tbuckley/cabot-search huggingface dataset:
Abstract LB063: Anti-tumor activity in preclinical models utilizing a conditional bispecific redirected activation molecule (COBRA) targeting Her2
Authors: Bradley Stringer, Johara Chouitar, Jacqualine Cerbone, Sarah Fortin, Alina Ainbinder, Cassie Kysilovsky, Brittany Scott, Antara Banerjee
Journal: Cancer Research (2024)

Abstract Among strategies to recruit cytotoxic T-cells into the tumor micro-environment (TME) are the use of T-cell engager molecules. One such therapeutic modality are molecules that recognize specific tumor associated antigens (TAA) but are activated preferentially in the TME. Conditional Bispecific Redirected Activation molecules (COBRA) are designed to be administered as a prodrug, and cleaved via matrix metalloproteinase to engage with both a tumor TAA and CD3 (Panachi, et.al. MAbs 2020 12(1) 1792130). In this study, we sought to determine the preclinical efficacy of a COBRA molecule targeting the Her2 receptor. Sub-cutaneous xenograft models (SCID mice using adoptive T-cell transfer) were utilized representing various levels of the TAA (HT-55, SNU-16, JIMT-1, and HCC827) to measure both efficacy and mechanism of action (T-cell extravasation). The COBRA molecule was dosed at 0.03, 0.1, 0.3, and 1 mg/kg using a Q3dx7 schedule. A non-cleavable COBRA molecule with the Her2 TAA was included as a control at 1 mg/kg. Efficacy was determined by caliper measurements of sub-cutaneous tumor size twice per week after dosing, and T-cell extravasation into the TME was measured by immunohistochemistry (IHC) at days 10, 19, and termination. IHC data was quantified using HALO imaging software. In our study, we measured dose-dependent tumor regression and/or stasis in all models tested. No anti-tumor activity was measured after dosing with the non-cleavable COBRA molecule. T-cell extravasation as measured by IHC and Halo analysis followed a dose and time dependent course. Comparison of Day 19 T-cell extravasation (one day after the last dose) showed a linear relationship to TAA expression. Our data indicate that treatment with a COBRA molecule in preclinical models with a Her2 TAA results in anti-tumor activity as measured by tumor stasis/regression, and exhibit the expected mechanism of action as evaluated by T-cell extravasation into the TME. Citation Format: Bradley Stringer, Johara Chouitar, Jacqualine Cerbone, Sarah Fortin, Alina Ainbinder, Cassie Kysilovsky, Brittany Scott, Antara Banerjee. Anti-tumor activity in preclinical models utilizing a conditional bispecific redirected activation molecule (COBRA) targeting Her2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB063.
Abstract LB044: Selective therapeutic antibodies against oncogenic mutations of the HER2 extracellular region
Authors: Injin Bang, Takamitsu Hattori, Nadia Leloup, Alexis Corrado, Atekana Nyamaa, Akiko Koide, Ken Geles, Elizabeth Buck, Shohei Koide
Journal: Cancer Research (2024)

Abstract Oncogenic mutations of HER2 have been identified in HER2-low tumors. Such mutations in the extracellular region could serve as tumor-specific antigens that are accessible to antibody therapeutics. Although multiple antibody therapeutics have been successfully developed against cancers that overexpress wild-type HER2, none is specifically applicable to treating tumors driven by HER2 mutants expressed at a low level. Here, we developed antibodies exquisitely selective to HER2 S310F and S310Y, two most common oncogenic mutations in the HER2 extracellular region. Cryo-EM structures of the homodimer of HER2 S310F and an antibody bound to HER2 S310F revealed that these antibodies recognize the mutations in a manner that mimic the dimerization arm of HER and inhibit HER2 dimerization. These antibodies as T-cell engagers selectively killed a HER2 S310F-driven cancer cell line in vitro and in a mouse xenograft model. These results validate HER2 extracellular region mutations as actionable therapeutic targets and offer promising candidates toward clinical development. More generally, they suggest that point mutations in the extracellular region of cell-surface receptors as actionable targets for anti-cancer therapy. Citation Format: Injin Bang, Takamitsu Hattori, Nadia Leloup, Alexis Corrado, Atekana Nyamaa, Akiko Koide, Ken Geles, Elizabeth Buck, Shohei Koide. Selective therapeutic antibodies against oncogenic mutations of the HER2 extracellular region [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB044.
Abstract CT214: Paricalcitol addition to chemotherapy in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (PINBALL)
Authors: David Propper, Gayle Jameson, Denise Roe, Betsy Wertheim, Dan Von Hoff, Erkut H. Borazanci
Journal: Cancer Research (2024)

Abstract Background Vitamin D agonism has been shown in preclinical studies to decrease the production of collagen, decrease myeloid derived suppressor cells, and decrease regulatory T cells in pancreatic ductal adenocarcinoma (PDAC). Paricalcitol is a vitamin D analog used for vitamin D replacement for those with secondary hyperparathyroidism. Two individuals with PDAC who had been developed resistance gemcitabine based combination therapy had shown clinical benefit with the addition of paricalcitol. This clinical study was done to study the effect of adding paricalcitol to individuals with metastatic PDAC receiving gemcitabine based combination therapy (NCT04054362, NCT03415854) . Methods Adults with a histologically- or cytologically-confirmed diagnosis of metastatic PDAC and who were previously untreated were eligible. Individuals received gemcitabine based combination- either gemcitabine plus nab-paclitaxel or gemcitabine plus nab-paclitaxel and cisplatin and had to either demonstrate progressive or stable disease. Paricalcitol was given at a fixed dose of 25 mcg IV three days a week. The combination continued until either disease progression or poor tolerance. The primary objective was to determine the clinical benefit of adding paricalcitol to gemcitabine based combination therapy for metastatic PDAC. Secondary objectives included assessing safety and pharmacodynamic through patient biopsies. Results A total of 34 patients were enrolled across two sites. 16 patients received paricalcitol. The overall response rate was 0% ( CR, PR). Disease control rate at 9 weeks was 21.4% (CR+PR+ SD). PFS upon addition of paricalcitol was 1.6 months. OS upon addition of paricalcitol was 4.8 months. Grade 3/4 AE's attributed to paricalcitol include 13% thrombocytopenia; 19% anemia; 6% transaminitis; 6% pleural effusion; 6% ascites- all grade 3. Conclusions The addition of paricalcitol demonstrated evidence of limited clinical benefit in individuals with metastatic PDAC receiving front-line gemcitabine based therapy. Paricalcitol was generally well tolerated. Tumor analysis is ongoing. Addition studies utilizing prospective treatment of paricalcitol for front line treatment of mPDAC are ongoing (NCT03520790). Trial funding provided by SU2C, CRUK, Lustgarten Foundation, and AACR. Citation Format: David Propper, Gayle Jameson, Denise Roe, Betsy Wertheim, Dan Von Hoff, Erkut H. Borazanci. Paricalcitol addition to chemotherapy in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (PINBALL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT214.
Abstract LB429: Discovery and identification of a novel cancer associated fibroblast target using Oxford Biotherapeutics (OBTs) OGAP discovery platform
Authors: Jeremy Sarnecky, Joseph Lewis, Jason Allen, Daniel Davies, Matthew Metzger, Ben Thomas, Christian Rohlff, Belinda Cairns
Journal: Cancer Research (2024)

Abstract Cancer Associated Fibroblasts (CAFs) are a major component of the tumor stromal microenvironment and have been indicated in promoting tumor growth as well as inhibiting tumor suppression mechanisms. One of the challenges in this field has been a lack of molecules that target CAFs specifically and can interfere with the CAF function. Here we describe a novel target discovered using OBTs proprietary OGAP platform, that appears to be specific for CAFs in a variety of tumor tissues. Interestingly this target appears to be minimally expressed in normal tissue fibroblasts by in situ hybridization RNA analysis but is highly upregulated in solid tissue stroma fibroblasts of colon, breast and pancreatic cancer tissues. The OGAP Discovery Platform utilizes a mass spectrometry approach to identify membrane targets on the surface of tumor cells as well as tumor microenvironment associated cells. This suggests that this novel target is expressed on the membrane of the CAFs making it a unique target for drug intervention. The identification of such a novel target is both exciting and a wonderful validation of OBTs OGAP Discovery Platform. Citation Format: Jeremy Sarnecky, Joseph Lewis, Jason Allen, Daniel Davies, Matthew Metzger, Ben Thomas, Christian Rohlff, Belinda Cairns. Discovery and identification of a novel cancer associated fibroblast target using Oxford Biotherapeutics (OBTs) OGAP discovery platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB429.
Abstract NG06: Tracing the developmental origins of group 3 medulloblastoma
Authors: Olivier Saulnier
Journal: Cancer Research (2024)

Abstract Citation Format: Olivier Saulnier. Tracing the developmental origins of group 3 medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr NG06.
Abstract LB021: BAU-243: A novel BCL-2 inhibitor inducing autophagic cell death in glioblastoma, unveiled through multistep virtual screening, comprehensive in vitro and in vivo animal model evaluation
Authors: Seyma Calis, Berna Dogan, Asuman Celebi, Ozlem Yapicier, Turker Kilic, Eda Tahir Turanli, Timucin Avsar, Serdar Durdagi
Journal: Cancer Research (2024)

Abstract The excessive expression of antiapoptotic members in the B-cell leukemia/lymphoma-2 (BCL-2) family proteins emerges as a noteworthy oncogenic target in cancer cells. Employing a multistep virtual screening and filtering approach that integrates structure and ligand-based drug design, we aimed to identify novel and potent BCL-2 inhibitors from a sizable small molecule database, comprising over 210,000 compounds. Subsequently, seven selected molecules underwent rigorous biological activity tests in human cancer cell lines and Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) assays. Four of these compounds exhibited notable inhibitory effects on cancer cell proliferation and led to an increase in apoptotic cell fractions. Among the identified compounds, BAU-243 displayed a substantial affinity for Bcl-2, demonstrating efficacy in reducing glioblastoma (GBM) cell proliferation, including cancer-initiating cells. Notably, in contrast to the selective Bcl-2 inhibitor ABT-199, BAU-243 induced autophagic cell death in GBM cells. In vivo investigations using orthotopic brain tumor models revealed a significant reduction in tumor growth with BAU-243 compared to both the vehicle group and animals treated with ABT-199. Computational modeling simulations, in concordance with in vitro findings, proposed that BAU-243 activates autophagic cell death by disrupting the Beclin 1:Bcl-2 complex. This positions BAU-243 as a promising small molecule for the treatment of GBM. Citation Format: Seyma Calis, Berna Dogan, Asuman Celebi, Ozlem Yapicier, Turker Kilic, Eda Tahir Turanli, Timucin Avsar, Serdar Durdagi. BAU-243: A novel BCL-2 inhibitor inducing autophagic cell death in glioblastoma, unveiled through multistep virtual screening, comprehensive in vitro and in vivo animal model evaluation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB021.
Abstract LB198: The PAX5 oncogene encodes circular RNA products involved in B cell cancer processes
Authors: Danick Martin, Brandon Hannay, Farrah McGraw, Alexis Martin, Vanessa Veilleux, Nicholas Finn, Gilles A. Robichaud
Journal: Cancer Research (2024)

Abstract Introduction: B-cell cancers represent some of the most prevalent hematological lesions in adult and children. B-cell cancers are also notable for their malignancy and resistance to drug therapies. Our group studies B-cell oncogenes and recently discovered that the prominent PAX5 oncogene, which usually encodes transcription factors, also generates non-coding circular RNA transcripts. Circular RNAs (circRNAs) represent a new class of gene products involved in many biological processes and cancer disease. Due to their innate ability to bind and modulate co-interacting proteins and microRNAs (miRs), circRNAs represent new signaling avenues in cancer biology. Hypothesis: Given that products from the PAX5 oncogene are important regulators of B-cell cancers, we hypothesized that PAX5 circRNAs (circPAX5) are also involved in B-cell oncogenesis. Objective: We therefore set out to study circPAX5 products, and their co-interacting miRs, in B-cell cancers. Results: Using a series of B-cell cancer models and clinical samples, we first profiled the expression of circPAX5 products and found that B-cell leukemias overexpress circPAX5 where its predominant circRNA isoform consisted of exons 2 to 5 sequences of the PAX5 locus. To establish a functional role of circPAX5 on cancer processes, we evaluated B-cell proliferation and chemosensitivity in cancer models expressing conditioned levels of circPAX5. Interestingly, we found that the suppression of circPAX5 levels resulted in the alteration of cancer growth rates, which were dependent upon B-cell differentiation state and population subtype. Mechanistically, we also found that circPAX5 interacts with specific miRs, which were profiled by circRNA precipitation and deep sequencing. Selected sponged miRs were then studied by bio-informatic analyses and mapped to downstream mRNA targets and B-cell cancer pathways. Conclusions: Altogether, our findings uncover PAX5 circular products, which are involved in B-cell cancer processes and could potentially represent a new cancer pathway targeted for therapeutic and/or diagnostic strategies in B-cell cancer lesions. Citation Format: Danick Martin, Brandon Hannay, Farrah McGraw, Alexis Martin, Vanessa Veilleux, Nicholas Finn, Gilles A. Robichaud. The PAX5 oncogene encodes circular RNA products involved in B cell cancer processes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB198.
Abstract LB260: Overexpression of ABCC1 and ABCG2 confers resistance to talazoparib, a poly polymerase inhibitor
Authors: Shuo Fang, Xiaona Fang
Journal: Cancer Research (2024)

Abstract Aims: The overexpression of ABC transporters on cancer cell membranes is one of the most common causes of multidrug resistance (MDR). This study investigates the impact of ABCC1 and ABCG2 on the resistance to talazoparib (BMN-673), a potent poly (ADP-ribose) polymerase (PARP) inhibitor, in ovarian cancer treatment. Methods: The cell viability test was used to indicate the effect of talazoparib in different cell lines. Computational molecular docking analysis was conducted to simulate the interaction between talazoparib and ABCC1 or ABCG2. The mechanism of talazoparib resistance was investigated by constructing talazoparib-resistant subline A2780/T4 from A2780 through drug selection with gradually increasing talazoparib concentration. Results: Talazoparib cytotoxicity decreased in drug-selected or gene-transfected cell lines overexpressing ABCC1 or ABCG2 but can be restored by ABCC1 or ABCG2 inhibitors. Talazoparib competitively inhibited substrate drug efflux activity of ABCC1 or ABCG2. Upregulated ABCC1 and ABCG2 protein expression on the plasma membrane of A2780/T4 cells enhances resistance to other substrate drugs, which could be overcome by the knockout of either gene. In vivo experiments confirmed the retention of drug-resistant characteristics in tumor xenograft mouse models. Conclusions: The therapeutic efficacy of talazoparib in cancer may be compromised by its susceptibility to MDR, which is attributed to its interactions with the ABCC1 or ABCG2 transporters. The overexpression of these transporters can potentially diminish the therapeutic impact of talazoparib in cancer treatment. Citation Format: Shuo Fang, Xiaona Fang. Overexpression of ABCC1 and ABCG2 confers resistance to talazoparib, a poly polymerase inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB260.
Abstract LB306: PD-L1-targeted radioimmunethrapeutics combined with oncolytic virus for treatment of pancreatic cancer
Authors: Arum Yoon, Chae-Ok Yun, Jin Su Kim
Journal: Cancer Research (2024)

Abstract Pancreatic cancer is difficult to treat, and the first line treatment provide only modest survival benefits to patients due to its highly desmoplastic and immune-desert phenotype. To overcome these hurdles, PD-L1-targeted radioimmunotherapy (RIT) using lutetium-177-labelled atezolizumab (177Lu-aPD-L1) combined with an oncolytic virus, named HY-oAd, that co-expresses three therapeutic genes (interleukin-12, granulocyte-macrophage colony-stimulating factor and relaxin) was investigated. HY-oAd treatment was shown to elevate PD-L1 expression level and promoted degradation of extracellular matrix (ECM) of pancreatic tumors, resulting in increased aPD-L1 or 64Cu-aPD-L1 accumulation in tumor tissues. Moreover, HY-oAd in combination with either aPD-L1 or 177Lu-aPD-L1 elicited more potent antitumor effect against the pancreatic tumors than respective monotherapy in pancreatic tumor models. The potent antitumor effect of HY-oAd+aPD-L1 combination therapy can lead to superior intratumoral infiltration and activation of dendritic cells and CD4+ or CD8+ T cells over the respective monotherapy. Collectively, our findings demonstrate that HY-oAd can potentiate PD-L1-targeted RIT through PD-L1 upregulation and ECM degradation, thus resulting in synergistic antitumor efficacy and antitumor immune response. Citation Format: Arum Yoon, Chae-Ok Yun, Jin Su Kim. PD-L1-targeted radioimmunethrapeutics combined with oncolytic virus for treatment of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB306.
Abstract LB071: Weaponizing CAR T-cells to attack PD-L1 presenting cells in solid tumors
Authors: Yaqing Qie, Emiliano Sanchez Garavito, Maria J. Ulloa Navas, Tanya Hundal, Alfredo Quinones-Hinojosa, Hong Qin, Yan Luo
Journal: Cancer Research (2024)

Abstract Despite its success in treating blood cancers, chimeric antigen receptor (CAR) T-cell therapy has not yielded anticipated clinical outcomes in patients with solid tumors. This discrepancy is primarily attributed to the lack of dependable antigens and the immunosuppressive nature of the tumor microenvironment (TME). A pivotal evasion mechanism employed by tumor to counter antitumor immunity involves the upregulation of programmed death ligand 1 (PD-L1), which interacts with PD1 on T cells, deactivating effector T cells. A variety of immunosuppressive cells within the TME employ similar mechanisms to inhibit T-cell functions. These findings provide a rationale for targeting PD-L1 in both tumors and the immunosuppressive cells. Using a humanized anti-PD-L1 monoclonal antibody, we engineered a second-generation PD-L1 CAR, namely MC9999. MC9999 CAR T-cells exhibited antigen-specific cytotoxicity in vitro and elicited potent in vivo antitumor effects against PD-L1-expressing MDA-MD-232 breast cancer cells. The effectiveness of MC9999 CAR T-cells was confirmed across three other solid tumor models: non-small cell lung cancer, melanoma and glioblastoma (GBM). Notably, intravenous administration of MC9999 CAR T-cells eradicated intracranially established LN229 GBM tumors, suggesting the potential to penetrate the blood-brain barrier. In addition to targeting tumor cells, MC9999 CAR T-cells exhibited cytotoxicity against three immunosuppressive cell models, including HMC3 microglia cells, M2 macrophages, and importantly, primary tumor-associated macrophages (TAMs) isolated from GBM. Furthermore, we engineered patient-derived MC9999 CAR T-cells and demonstrated their effectiveness against two primary tumor cell lines derived from GBM tumors and HMC3 cells. Collectively, these proof-of-principle study findings substantiate the viability of targeting PD-L1 against both tumors and their immunosuppressive microenvironment. This prototype MC9999 CAR lays the groundwork for further development of clinically applicable CAR T-cell therapy against solid tumors. Citation Format: Yaqing Qie, Emiliano Sanchez Garavito, Maria J. Ulloa Navas, Tanya Hundal, Alfredo Quinones-Hinojosa, Hong Qin, Yan Luo. Weaponizing CAR T-cells to attack PD-L1 presenting cells in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB071.