tbuckley/cabot-search huggingface dataset:
Abstract 5278: Immunological control by PARP inhibitors for successful immunotherapy in metastatic ovarian carcinoma
Authors: Peter Holicek, Sarka Vosahlikova, Irena Moserova, Sandra Orsulic, Romana Mikyskova, Michal Hensler, Lenka Kasikova, Tereza Lanickova, Ondrej Novotny, Milan Reinis, Jana Drozenova, Ales Ryska, Jan Laco, Lukas Rob, Michael Halaska, David Cibula, Radek Spisek, Jitka Fucikova
Journal: Cancer Research (2024)

Abstract Epithelial ovarian carcinoma (EOC) is among the top five causes of cancer-related death in women. Most women with EOC achieve indeed complete remission after primary or interval cytoreductive surgery combined with chemotherapy based on a platinum-taxane doublet. Homologous recombination (HR) defects imposed by germline or somatic BRCA1 DNA repair-associated (BRCA1) or BRCA2 mutations are not only key determinants of platinum sensitivity in EOC patients but also provide a strong rationale for maintenance therapy based on poly(ADP-ribose) polymerase (PARP) inhibitors, which is generally associated with improved progression-free survival (PFS). Besides direct cytotoxic and cytostatic properties, PARPi have been shown to mediate multipronged immunostimulatory effects, largely reflecting their ability to inhibit DNA repair in malignant cells and indicating the possibility to synergy with immune-check point inhibitors (ICIs). Here, using multiparametric flow cytometry, multiplex immunostaining, single cells transcriptomics and functional studies in experimental syngeneic BR5Brca1-/- mouse model and EOC tumor samples, we discuss PARPi immunomodulatory activity, with a specific focus on molecular and cellular pathways that can be harnessed to develop superior combinatorial regimens for clinical management. Thus, PARPi might enhance the mutational load of EOCs as consequence of unrepaired DNA damage and DAMPs exposure, favoring T cell infiltration, but also appear to drive robust type I IFN secretion downstream of cyclic GMP-AMP synthase and stimulator of IFN response cGAMP interactor 1 activation. In addition, the combination of PARPi with ICIs positively regulate the balance between adaptive anti-tumor immunity and innate myeloid components and significantly improve the cytotoxic T cell profile as shown in both experimental mice model and HGSOC tumor samples. We surmise that rationally designed combinations of PARPi and immunotherapeutic agents might be critical to unlock immunosuppression in the EOC microenvironment in support of clinical efficacy. Citation Format: Peter Holicek, Sarka Vosahlikova, Irena Moserova, Sandra Orsulic, Romana Mikyskova, Michal Hensler, Lenka Kasikova, Tereza Lanickova, Ondrej Novotny, Milan Reinis, Jana Drozenova, Ales Ryska, Jan Laco, Lukas Rob, Michael Halaska, David Cibula, Radek Spisek, Jitka Fucikova. Immunological control by PARP inhibitors for successful immunotherapy in metastatic ovarian carcinoma [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 5278.
Abstract 4259: A novel human model of lung squamous cell carcinoma to deconvolve the cell-intrinsic effects of key dysregulated pathways
Authors: Julia Ogden, Robert Sellers, Anthony Oojageer, Sudhakar Sahoo, Anshuman Chaturvedi, Carlos Lopez-Garcia
Journal: Cancer Research (2024)

Abstract Tractable, patient relevant models are needed to investigate the essential components of normal cell transformation. We developed a unique in vitro model of early lung squamous cell carcinoma (LUSC) genetic alterations and driver pathway dysregulation using genetically modified primary human bronchial basal cells (hBCs) from three independent donors. The co-operation of ubiquitous and early LUSC alterations (TP53 and CDKN2A loss) and commonly deregulated pathways including squamous differentiation (SOX2), PI3K signaling (PTEN) and the oxidative stress response (KEAP1) was investigated using a combinatorial approach, culminating in eight unique hBC mutants harboring cumulative pathway alterations in a TP53-/-/CDKN2A-/- background. Phenotypes indicative of mutant hBC transformation were investigated using proliferation assays, organotypic cultures and anchorage independent growth assays. Organotypic cultures revealed LUSC pathway alterations to drive dramatic changes in airway histology, ranging from a normal epithelium to severe dysplasia. Furthermore, these analyses confirmed the role of SOX2-overexpression in initiating transformation by inducing squamous cell commitment and anchorage independent growth. We also identified a co-operation of SOX2-overexpression with the oxidative stress response and PI3K pathways to drive more advanced lesions in-vivo and in-vitro. Importantly, we were able to map changes in the expression of immunomodulatory factors with the pathway dysregulation. We demonstrated that this strategy constitute an alternative and patient-relevant system to model LUSC and identify genotype-phenotype correlations of clinical relevance. Citation Format: Julia Ogden, Robert Sellers, Anthony Oojageer, Sudhakar Sahoo, Anshuman Chaturvedi, Carlos Lopez-Garcia. A novel human model of lung squamous cell carcinoma to deconvolve the cell-intrinsic effects of key dysregulated pathways [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 4259.
Abstract 5253: Epigenetic drugs partially restored anti-cholangiocarcinoma activity of dysfunctional CD3+CD56+ cells
Authors: Adisak Wongkajornsilp, Porncheera Chusorn, Kriengkrai Phongkitkarun, Khin Su Su Htwe, Sunisa Duangsa-ard, Kanda Kasetsinsombat, Nathawadee Sawatpiboon
Journal: Cancer Research (2024)

Abstract The cholangiocarcinoma cell-exposed cytokine-induced killer (CIK) cells or their most efficacious CD3+CD56+ subset displayed weaken anti-tumor cytotoxicity upon subsequent exposure. RNAseq analysis of the resistant phenotype gave rise to a list of drugs that could potentially counter the activity of genes associated with resistance to the anti-tumor activity of CIK cells. The top-ranking drugs appeared to be epigenetic drugs. Sublethal concentration of these drugs were assayed for their synergistic activity with CIK cell or the CD3+CD56+ subset for cytolysis of resistant CCA cells in tissue culture model. These drugs, although in low concentration, contained anti-tumor activity. The tumor cytolysis was greater after the combination with either CIK cells or the CD3+CD56+ subset. An in vivo model of CCA-implanted mice exhibited the synergistic activity of subtherapeutic dose of these drugs and CD3+CD56+ subset in suppressing tumor growth. It is concluded that epigenetic drugs in subtherapeutic dose could prevent the dysfunction of CCA-exposed CIK cells. Citation Format: Adisak Wongkajornsilp, Porncheera Chusorn, Kriengkrai Phongkitkarun, Khin Su Su Htwe, Sunisa Duangsa-ard, Kanda Kasetsinsombat, Nathawadee Sawatpiboon. Epigenetic drugs partially restored anti-cholangiocarcinoma activity of dysfunctional CD3+CD56+ 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 5253.
Abstract 1811: Efficient identification of new small molecules targeting succinate dehydrogenase in non-small cell lung cancer
Authors: Luis Silva, Nicholas Skiados, Nikitha Murugavel, Nastassja Luna, Karen Cover, Manish K. Gupta, Stephanie C. Contreras, Terrence E. O'Brien, Wen Cai Zhang
Journal: Cancer Research (2024)

Abstract Efficient lung cancer treatment remains challenging due to the lack of therapeutic targets. The succinate dehydrogenase (SDH) enzyme plays a critical metabolic role as an intermediate between the citric acid cycle and the electron transport chain associated with the cancer disease state. Although several existing compounds have been applied to target metabolic diseases in vitro, modulating SDH for lung cancer treatment is still elusive. By integrating the AtomNet® technology for compound identification with mitochondria- and cell-based enzyme activity assays, we identified four new small molecules from 96 predicted candidates. Cellular thermal shift assay confirmed that these small molecules bind directly to SDH subunits in lung cancer cells. Mechanistically, treatment with these small molecules increased cellular and mitochondrial reactive oxygen species, accumulated succinate, and DNA damage-induced apoptosis in lung cancer cell lines. Functionally, these small molecules reduced the growth, migration, and formation of 3D organoids in vitro in lung cancer cell lines, both in the short and long term. Our study sheds light on the function of SDH in metabolic dysfunction related to cancer and highlights the potential of modulating SDH as a viable therapeutic strategy for targeting lung cancer and other cancer types. LS, NS, and WCZ contributed equally to this work. Citation Format: Luis Silva, Nicholas Skiados, Nikitha Murugavel, Nastassja Luna, Karen Cover, Manish K. Gupta, Stephanie C. Contreras, Terrence E. O'Brien, Wen Cai Zhang. Efficient identification of new small molecules targeting succinate dehydrogenase in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1811.
Abstract 4392: Neuropeptide Y system in glioblastoma
Authors: Nouran Abualsaud, Jason Tilan, Bahauddeen M. Alrfaei, Harrison Glor, Taylor Polk, Ewa Izycka-Swieszewska, Joanna Kitlinska
Journal: Cancer Research (2024)

Abstract Gliomas constitute the most common primary cerebral tumors of the central nervous system (CNS), with glioblastoma (GBM) representing the most aggressive subtype. Neurotransmitters are important players in maintaining physiological processes in CNS and abnormal levels of their expression is pathogenic, leading to different processes, including neoplasia. Neuropeptide Y (NPY) is one of the neurotransmitters that is found to play a pivotal role in several malignancies. NPY, acting via its cognate receptors Y1, Y2 and Y5 (Y1R, Y2R and Y5R), has been shown to stimulate cancer cell proliferation, migration, invasiveness and dissemination, as well as tumor vascularization in various malignancies including neuroblastoma, Ewing sarcoma, colon, breast, prostate and liver cancers. Thus, the goal of this study was to determine if the NPY system is involved in glioma biology. Our immunohistochemistry staining of NPY, Y1R, Y2R, and Y5R in human GBM tissues revealed positive staining for NPY and Y2R in GBM cells. No expression of Y1R and Y5R was detected in GBM neoplastic population. To further elucidate the association between NPY and its receptors with GBM tumor stage and patients' survival, we used the available clinical data from the Cancer Genome Atlas Program (TCGA) database to analyze the gene expression of the NPY system. Y2R expression was increased in high-grade gliomas, while mRNA levels of NPY, Y1R and Y5R inversely correlated with the degree of glioma malignancy. Moreover, high Y2R expression was associated with worse survival in GBM patients. Importantly, endothelial Y2R is also responsible for angiogenic effects of NPY, suggesting its role in GBM vascularization. Altogether, these data suggest the involvement of NPY/Y2R axis in glioma progression toward more aggressive phenotype. Further functional studies are required to determine the role of the Y2R axis in this process. Citation Format: Nouran Abualsaud, Jason Tilan, Bahauddeen M. Alrfaei, Harrison Glor, Taylor Polk, Ewa Izycka-Swieszewska, Joanna Kitlinska. Neuropeptide Y system 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 4392.
Abstract 5108: Immunomodulatory and anti-tumor effect of radiation and induced telomere damage to treat pediatric high-grade gliomas
Authors: Umaru Banlanjo, Shiva Senthil Kumar, Sergei Gryaznov, Rachid Drissi
Journal: Cancer Research (2024)

Abstract Pediatric high-grade gliomas (pHGGs), including diffuse intrinsic pontine glioma (DIPG) are among the most treatment refractory cancers in children. Despite multimodal therapy, prognosis is dismal with survival of &amp;lt;1 year for DIPG and a 5-year overall survival &amp;lt;10% for other pHGGs. Radiotherapy remains the only standard of care for DIPG that extends the survival by few months. In recent years, immunotherapy is emerging as a potential alternative treatment option. However, several factors have hindered the use of immunotherapy for pHGGs including “cold” immune environment with lack of immune cells infiltration, low tumor mutational burden, and lack of neo-antigen expression that prevents tumor recognition by the immune system. Therefore, novel therapies that activate the immune system while evading the tumor immunosuppression are highly needed. Here, we aim to demonstrate the immunomodulatory anti-tumor effects of THIO (6-thio-2’deoxyguanosine), a nucleoside analog and a telomerase-dependent telomere targeting agent, in DIPG mouse models. Our preclinical in vitro and in vivo data have demonstrated the efficacy of THIO in inducing telomeric damage, G2/M cell cycle arrest, and apoptosis in high-risk medulloblastoma and DIPG. Importantly, we have demonstrated that THIO crosses the blood-brain barrier and specifically targets tumor cells in an orthotopic mouse model of DIPG. THIO was shown to induce anti-tumor immunity through micronuclei formation leading to cGAS-STING pathway mediated activation of the innate and adaptive immune response in colon, lung, and hepatocellular carcinoma tumor models. Our preliminary data demonstrate the THIO-dependent induction of micronuclei formation co-localizing with cGAS and leading to STAT1 activation in DIPG cell lines. We have also shown that THIO synergistically sensitizes DIPG cells to ionizing radiation (IR), significantly decreasing cell proliferation. We are currently testing the combination of THIO+IR in an orthotopic mouse model for DIPG. We will present results on the potential of THIO and IR treatments to stimulate anti-tumor immunity through the activation of STING pathway in a syngeneic mouse model of DIPG. These preclinical studies will support the potential use of THIO and IR to treat children with high-risk pediatric brain tumors. Citation Format: Umaru Banlanjo, Shiva Senthil Kumar, Sergei Gryaznov, Rachid Drissi. Immunomodulatory and anti-tumor effect of radiation and induced telomere damage to treat pediatric high-grade gliomas [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 5108.
Abstract 2705: Hyaluronic acid impairs NK killing towards breast tumor spheroids despite elevated cytotoxicity
Authors: Brian C. Cheung, Alan T. Li, Jeffrey E. Segall, Mingming Wu
Journal: Cancer Research (2024)

Abstract The tumor microenvironment (TME) is often regarded as a critical component in tumor progression and metastasis. Among the main structural components of the TME, such as collagen and glycosaminoglycans (GAGs), hyaluronic acid (HA) is highly elevated in the breast TME, and is associated with poor prognosis. In recent years, immunotherapy has gained tremendous success in the battle against hematological cancers. Yet, solid tumors have remained a significant clinical challenge for immunotherapy due to the physical constraints they impose on immune cells. Mechanically, our previous work has shown that the abundance of high molecular weight (HMW) HA significantly reduces matrix pore sizes and softens the collagen and HA cogel, and impairs breast tumor invasion. However, it is still unclear how modulating tumor invasion through the mechanics of the TME may correlate with the efficacy of immunotherapy. In this study, we aim to investigate the effect of HMW HA on natural killer (NK) cell-based immunotherapy using a tumor spheroid model (GFP-labeled MCF-7). We introduced NK-92 MI cells into tumor spheroid embedded collagen gels with or without HA, and followed spheroid-NK cell interactions through live cell imaging. Preliminary data shows that while tumor spheroids were still able to invade in the collagen only gel, they underwent apoptosis in the presence of NK cells. More importantly, the presence of HA within the ECM reduced NK cells’ ability to kill tumor spheroids. Specifically, when surrounded by NK cells, tumor spheroids remained intact and viable in the collagen-HA cogel, while they underwent apoptosis in collagen only gels. In a parallel experiment, multicolor flow cytometry data showed that HA increased NK activation and certain cytotoxic markers (interferon-gamma, perforin, and granzyme-B), despite the fact that spheroids appeared to be more resistant towards NK cells in the presence of HA. Taken together, we speculate that the presence of HMW HA in the TME may protect solid tumors from immune attacks by modulating the mechanical environment. Citation Format: Brian C. Cheung, Alan T. Li, Jeffrey E. Segall, Mingming Wu. Hyaluronic acid impairs NK killing towards breast tumor spheroids despite elevated cytotoxicity [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 2705.
Abstract 3598: A new strategy for T cell therapy: T cells secreting TCR anti-CD3 bispecific T-cell engager
Authors: Hanli Sun, Jiao Huang, Kai Zhan, Wanli Wu, Xianqing Tang, Min Liu, Shanshan Guo, Hongjun Zheng, Yingjie Huang, Shi Zhong
Journal: Cancer Research (2024)

Abstract TCR-engineered T (TCR-T) cells and TCR-anti-CD3 bispecific T-cell engagers (TCEs) are potent TCR-based therapeutic agents with distinct advantages and limitations in tumor treatment. TCR-T cells offer durable persistence within patients but necessitate personalized manufacturing and lack the capacity to harness bystander T cells. Conversely, TCEs are readily available as "off-the-shelf" products and can recruit bystander T cells, yet they exhibit a shorter lifespan. In our study, we sought to merge the merits of both approaches by engineering T cells to secrete a TCR-anti-CD3 TCE specific for alpha fetoprotein (AFP), a tumor-associated antigen abundantly expressed in hepatocellular carcinoma (HCC). We initially identified a TCR with specificity for the AFP158-166 peptide bound to HLA-A*02:01 and enhanced its affinity to picomolar via phage display. To facilitate efficient secretion by T cells, we adapted the high-affinity TCR to a single-chain format (scTCR) and fused it with a CD3-specific single-chain antibody fragment (scAFP-TCE). Our findings demonstrated that scAFP-TCE effectively redirected bystander T cells to engage in the lysis of HCC cells. Moreover, scAFP-TCE could be secreted by T cells transduced with lentiviral particles encoding the TCE gene. These transduced T cells exhibited potent antitumor activity both independently and by enlisting bystander T cells. This innovative T cell strategy, combining the bystander-recruiting ability of fusion proteins with the durable persistence seen in T cell therapy after a single infusion, presents a promising alternative to conventional TCR-based therapeutic agents. We anticipate that this novel approach may hold substantial potential for enhancing HCC treatment and expanding the scope of TCR-based immunotherapies. Citation Format: Hanli Sun, Jiao Huang, Kai Zhan, Wanli Wu, Xianqing Tang, Min Liu, Shanshan Guo, Hongjun Zheng, Yingjie Huang, Shi Zhong. A new strategy for T cell therapy: T cells secreting TCR anti-CD3 bispecific T-cell engager [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 3598.
Abstract 2003: Chromatin based targeting of a master regulatory complex in estrogen receptor epithelial ovarian cancer
Authors: Sushil K. Jaiswal, Kevin Fedkenheuer, Ronak Khamar, Hua Tan, Valer Gotea, Abdel Elkahloun, Christina Annunziata, Laura Elnitski
Journal: Cancer Research (2024)

Abstract Ovarian cancer remains a significant contributor to cancer-related mortality in the United States, with low survival rates over the past decades. Hormonal therapies targeting estrogen receptors have shown limited efficacy. To explore mechanism of the inefficacy, our approach involved investigating ESR1 degradation within the higher order chromatin structure formed by Megacomplex. We identified a 1.3MDa Megacomplex containing ESR1, FOXA1 and PITX1, with colocalization at 2,440 genomic positions within the PEO4 cell line. Unlike cytoplasmic ESR1, the nuclear form was degraded minimally by ICI182780 (ICI), moreover, ESR1 incorporated into the Megacomplex macromolecule was least degraded. We hypothesized that this resistance might be due to sequestration within the Megacomplex, thereby preventing ICI from effectively targeting ESR1. Addition of a small molecule inhibitor of active chromatin, JQ1, in combination with ICI effectively enhanced the degradation of ESR1 within Megacomplex. The combination stopped nuclear occupancy of ESR1 and also degraded the cytoplasmic protein, thus breaking the ESR1 signaling circuit responsible for tumor cell proliferation. Pathway enrichment results consistently identified similar gene sets obtained independently for RNA-seq analysis after ESR1 modulation, and ChIP-seq analysis of Megacomplex bound genes. Likewise, proteins enriched within the Megacomplex macromolecule, as revealed from mass-spec analysis, returned similar pathway enrichments, directly implicating Megacomplex in ESR1 ovarian cancer gene regulation. We conclude, ESR1 in Megacomplex is resistant to ICI and sensitized by combining ICI with JQ1. This combined treatment strategy showed inhibition of cell proliferation and viability by uncovering ESR1 within the Megacomplex, thus elucidating a novel drug resistance mechanism. Citation Format: Sushil K. Jaiswal, Kevin Fedkenheuer, Ronak Khamar, Hua Tan, Valer Gotea, Abdel Elkahloun, Christina Annunziata, Laura Elnitski. Chromatin based targeting of a master regulatory complex in estrogen receptor epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2003.