancer. miR-18a is part of the vastly researched miR-17-92 cluster. Although most members of this cluster have been associated with pro-tumorigenic roles in several cancers, recent findings suggest that miR-18a plays a tumor-suppressive role in ovarian cancer. However, the specific role of miR-18a in platinum resistance has yet to be elucidated. In this study, Real-Time PCR analysis was performed to measure the levels of miR-18a in several ovarian cancer cell lines. We found miR-18a downregulation in cisplatin-resistant ovarian cancer cells relative to their sensitive counterparts. Therefore, we assessed the effect of miR-18a upregulation by oligonucleotide microRNA mimics (OMM) in tumor growth using a xenograft mouse model of cisplatin-resistant ovarian cancer. As ovarian tumors have been shown to overexpress the Folate Receptor α (FRα), we used nanoliposomes conjugated to folic acid as vehicles to deliver the OMMs. Following intraperitoneal injections of OMM-loaded liposomes (twice per week for three weeks), there was a significant decrease in tumor weight of miR-18a-OMM treated mice in comparison to the control-OMM group. Moreover, immunohistochemical analysis was performed on the mice tumor tissues to assess the levels of cell proliferation and angiogenesis markers (ki67 and CD31, respectively). Our study suggests that miR-18a halts cisplatin-resistant ovarian cancer tumor progression. This work was supported by the RCMI grant: U54 MD007600, UPR Comprehensive Cancer Center and NIGMS-RISE R25-GM061838. Citation Format: Blanca Iris Quiñones-Díaz, Jeyshka M. Reyes-González, Fatma Valiyeva, Pablo E. Vivas-Mejía. MicroRNA-18a targeting inhibits the tumor growth of cisplatin-resistant ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1407.
Abstract 653: Enhancing therapies for MYC-overexpressing Non-Hodgkin's lymphoma: A role for MYC downregulation and new combination therapies
Authors: Alexandra Maria Psaras, Tracy Ann Brooks
Journal: Cancer Research (2020)

Abstract Background: Non-Hodgkin's Lymphoma (NHL) is the fifth most common cancer in the United States. Up to 40% of NHL is diffuse large B-cell lymphoma (DLBCL); while only 3% of NHL is classified as mantle cell lymphoma, it is a particularly lethal disease. DLBCL and MCL patients that aberrantly express MYC, which occurs up to 20 and 50% of the time, respectively, have worse survival rates and a lack of sustained clinical response to the standard R-CHOP therapy. We sought to examine both the effect of MYC downregulation on the efficacy of standard of care drugs and enhanced anti-cancer activity with a novel NF-kB targeting steroid, in place of prednisone/prednisolone, and also under conditions of MYC modulation, in NHL cells. Methods and Summary of Findings: The downregulation of MYC was achieved in two distinct manners: with siRNA and with our pioneered MYC G-quadruplex (G4)-stabilizing DNA interference (DNAi) oligonucleotide. This DNAi was optimized for stability, specificity, and in cell activity, from our previously work developing this approach (Hao, et al, NAR 2016). The optimization was done using EMSA, chemical (DMS) footprinting, cell viability assays, qPCR, and microscopy. The lead steroid compound, which is selective for NF-κB signaling inhibition over DNA binding and transcription effects, was more cytotoxic than prednisolone, as determined by cell viability assays in NHL cells. Moreover, its effects on cell growth were additive with doxorubicin, and the overall effect of both drugs on cytotoxicity were enhanced by MYC downregulation. The combination studies were also performed with prednisolone; effects on decreased cell viability were more notable with the novel steroid, as compared to prednisolone. Conclusion: MYC-overexpressing NHL, particularly DLBCL and MCL, respond poorly to the standard R-CHOP therapy. The addition of a MYC-downregulating DNAi, a novel NF-kB targeting steroid, or both, have been noted to enhance the cytotoxic effects of standard drugs. Work is expanding to evaluate the utility of an updated R-CHOP regimen in order to enhance survival for patients with MYC-overexpressing NHL. Citation Format: Alexandra Maria Psaras, Tracy Ann Brooks. Enhancing therapies for MYC-overexpressing Non-Hodgkin's lymphoma: A role for MYC downregulation and new combination therapies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 653.
Abstract 2927: Targeted combination treatment for B-cell acute lymphoblastic leukemia
Authors: Shriya Kane, Yali Ding, Chandrika Gowda, Jonathon Lee Payne, Soumya Iyer, Pavan K. Dhanyamraju, Chunhua Song, Dhimant Desai, Arati Sharma, Kimberly J. Payne, Sinisa Dovat
Journal: Cancer Research (2020)

Abstract The CCND3 gene encodes Cyclin D3–a protein that is essential for G1/S cell cycle progression and proliferation of malignant cells. Targeting Cyclin D3 is used to treat B-cell acute lymphoblastic leukemia (B-ALL); however, the mechanisms that regulate expression of the CCND3 gene in B-ALL are largely unknown. Here, we present evidence that oncogenic Casein Kinase II (CK2) regulates expression of CCND3 and G1/S cell cycle progression via direct phosphorylation of Ikaros, a transcription regulator and tumor suppressor protein. Global genome-wide DNA-binding analysis using ChIP-seq, show that Ikaros binds the promoter of CCND3 in primary human B-ALL. The role of Ikaros in regulating CCND3 expression in B-ALL was tested using gain-of-function and loss-of-function experiments. Ikaros knock-down with shRNA results in increased transcription of CCND3 in B-ALL. Overexpression of Ikaros in human B-ALL was associated with reduced expression of CCND3. Since Ikaros activity in leukemia is regulated by pro-oncogenic Casein Kinase II (CK2), we tested whether CK2 regulates expression of CCND3 in B-ALL. Increased expression of CK2 in B-ALL results in increased expression of the CCND3 gene. This was associated with a loss of Ikaros binding to the promoter of the CCND3 gene. Inhibition of CK2 with shRNA, and/or a specific CK2 inhibitor, CX-4945, resulted in increased Ikaros binding to the CCND3 promoter and reduced expression of Cyclin D3 in B-ALL. Treatment with CX-4945 showed strong therapeutic activity in preclinical models of B-ALL. A combination treatment with CX-4945 and dexamethasone that targets G1/S cell cycle progression shows a strong synergistic effect on B-ALL cells. In conclusion, presented data show that CK2 and Ikaros regulate G1/S cell cycle progression via transcriptional regulation of the CCND3 gene in B-ALL and that CK2 inhibition represses CCND3 expression by enhancing Ikaros tumor suppressor function. Results demonstrate the synergistic efficacy of a combination treatment with CK2 inhibitor and dexamethasone and provide a rationale for the use of this combination treatment as a novel therapeutic approach for B-cell acute lymphoblastic leukemia. Citation Format: Shriya Kane, Yali Ding, Chandrika Gowda, Jonathon Lee Payne, Soumya Iyer, Pavan K. Dhanyamraju, Chunhua Song, Dhimant Desai, Arati Sharma, Kimberly J. Payne, Sinisa Dovat. Targeted combination treatment for B-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2927.
Safety and Clinical Activity of MEDI1873, a Novel GITR Agonist, in Advanced Solid Tumors
Authors: Ani S. Balmanoukian, Jeffrey R. Infante, Raid Aljumaily, Aung Naing, Ashish V. Chintakuntlawar, Naiyer A. Rizvi, Helen J. Ross, Michael Gordon, Philip R. Mallinder, Nairouz Elgeioushi, Ignacio González-García, Nathan Standifer, Jennifer Cann, Nicholas Durham, Shahram Rahimian, Rakesh Kumar, Crystal S. Denlinger
Journal: Clinical Cancer Research (2020)

Abstract Purpose: The safety and preliminary efficacy of MEDI1873, an agonistic IgG1 fusion protein targeting glucocorticoid-induced TNF receptor–related protein (GITR), were evaluated in an open-label, first-in-human, phase I, dose escalation study in previously treated patients with advanced solid tumors. Patients and Methods: Two single-patient cohorts at 1.5 and 3 mg i.v. were followed by 3+3 dose escalation in six cohorts at 7.5, 25, 75, 250, 500, and 750 mg, all every 2 weeks, for up to 52 weeks. Primary endpoints were safety and tolerability, dose-limiting toxicities (DLT), and MTD. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics. Results: Forty patients received MEDI1873. Three experienced DLTs: grade 3 worsening tumor pain (250 mg); grade 3 nausea, vomiting, and headache (500 mg); and grade 3 non-ST segment elevation myocardial infarction (750 mg). An MTD was not reached and treatment was well tolerated up to 500 mg. Most common treatment-related adverse events were headache (25%), infusion-related reaction (17.5%), and decreased appetite (17.5%). MEDI1873 exposure was dose proportional. Antidrug–antibody incidence was low. MEDI1873 increased peripheral CD4+ effector memory T-cell proliferation as well as cytokines associated with effector T-cell activation at dose levels ≥75 mg. The best response was stable disease (SD) in 17 patients (42.5%), including 1 unconfirmed partial response. Eight patients (20.0%) had SD ≥24 weeks. Conclusions: MEDI1873 showed acceptable safety up to 500 mg i.v. every 2 weeks with pharmacodynamics activity, and prolonged SD in some patients. However, further development is not planned because of lack of demonstrated tumor response.