tbuckley/cabot-search huggingface dataset:
Abstract 3180: Suppression of the CPEB3 ribozyme modulates the progression of glioblastoma
Authors: Claire Chen, Eric Wang, Lily Tong, Mehran Nikan, Daniela A. Bota, Claudia Benavente, Andrej Luptak
Journal: Cancer Research (2024)

Abstract Glioblastoma multiforme (GBM) is the most aggressive primary malignant brain tumor in adults, with a poor prognosis that highlights a dire clinical need for innovative therapeutic interventions. Despite significant advances in diagnoses and multimodality therapies, the overall prognosis for patients with GBM remains poor, with a median survival time of 15-18 months. Therefore, there is an unmet medical need to develop alternative treatment strategies to improve clinical outcomes. Dysregulation of post-transcriptional control and translational machinery have been implicated in malignant tumor development. Cytoplasmic polyadenylation element binding proteins (CPEB1-CPEB4) are RNA-binding proteins that regulate poly(A) tail elongation of target mRNAs and subsequently contribute to phenotypic changes in cancer cells. Notably, a self-cleaving ribozyme was identified in the CPEB3 gene, but its role in cancer is wholly unexplored. Considering the role of CPEB3 as a tumor suppressor gene and the promotion of cancer progression through the downregulation of CPEB3, our hypothesis is that the CPEB3 ribozyme regulates CPEB3 expression, and its activity contributes to the progression of tumors. Using antisense oligonucleotides (ASOs) as an approach, we demonstrated that inhibition of CPEB3 ribozyme resulted in an increase of CPEB3 mRNA and protein expression. Blocking the CPEB3 ribozyme led to a significant reduction in cell proliferation, migration, and invasion in GBM cell lines. Gene set enrichment analysis (GSEA) revealed the downregulation of epithelial-mesenchymal transition (EMT), angiogenesis, and hypoxia gene sets in GBM cells treated with ASO compared to Ctrl-ASO. We further measured VEGFA mRNA and protein expression and found that ASO-treated GBM cells secreted significantly less VEGF in conditioned media. Inhibition of the CPEB3 ribozyme also mitigated the EMT process in GBM cells. Subsequently, ASO strategies were applied to patient-derived glioma stem cells (GSCs), representing a clinically relevant model for pre-clinical therapeutic intervention. We found that treatment of CPEB3 ribozyme ASO up-regulated CPEB3 mRNA and inhibited cell proliferation in GSCs. Furthermore, the combination of ASO and temozolomide chemotherapy exhibited a more pronounced decrease in GSCs proliferation compared to individual treatment alone. Collectively, this study highlights the significance of the CPEB3 ribozyme in GBM and explores therapeutic approaches focused on targeting CPEB3 in cancer. Citation Format: Claire Chen, Eric Wang, Lily Tong, Mehran Nikan, Daniela A. Bota, Claudia Benavente, Andrej Luptak. Suppression of the CPEB3 ribozyme modulates the progression of 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 3180.
Abstract 5275: Celecoxib and chloroquine enhance the antitumor effect of immune checkpoint blockade therapy, in a syngeneic mouse model for pancreatic cancer
Authors: Jaeger Moore, Dhan Chand, Daniel Levey, Daniel Von Hoff, Haiyong Han
Journal: Cancer Research (2024)

Abstract Immune checkpoint inhibitors (ICIs) have shown impressive clinical activities in some cancer types, but they have yet to demonstrate any meaningful clinical benefit in patients with pancreatic ductal adenocarcinoma (PDAC) except those with microsatellite instability high (MSI-H) tumors. Several recent studies showed that concomitant use of NSAIDs such as celecoxib by patients with certain cancers could improve the survival benefit of ICI treatment (e.g., Sebastian et al, Clin Lung Cancer, 2023;). Furthermore, autophagy inhibitors such as chloroquine were also reported to sensitize pancreatic tumors to the treatment of ICIs in mouse models for PDAC (Yamamoto, et al, Nature, 2020). We recently reported that the combination of chemotherapy (triple combination of nab-paclitaxel + gemcitabine + cisplatin) and a mouse surrogate of the IFc-enhanced anti-CTLA-4 antibody botensilimab, showed significantly improved antitumor activity in immune competent KPC syngeneic mouse model for PDAC [Tanne, et al, Cancer Res (13_Supplement), 2020]. In this study, we sought to determine whether or not the addition of celecoxib and/or chloroquine further improve the antitumor activity of triple chemotherapy and ICI in the syngeneic KPC model. We first found that celecoxib (30mg/kg P.O. QDx21) significantly enhanced the tumor growth inhibition when added to triple chemotherapy (Gemcitabine 70mg/kg I.P., Cisplatin 4mg/kg I.P., Nab-paclitaxel 25mg/kg I.V. days 1,4 and 7) plus the murine equivalents of botensilimab (100ug I.P. BIW for three weeks) and balstilimab (200ug I.P. BIW for three weeks) (p=0.004, N=10). We then performed a pilot study to assess if adding chloroquine could further improve the activity. While adding chloroquine (60mg/kg I.P. QDx21) alone did not significantly affect tumor growth the addition of both chloroquine and celecoxib greatly improve the tumor growth inhibition compared to just the triple chemotherapy and ICIs (p=0.009, N=5). Overall, our data showed that celecoxib or the combination of celecoxib and chloroquine could substantially sensitize the mouse pancreatic tumors to the treatment of chemotherapy and ICIs. (This work was supported in part by the Seena Magowitz Foundation and the Purple Pansies) Citation Format: Jaeger Moore, Dhan Chand, Daniel Levey, Daniel Von Hoff, Haiyong Han. Celecoxib and chloroquine enhance the antitumor effect of immune checkpoint blockade therapy, in a syngeneic mouse model for pancreatic 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 5275.
Abstract 3198: An analysis of breast cancer membrane lipid-modified nanoliposomes for enhanced targeting of triple-negative breast cancer
Authors: Christiana Ayertey, Parmida Amid, Mohammed H. Almozain, Robert B. Campbell
Journal: Cancer Research (2024)

Abstract Background: Every breast cancer diagnosis is unique in its own way. Triple-negative breast cancer (TNBC), has a highly aggressive phenotype characterized by a rapid growth rate profile, increased risk of metastasis and recurrence. TNBC is devoid of epidermal growth factor receptor 2, estrogen, and progesterone receptors. All three are commonly present in other forms of breast cancer disease. The aim of this study was to develop a cell membrane lipid-extracted nanoliposomes (CLENs) for selective targeting compared to conventional nanoliposomal varieties. An additional objective was to investigate the role of microenvironment on targeting using cell model of TNBC, and representations of non-target tissue environments for comparison. Method: Lipid extracts (LE) obtained from 4T1, a murine mammary carcinoma cell line from a BALB/cfC3H mouse was used to formulate the CLENs (cell membrane lipid-extracted nanoliposomes) with different ratios of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), a phospholipid used in most conventional drug delivery liposomes. Different lipid compositions and ratios were employed to evaluate cellular uptake in target, non-target and off-target cells. The target cell line, 4T1, off-target and non-target cell populations included CRL-2089, normal breast fibroblasts, SKBR3 a (human breast cancer), and A549 a (lung cancer) cell lines. Other studies involved determination of molecular charge and zeta potential of various nanoliposomal preparations and corresponding fluorescence studies in vitro. Results: The physicochemical properties of CLENs such as particle size and surface charge characteristics were vital when assessing benefit of the lipid-based preparations. The size of the CLENs typically ranged between 130 - 165 nm and zeta potential values were negatively-charged. The inclusion of 70 mol% of LE in preparation of 4T1-CLENs demonstrated increased cellular uptake and binding by the 4T1 target cells compared to the control DOPC (100%). The highest degree of selectivity was observed in early cell binding events, and with studies involving more extended incubation time points under different experimental conditions. Off-target cells demonstrated reduced uptake by comparison. Overall, 4T1-CLENs was most efficient when applied against intended target 4T1 cells, when compared to relevant control cell populations. In conclusion, studies performed to date suggest the notion that lipid extracts derived from TNBC improves targeting. Citation Format: Christiana Ayertey, Parmida Amid, Mohammed H. Almozain, Robert B. Campbell. An analysis of breast cancer membrane lipid-modified nanoliposomes for enhanced targeting of triple-negative breast 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 3198.
Abstract 5447: Microtubule-associated protein MAP2 promotes drug resistance and cancer stemness in hepatocellular carcinoma through integrin dysregulation
Authors: Ut Kei Lou, Ka-Hei Lam, Huajian Yu, Jia Jian Loh, Ki-Fong Man, Lei Zhou, Yuan Gao, Tin-Lok Wong, Cheng-Han Yu, Stephanie Ma
Journal: Cancer Research (2024)

Abstract Integrins are adhesion molecules that mediate mechanical and chemical signal transduction pathways to support cell survival and proliferation. Dysregulated integrin signaling empowers tumor cells to drive oncogenic stemness functions, including tumor initiation, epithelial plasticity, metastatic reactivation, and resistance to therapies. However, the interplay between cancer stemness and integrin signaling in hepatocellular carcinoma (HCC) remains poorly understood. HCC cells marked by CD133 represent an important functional subset of HCC tumors, displaying a dedifferentiated status with stem cell traits. In this study, transcriptome profiling reveals specific downregulation of integrin α family genes and integrin signaling in ‘HCC’ CD133+ cells isolated from NRAS+AKT-driven HCC, but not epithelial-specific ‘normal’ CD133+ cells isolated from regenerating liver. Of note, one of the most differentially upregulated genes identified in CD133+ HCC cell profiling, microtubule-associated protein MAP2, demonstrates the ability to suppress integrin expression. MAP2 overexpression is frequently observed in HCC and correlates with aggressive clinical and stemness features, including survival, tumor stage, and stemness signatures. Epigenetic modifications by H3K27Ac contribute to MAP2 upregulation. Functionally, MAP2 promotes cancer stemness and cell invasion, and confers resistance to the targeted therapy sorafenib. Mechanistically, the inhibition of collagen-binding integrin α subunits by MAP2 subsequently ablates integrin β1-mediated cell adhesion and FAK signaling. Estramustine Phosphate (EMP), previously reported to inhibit the interaction of MAP2 with actin filaments, attains a synergistic effect in suppressing tumor initiation and growth of HCC cell lines, HCC patient-derived organoids and NRAS+AKT HCC mouse model when used in combination with sorafenib. In summary, MAP2 inhibition may represent a potential novel therapy for HCC by targeting its cancer stemness roots and altering integrin signaling. Ongoing work is focused on the study of MAP2 regulation of integrin signaling and cell behaviours in the maintenance of a more stemness state in HCC. Citation Format: Ut Kei Lou, Ka-Hei Lam, Huajian Yu, Jia Jian Loh, Ki-Fong Man, Lei Zhou, Yuan Gao, Tin-Lok Wong, Cheng-Han Yu, Stephanie Ma. Microtubule-associated protein MAP2 promotes drug resistance and cancer stemness in hepatocellular carcinoma through integrin dysregulation [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 5447.
Abstract 1806: Induction of KRAS G13D dimers as a therapeutic strategy for colorectal cancer
Authors: Deekshi Angira, anbo Li, Zhiwei Zhou, Seungheon Lee, Joseph Ready, Kenneth Westover
Journal: Cancer Research (2024)

Abstract Colorectal cancer (CRC) is the third leading cause of cancer deaths. Most CRCs arise from polyps in the colon/rectum that acquire gene mutations, including frequent activation of the oncogene Kirsten rat sarcoma virus (KRAS) observed in 40% of cases, particularly at codons 12, 13, and 61. KRAS oligomerization is critical for MAPK pathway signaling, which drives CRC pathogenesis. This study evaluated compounds that bind mutant KRAS G13D to induce non-physiological dimerization. Screening of a 4.1 billion compound DNA-encoded library led to the identification of pyridinylpiperazine/quinoline compounds. These compounds demonstrated the ability to induce RAS dimer formation, subsequently reducing MAPK signaling, exhibiting similarities to BI-2852, which is known to induce formation of non-physiologic RAS dimers. Structure-activity studies yielded indole, piperidine, and morpholine variants showing improved activity in thermal shift assays (DSF) and in cell-based assays evaluating RAS signaling (p-ERK inhibition). Citation Format: Deekshi Angira, anbo Li, Zhiwei Zhou, Seungheon Lee, Joseph Ready, Kenneth Westover. Induction of KRAS G13D dimers as a therapeutic strategy for colorectal 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 1806.
Abstract 526: Identification of CDK6 binding proteins by proximity labeling reveals novel mechanisms for CDK4/6 inhibitor resistance in breast cancer
Authors: Chung Wei Ting, Yong-Ji Zhuang, Chih-Yi Lin, Chung-Jen Yu, Ta-Chung Chao, Ling-Ming Tseng, Chun-Yu Liu, Yi-Fang Tsai, Chi-Cheng Huang, Jiun-I Lai
Journal: Cancer Research (2024)

Abstract Breast cancer is one of the most prevalent cancer type in human, and the majority (~70%) is the hormone positive (HR+) subtype. The current frontline treatment of choice in metastatic HR(+) breast cancer is CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy. Current guidelines recommend CDK4/6i treatment as 1st or 2nd line, as CDK4/6i provides survival benefit and good quality of life. However, resistance eventually emerges, leading to discontinuation of CDK4/6i and switching to subsequent treatment. Investigation of mechanisms to CDK4/6i resistance is an active area of intense research. CDK6 overexpression has been reported as an important mechanism for CDK4/6i resistance by several independent groups. We incidentally discovered a point mutation in the CDK6 protein that abolishes the CDK4/6i resistance conferred by CDK6 overexpression. When treated with CDK4/6i, overexpression of wild type CDK6 did not suppress G1/S, while both non-transfected and overexpression of mutant CDK6 both had similar suppression of G1/S. We hypothesized that a binding partner to CDK6 demonstrated differential binding activity to the mutant which abolished the resistance by CDK6 overexpression. To assess this hypothesis, we performed proximity labeling (PL) by APEX2. Both wild type and mutant CDK6 were cloned into APEX-Flag/V5 vectors with either cytoplasm (NES) or nuclear (NLS) signals. Mass spectrometry following treatment by H2O2 induced biotinylation produced candidate peptides that bound with overexpressed CDK6. We identified leading candidates of differentially binding partners that bound to mutant CDK6. Further experimental validation was performed to confirm physical proximity between CDK6 and the candidate protein. Our research uncovered novel insights to how CDK6 conferred resistance towards CDK4/6i and expands knowledge into further therapeutic development. Citation Format: Chung Wei Ting, Yong-Ji Zhuang, Chih-Yi Lin, Chung-Jen Yu, Ta-Chung Chao, Ling-Ming Tseng, Chun-Yu Liu, Yi-Fang Tsai, Chi-Cheng Huang, Jiun-I Lai. Identification of CDK6 binding proteins by proximity labeling reveals novel mechanisms for CDK4/6 inhibitor resistance in breast 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 526.
Abstract 528: CDK9 inhibition activates innate immune response in prostate cancer cells
Authors: Shivani Yalala, Aishwarya Gondane, Ninu Poulose, Jing Liang, Ian G. Mills, Harri M. Itkonen
Journal: Cancer Research (2024)

Abstract Hyper-activation of transcription is frequent in cancer, which often leads to increased sensitivity to compounds targeting the transcriptional kinases, in particular cyclin-dependent kinase 9 (CDK9). However, mechanistic details as to why CDK9 inhibition selectively kills cancer cells remain largely unknown. Here, we report that CDK9 inhibition activates innate immune response through viral mimicry. In MYC over-expressing prostate cancer cells, CDK9 inhibition leads to excessive accumulation of mis-spliced RNA. Double-stranded RNA (dsRNA)-activated kinase can recognize these mis-spliced RNAs, and we show that this kinase is required for the CDK9 inhibitor-induced anti-proliferative effects. Using time-resolved transcriptional profiling (SLAM-seq), targeted proteomics and ChIP-seq, we show that, similar to viral infection, CDK9 inhibition significantly suppresses transcription of most genes but allows selective transcription and translation of certain genes. In particular, CDK9 inhibition activates NFκB-driven cytokine-signaling at the transcriptional- and secretome-levels. Transcriptional signature induced by CDK9 inhibition identifies prostate cancers with high level of genome instability, and we propose that it is possible to induce similar effects using CDK9 inhibitors. In summary, here we show that inhibition of CDK9 activates innate immune response through viral mimicry. In the future, it is important to establish if CDK9 inhibitors can potentiate the effects of immunotherapy against the late-stage prostate cancer, a currently lethal disease. Citation Format: Shivani Yalala, Aishwarya Gondane, Ninu Poulose, Jing Liang, Ian G. Mills, Harri M. Itkonen. CDK9 inhibition activates innate immune response in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 528.
Abstract 6265: FLCN variants and their role in parathyroid cancer and atypical parathyroid tumors
Authors: Callie Burke, Justin Bellizzi, Jessica Costa-Guda, Andrew Arnold
Journal: Cancer Research (2024)

Abstract Parathyroid carcinoma (PC) is rare, poses challenges in definitive diagnosis and treatment, and carries a high rate of recurrence and mortality. Atypical parathyroid tumors (APT) have histopathologic features of malignancy but lack unequivocal evidence of invasion and are of uncertain malignant potential. Analysis of genetic alterations that may play a role in PC development, particularly those that might serve as markers of malignant potential, is important for further understanding this disease. FLCN is a gene found on chromosome 17 that encodes folliculin, a ubiquitously expressed protein with roles in multiple cellular processes such as apoptosis and cell signaling. Inactivating FLCN mutations cause Birt-Hogg-Dubé syndrome (BHD), an autosomal dominant condition characterized by benign fibrofolliculomas, pulmonary cysts and spontaneous pneumothorax, and increased risk of renal cancer. Benign parathyroid tumors had previously been reported in a few BHD patients and recently one study has reported a link between FLCN mutations and parathyroid carcinoma. Germline frameshift mutations in FLCN, accompanied by somatic loss of the normal allele, were reported in two unrelated PC patients, both with clinical features suggestive of BHD, but no established diagnosis of BHD. An identical somatic frameshift FLCN mutation was reported in one PC and one APT. Interestingly, the authors noted low coverage of FLCN on whole exome sequencing, resulting in the failure to detect variants identified by Sanger sequencing, thus raising the possibility that prior studies may have missed FLCN variants. To better understand the frequency of germline or somatic FLCN mutations in PC and APT, we performed Sanger sequence analysis of the entire coding region of the FLCN gene on available tumor DNA from 11 PCs and 15 APTs. We identified no inactivating FLCN mutations in any of the PC or APT samples examined. A germline missense variant, resulting in a p.Gly325Val change, predicted to be benign/tolerated by in silico analyses, was seen in one PC and a synonymous variant (c.1233G&amp;gt;A) was seen in one APT. The absence of pathogenic mutations in our series parathyroid carcinoma and atypical parathyroid tumors suggests that FLCN mutations are rare in these parathyroid tumors. Nevertheless, germline FLCN testing and/or additional screening for BHD-related lesions in parathyroid carcinoma patients merits further consideration and study. Citation Format: Callie Burke, Justin Bellizzi, Jessica Costa-Guda, Andrew Arnold. FLCN variants and their role in parathyroid cancer and atypical parathyroid tumors [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 6265.
Abstract 2687: NK cell plasticity in SCLC is linked to tumor transcriptional diversity
Authors: Justin Malin, Sophie Zhuang, Ajit Kumar Sharma, Joseph Clara, Anish Thomas
Journal: Cancer Research (2024)

Abstract Natural Killer (NK) cells are innate lymphoid cells that are pivotal in the body’s response to cancer. To harness their cytotoxicity in clinical interventions, it is critical to understand their biology, which is highly tissue- and tumor-specific. In Small Cell Lung Cancer (SCLC), reports have described widely divergent levels of NK activity in neuroendocrine (NE) and non-neuroendocrine (non-NE) subtypes. Diminished self-antigen presentation by MHC-I is a classic trigger of NK cell activity but, counter-intuitively, NK cells exhibit reduced cytotoxicity in MHC-I downregulated NE SCLC. To explore potential causes for depressed NK activity in NE SCLC relative to non-NE, we applied scRNA-Seq to 45 SCLC patient biopsies and rapid autopsies, and identified 4000 NK cells based on gene expression signature. There was a notable dip in NK cell infiltration in NE tumors compared to non-NE tumors. Tumor cell-surface ligands recognized by activating and, unexpectedly, inhibitory NK cell receptors were generally both more highly expressed in non-NE tumors. While inhibitory NK receptors were comparable in NE and non-NE tumors, activating NK receptors were expressed significantly, though modestly, higher in non-NE. We observed tumor site-specific gene expression patterns in NK cells from different metastatic sites. Overall, there were a remarkably high number of differentially expressed genes (&amp;gt;1k) between NK cells from NE and non-NE tumors, even after controlling for tumor site. Together, our work suggests that NK cell plasticity is manifest at the level of SCLC transcriptional subtypes. Citation Format: Justin Malin, Sophie Zhuang, Ajit Kumar Sharma, Joseph Clara, Anish Thomas. NK cell plasticity in SCLC is linked to tumor transcriptional diversity [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 2687.