tbuckley/cabot-search huggingface dataset:
Abstract LB347: PLA2G2D/PGD2-PTGDR signaling deficiency restricts the melanoma progression and lung metastasis
Authors: Hima Dhakal, Jian Zheng
Journal: Cancer Research (2024)

Abstract Normal 0 false false false EN-US KO X-NONE/* Style Definitions */table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin-top:0in; mso-para-margin-right:0in; mso-para-margin-bottom:8.0pt; mso-para-margin-left:0in; line-height:107%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri",sans-serif; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-font-kerning:1.0pt; mso-ligatures:standardcontextual;} Melanoma is a serious form of skin cancer with an approximate incidence more than 160,000 cases and 41,000 melanoma-associated death per annual globally. Malignant Melanoma is more dangerous because of its rapid spread and metastasis if it were not treated at an early stage. The high mortality of malignant melanoma incites an urgent need to refine the current treatments. Phospholipase A2 group IID (PLA2G2D) is an inducible enzyme expressed in myeloid cells, positively associated with immune infiltration through producing anti-inflammatory prostaglandin D2 (PGD2). The aging-related increase of PLA2G2D and PTGDR, a PGD2 receptor, makes them attractive targets for treating aged-related diseases, such as chronic inflammation and cancer diseases. In this study, by using Pla2g2d-/- and Ptgdr-/- mice, we found that PLA2G2D or PTGDR deficiency effectively restricted the in-situ growth and lung metastasis of subcutaneously implanted melanoma B16F10. These benefits are associated with the early enrichment of γδ-T cells in the tumor mass. The activation and accumulation of γδ-T cells can be induced in B16F10-bearing WT mice by the adoptive transfer of Pla2g2d-/- or Ptgdr-/- DCs. Pro-inflammatory characteristics of Pla2g2d-/- or Ptgdr-/- DCs, especially the production of IL-1b, contribute to γδ-T cells recruitment. These tumor-restraining effects were further confirmed in DC-specific PTGDR deficient (zDCcrePtgdrfloxp ) mice. Taken together with the prominent expression of PLA2G2D and PTGDR in human lung cancer tissue, this study demonstrates the potential of PLA2G2D-PGD2/PTGDR signaling-targeted therapy in treating melanoma and lung metastasis. Citation Format: Hima Dhakal, Jian Zheng. PLA2G2D/PGD2-PTGDR signaling deficiency restricts the melanoma progression and lung metastasis [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 LB347.
Abstract LB343: Golgihi T cells exhibit reduced susceptibility to exhaustion and improved tumor control
Authors: Nathaniel Oberholtzer, Paramita Chakraborty, Mohamed Faisal Kassir, James Dressman, Zacharia Hedley, Gina Scurti, Monika Gooz, Lauren E. Ball, Elizabeth Hill, Anand S. Mehta, Eduardo N. Maldonado, Michael I. Nishimura, Besim Ogretmen, Shikhar Mehrotra
Journal: Cancer Research (2024)

Abstract The role of tumor microenvironment mediated disruption of Golgi architecture and function,termed Golgi stress, in the regulation of T cell survival and function are largely unknown. Here weshow that the disruption of Golgi architecture, identified by the decreased expression of GM130,was reverted upon treatment with hydrogen sulfide (H2S) donor GYY4137, or over-expressingcystathionine β-synthase (Cbs), an enzyme involved in the biosynthesis of endogenous H2S -that promoted stemness, antioxidant capacity and exhibited increased protein translationmediated in part by ER-Golgi shuttling of Peroxiredoxin-4. In in vivo models of melanoma andlymphoma, anti-tumor T cells conditioned ex vivo with exogenous H2S or overexpressing Cbsdemonstrated superior tumor control upon adoptive transfer. Further, Golgihi T cells, with highGolgi content, exhibited unique metabolic and glycation signature with enhanced anti-tumorcapacity. These data suggest that strategies to mitigate Golgi network stress or using Golgihitumor-reactive T cells can improve tumor control upon adoptive transfer. Citation Format: Nathaniel Oberholtzer, Paramita Chakraborty, Mohamed Faisal Kassir, James Dressman, Zacharia Hedley, Gina Scurti, Monika Gooz, Lauren E. Ball, Elizabeth Hill, Anand S. Mehta, Eduardo N. Maldonado, Michael I. Nishimura, Besim Ogretmen, Shikhar Mehrotra. Golgihi T cells exhibit reduced susceptibility to exhaustion and improved tumor control [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 LB343.
Abstract LB268: Discovery of a potent, selective and brain penetrating PARP1 inhibitor, XZP-7797
Authors: Yeqing Gao, Yuqian Lu, Bo Chen, Benke Jiang, Feng Wang, Genyan Zhang, Xifeng Ma, Dapeng Zhou, Chunmin Shi, Yunling Wang, Zhipeng Liu, Jun Sun, Huimin Zhou, Mei Xu, Jiakui Li, Bin Liu
Journal: Cancer Research (2024)

Abstract First-generation PARP1/2 inhibitors are approved for the treatment of cancers, such as ovarian, prostate, pancreas, and breast cancers, with maximal activity against tumors harboring BRCA1/2 mutation or homologous recombination deficiency (HRD). However, PARP1/2 inhibitors in clinical use have severe hematological toxicities due to the inhibition of PARP2, which has been shown to play an important role in the survival of hematopoietic progenitor cells. Furthermore, the current data indicate that synthetic lethality with BRCA mutations is primarily caused by PARP1 inhibition and trapping, whereas PARP2 inhibition and trapping are not critical for anticancer activity. Therefore, the development of selective PARP1 inhibitors is expected to reduce the hematological adverse effects associated with PARP2 inhibition while maintaining the required efficacy. XZP-7797 is a potent, selective, and brain-penetrating PARP1 inhibitor with trapping ability. In biochemical assays, XZP-7797 is more than 1000-fold selective for PARP1 over PARP2 and other members of the PARP family, including PARP3, PARP5a, PARP5b, and PARP6. XZP-7797 can significantly inhibit MDA-MB-436 cell proliferation in vitro (IC50=2.4nM). In MDA-MB-436 tumor cells, XZP-7797 inhibits PARylation and increases γH2AX level in a concentration-dependent manner. XZP-7797 demonstrates rapid tumor regression in a dose-dependent manner in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. In a pancreatic cancer xenograft model, XZP-7797 can also significantly inhibit tumor growth. To evaluate the ability of XZP-7797 to cross the blood-brain barrier, an intracranial xenograft model of breast cancer is used. The results show that XZP-7797 can significantly inhibit the growth of intracranial tumors in mice at a dose of 10 mg/kg, demonstrating the brain-penetrating ability of XZP-7797. Additionally, XZP-7797 has great PK profiles in preclinical species after oral dosing and good ADME properties. In a 14-day toxicology study of XZP-7797 in SD Rats, XZP-7797 has no hematological adverse effects at the exposure that is 10 times higher than the exposure required to achieve superior efficacy. Citation Format: Yeqing Gao, Yuqian Lu, Bo Chen, Benke Jiang, Feng Wang, Genyan Zhang, Xifeng Ma, Dapeng Zhou, Chunmin Shi, Yunling Wang, Zhipeng Liu, Jun Sun, Huimin Zhou, Mei Xu, Jiakui Li, Bin Liu. Discovery of a potent, selective and brain penetrating PARP1 inhibitor, XZP-7797 [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 LB268.
Abstract ND01: ABBV-303: A novel NK and CD8 T cell engager specific for c-Met-expressing tumors
Authors: Jennifer Stone, Kamonwan Pear Fish, Devika Ashok, Laura McKay, Saeed Akhand, Weilong Zhao, Si Wu, Amani Makkouk, Cormac Cosgrove, Paul Ellis, David Peetz, Stephanie Shee, Richard Peterson, Shelby Anderson, Adam Chervin, Claudina Stevenson, Tamar Uziel, Edward Reilly
Journal: Cancer Research (2024)

Abstract Natural killer (NK) cell redirecting therapies are emerging as promising “off the shelf” treatments for cancer without the safety issues associated with T cell directed therapies. ABBV-303 is a novel c-Met targeted multispecific NK cell engager based on Dragonfly Therapeutics’ TriNKET® technology. ABBV-303 includes three functional arms: (1) a c-Met binding scFv based on ABT-700, common to c-Met-targeting antibody-drug conjugates ABBV-400 and Teliso-V; (2) a Fab arm that binds NKG2D, a stimulatory receptor expressed by NK cells and activated CD8+ T cells; and (3) a heterodimeric IgG1 Fc which binds CD16a on NK cells and links the other two binding moieties. ABBV-303 binding to NKG2D and CD16a results in redirection of both innate (NK cells) and adaptive (CD8+ T cells) immune cells to lyse c-Met expressing tumor cells. Treatment of peripheral blood mononuclear cells (PBMCs) from healthy donors and cancer patients with ABBV-303 in the presence of c-Met+ tumor cells stimulates NK and CD8+ T cells as demonstrated by modulation of activation-associated surface proteins and release of soluble factors. ABBV-303 drives sub-nanomolar redirected killing potency against tumor cells expressing a broad range of c-Met. Additionally, anti-tumor activity of ABBV-303 has been demonstrated against established xenografts in CD34 humanized NSG mice. NK and CD8+ T cell activity in response to ABBV-303 has been observed in c-Met-expressing fresh patient tumor explants. A benign safety profile was observed in non-human primates through three repeat doses up to 150 mg/kg given every two weeks, with antibody-like exposures and a serum half-life around 8 days. Based on these findings, the First in Human ABBV-303 study will initiate in 1H 2024 in solid tumors as a monotherapy and in combination with an anti-PD-1 checkpoint inhibitor. All authors are current employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Citation Format: Jennifer Stone, Kamonwan Pear Fish, Devika Ashok, Laura McKay, Saeed Akhand, Weilong Zhao, Si Wu, Amani Makkouk, Cormac Cosgrove, Paul Ellis, David Peetz, Stephanie Shee, Richard Peterson II, Shelby Anderson, Adam Chervin, Claudina Stevenson, Tamar Uziel, Edward Reilly. ABBV-303: A novel NK and CD8 T cell engager specific for c-Met-expressing 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 ND01.
Abstract LB436: Using FCCS to monitor target occupancy in cells and patient biopsies
Authors: Frank Becker
Journal: Cancer Research (2024)

Abstract Lack of target engagement is one of the major reasons for failures in clinical studies. We developed an assay platform to detect and quatify target occupancy values in patient and animal biopsies to guide the development and dosing during the drug development process. FCCS (fluorescence cross correlation spectroscopy) is a powerful tool to characterize drug target interaction in physiological environments. Over the last decade this technology was used to understand the binding and kinetics of small molecules and antibodies to challenging target proteins in great details and accuracy. Over the last decade Intana Bioscience expanded the application of FCCS from affinity measurements to comprehensive interaction studies including kinetics, multi component complex formation, assessing stoichiometry and quantification of aggregation, PK studies and target engagement. This presentation will highlight examples of results obtained with FCCS in projects ranging from early stages in the drug discovery up to the support of clinical trials to quantify target occupancies in patient samples. Citation Format: Frank Becker. Using FCCS to monitor target occupancy in cells and patient biopsies [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 LB436.
Abstract LB052: PTP1B inhibitors activate a novel hypoxia-induced inflammatory cell death pathway in breast cancer
Authors: Benjamin G. Neel, Abhishek Bhardwaj, Maria Antonelli, Beatrix Ueberheide
Journal: Cancer Research (2024)

Abstract Dual PTP1B/TC-PTP (PTPN1/2) inhibitors are in clinical trials for multiple cancer types, primarily because they augment anti-tumor immunity, but they can also have cancer cell-autonomous effects. Hypoxic cancer cells resist many anti-neoplastic therapies and can seed recurrence. We found previously that PTP1B deficiency/inhibition promotes HER2+ breast cancer cell death in hypoxia by activating RNF213, an ~600kDa protein containing AAA-ATPase domains and two ubiquitin ligase domains (RING and RZ) that also is implicated in Moyamoya disease (MMD), lipotoxicity, and innate immunity. We now report that PTP1B and ABL1/2 reciprocally control RNF213 phosphorylation on tyrosine-1275. This phosphorylation promotes RNF213 oligomerization and RZ domain activation. The RZ domain ubiquitylates CYLD/SPATA2, and together with the LUBAC complex, induces their degradation. Decreased CYLD/SPATA2 causes NF-κB activation, which together with hypoxia-induced ER-stress triggers GDSMD-dependent pyroptosis. Mutagenesis experiments show that the RING domain negatively regulates the RZ domain. CYLD-deleted HER2+ cell-derived xenografts phencopy the effects of PTP1B deficiency, and reconstituting RNF213 knockout lines with RNF213 mutants shows that the RZ domain mediates PTP1B-dependent tumor cell death. Our results identify a novel, potentially targetable PTP1B/RNF213/CYCLD/SPATA pathway critical for controlling inflammatory cell death in hypoxic tumors that could be exploited to target hypoxic tumor cells, potentially turning “cold” tumors “hot”, thereby increasing the potential clinical utility of PTP1B inhibitors. Citation Format: Benjamin G. Neel, Abhishek Bhardwaj, Maria Antonelli, Beatrix Ueberheide. PTP1B inhibitors activate a novel hypoxia-induced inflammatory cell death pathway in breast 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 LB052.
Abstract LB062: ADT3_A potential first-in-class Vδ1-engager for in situ activation of Vδ1 γδ T cells and enhanced cytotoxicity towards solid tumors
Authors: Joshua Freedman, Georgia Stevens, Julie Julie Hoong, Mihirban Tuna, Yaoyao Shi, Kathy J. Seidl, Katherine Galvin, Andrew Hutton, Antara Banerjee
Journal: Cancer Research (2024)

Abstract Gamma delta (γδ) T cells are crucial in stress surveillance for infections and cancer. Studies have shown that tumour-infiltrating γδ T cells are a positive prognostic factor in cancer therapy. While γδ T cells share many characteristics with their αβ T cell counterpart, such as cytotoxic effector functions, they express a distinct TCR that is composed of a γ and a δ chain, belong to the HLA-class-I unrestricted immune cell subset with the ability to discriminate and specifically kill tumor cells via recognition of tumor stress ligands. Clinical trials using Vδ1 γδ T cell therapies have demonstrated promising results in Ph 1 trials, with early signs of favorable efficacy and safety profile.ADT3, is a novel bispecific engager that activates tissue-resident Vδ1+ T cells via (Epidermal Growth Factor Receptor) EGFR crosslinking on tumor cells. VD1 T cells isolated from skin biopsies, when activated, enhance the selective killing of EGFR positive tumor cells through innate mechanisms that recognize stress ligands that are otherwise absent on healthy cells. As a bispecific engager, ADT3 preserves high affinity binding to VD1 TCR through the Fab end of the molecule, and binding to two EGFR binding sites via the modified Fc domain. Crosslinking of VD1 and EGFR+ tumor cells with ADT3, mediates a series of events leading to proliferation of VD1 cells, upregulation of activation markers, CD107a degranulation and secretion of chemokines and cytokines (such as TNFa and IFNg) and tumor kill as determined by its potent cytotoxic activity in a T-cell dependent cellular cytotoxicity assay (TDCC). Apart from direct tumor kill, the secretion of such cytokines and chemokines via ADT3 activation are required for induction of immune orchestration of non-Vδ1 immune cells to enhance tumor kill. Preclinical data supports future clinical entry of ADT3, and IND enabling studies are in progress Citation Format: Joshua Freedman, Georgia Stevens, Julie Julie Hoong, Mihirban Tuna, Yaoyao Shi, Kathy J. Seidl, Katherine Galvin, Andrew Hutton, Antara Banerjee. ADT3_A potential first-in-class Vδ1-engager for in situ activation of Vδ1 γδ T cells and enhanced cytotoxicity towards 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 LB062.
Abstract LB215: Polymerase θ (POLθ) inhibitors (novobiocin, ART-558, RP6685) were tested with 22 approved and investigational agents in multi-cell type spheroids of genetically selected patient-derived human tumor cell lines
Authors: Beverly A. Teicher, Thomas S. Dexheimer, Thomas Silvers, Nathan P. Coussens, J Paul Eder, James H. Doroshow
Journal: Cancer Research (2024)

Abstract The potential of novobiocin to augment cancer chemotherapy was explored in the late 1980s and early 1990s in tumor cells and tumor-bearing mice and in Phase 1 clinical trials with cyclophosphamide or cisplatin. The molecular target of novobiocin was identified to be DNA POLθ which has a role in repair of DNA double strand breaks (DSB) during mitosis. Genetic alterations which may increase or decrease POLθ inhibitor effects have been elucidated. Thirty patient-derived tumor cell lines with known BRCA, ATM, ATR, POLQ, XRCC1, PALB2, PARP1, and LIG3 alterations were screened in a complex spheroid assay (tumor cells, endothelial cells, mesenchymal stem cells) with a POLθ inhibitor (novobiocin, ART-558, or RP6685), alone or in simultaneous combination with a FDA approved or investigational anticancer small molecule, using a 7-day exposure and a CellTiter-Glo 3D luminescence endpoint. As single agents, the POLθ inhibitors had little or no cytotoxicity. Potentiation of the topoisomerase II inhibitors doxorubicin (DOX) and etoposide by the POLθ inhibitors ART-558 or RP6685 was observed in spheroids grown from the serous endometrial adenocarcinoma 922993-354-T-J3, which has ATM and BRCA2 variants. The 379773-124-R-J2 endometrioid endometrial adenocarcinoma which harbors mutant POLθ demonstrated antagonism with ART-558 in combination with PARP inhibitors and less than additive to additive cytotoxicity in combination with DOX. Activity of the Chk1/2 inhibitor prexasertib was potentiated by either ART-558 or RP6685 in the 922993-354-T-J3 complex spheroids. The combination of POLθ inhibitor ART-558 and the Chk1/2 inhibitor prexasertib produced up to 1 log increase in cytotoxicity in the 922993-354-T-J3 complex spheroids. KRAS G12D inhibitor MRTX-133 cytotoxicity against 186277-243-T-J2 colon adenocarcinoma with the KRAS G12D variant was potentiated by either ART-558 or RP6685. Potential combinations to advance into in vivo studies will be presented. This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261201500003I. Citation Format: Beverly A. Teicher, Thomas S. Dexheimer, Thomas Silvers, Nathan P. Coussens, J Paul Eder, James H. Doroshow. Polymerase θ (POLθ) inhibitors (novobiocin, ART-558, RP6685) were tested with 22 approved and investigational agents in multi-cell type spheroids of genetically selected patient-derived human tumor cell lines [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 LB215.
Abstract SY34-01: Plasticity, dormancy, and glycosylation of circulating tumor cell clusters in response to therapy
Authors: Huiping Liu
Journal: Cancer Research (2024)

Abstract Cellular plasticity and stemness properties enable dynamic changes of circulating tumor cells (CTCs) during cancer dissemination, such as aggregation or cohesion of single CTCs into multicellular CTC clusters with 20-100 times higher metastatic propensity than the singles. Our work demonstrated that stemness glycoproteins on breast cancer stem cells, such as CD44, CD81, and ICAM1 drive CTC aggregation in metastatic breast cancer, such as triple negative breast cancer (TNBC). To determine the glycosylation patterns in CTCs and its association with clinical outcomes, we established multiple CTC analysis approaches including CellSearch, flow cytometry, and immunohistochemistry using patient blood and tissue sections collected at the pre-treatment baseline and after-therapy timepoints. We found that chemotherapy-evasive CTC clusters are relatively quiescent with a specific loss of terminal sugar residues α2,6-sialic acids in glycoproteins. CTCs showed dynamic hypo-sialylation in the blood with loss of the sialyl-transferase ST6GAL1, promoting CTC cluster formation with cellular quiescence (proliferative dormancy) and evading chemotherapy in breast cancer. Seeded tumor cells regained ST6GAL1 to enable metastatic colonization. Many adhesion proteins and stemness drivers as glycoprotein substrates of ST6GAL1 drive CTC clustering and metastatic seeding. Neutralizing antibodies against these clustering drivers inhibit CTC cluster formation and improve therapy response, thereby blocking lung metastasis in TNBC. Citation Format: Huiping Liu. Plasticity, dormancy, and glycosylation of circulating tumor cell clusters in response to therapy [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 SY34-01.