tbuckley/cabot-search huggingface dataset:
Abstract 3286: Synergistic impact of long non-coding RNA TUG1 depletion in overcoming temozolomide chemoresistance in glioblastoma
Authors: Hidekazu Kito, Yuji Kibe, Miho Suzuki, Keiko Shinjo, Yutaka Kondo
Journal: Cancer Research (2024)

Abstract Glioblastoma (GBM) stands out as the most prevalent and aggressive primary brain tumor in adults, marked by a high mortality rate. Standard therapy involves temozolomide (TMZ) chemotherapy, an alkylating agent. However, most cases develop resistance to TMZ, necessitating the development of new treatment options to overcome TMZ-resistant GBM. Long non-coding RNAs (lncRNAs) constitute a class of RNA molecules that, despite not encoding proteins, play pivotal roles in regulating diverse cellular processes. Overexpression of specific lncRNAs in cancer is linked to crucial aspects of cancer progression, such as cell proliferation, apoptosis, and metastasis. Taurine upregulated gene 1 (TUG1) is a highly expressed lncRNA in GBM, playing a crucial role in preventing excessive DNA replication stress and associated DNA damage (Nat Commun 2023).This study aimed to investigate the combined effects of TUG1 depletion and TMZ in TMZ-resistant GBM. First, we established a TMZ-resistant U251MG cell line, U251MG-R, characterized by a low DNA methylation level of the O6-methylguanine-DNA methyltransferase (MGMT) promoter. We observed that TMZ increased DNA replication stress in the U251MG-R. Depleting TUG1 by using antisense oligonucleotide (TUG1-ASO) sensitized U251MG-R cells to TMZ. Treatment with TMZ or TUG1-ASO alone inhibited cell proliferation, with the most significant inhibition observed when both were combined. Next, we employed a xenograft mouse model to evaluate the efficacy of intravenous TUG1-ASO treatment coupled with a tumor-specific drug delivery system (antiTUG1-DDS). The combination of antiTUG1-DDS with TMZ displayed the most effective suppression of tumor growth compared to either TMZ or antiTUG1-DDS alone. Targeted therapy aimed at TUG1 may be a promising approach for overcoming TMZ resistance in GBM. Citation Format: Hidekazu Kito, Yuji Kibe, Miho Suzuki, Keiko Shinjo, Yutaka Kondo. Synergistic impact of long non-coding RNA TUG1 depletion in overcoming temozolomide chemoresistance 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 3286.
Abstract 7226: Synergy between ONC201 and temozolomide on ATF4 integrated stress response in glioblastoma
Authors: Josephine Chen, Tyler J. Roady, Lanlan Zhou, Wafik S. El-Deiry
Journal: Cancer Research (2024)

Abstract Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, with a median survival of 15 months. The standard of care involves surgical resection followed by chemoradiotherapy. Even with the full course of treatment, GBM is uncurable, and patients eventually relapse. Although temozolomide (TMZ) is the first-choice chemotherapeutic for GBM, tumor drug resistance limits the effects of the treatment. There is a growing need for new therapies with enhanced efficacy on GBM tumors. Dordaviprone (ONC201) is a TNF-related apoptosis inducing ligand (TRAIL)-inducing compound that is increasingly being studied for GBM treatment. This imipridone small molecule induces apoptosis by activating the integrated stress response, which involves transcription factors ATF4 and CHOP. Subsequently, these transcription factors upregulate proapoptotic protein TRAIL and its receptor, Death Receptor 5 (DR5). This study aims to investigate the combinatory effects of chemotherapeutics TMZ and ONC201 on GBM. Preliminary studies examined the cell viability of GBM cell line U251MG after dual treatment of 0 to 10uM of ONC201 and 0 to 200uM of TMZ using the CellTiter-Glo assay. Synergy was observed between the two drugs at higher concentrations of TMZ. This synergistic interaction was further characterized using western blots. When 0, 2, and 4uM of ONC201 were administered alone or in combination with 0, 60, and 120uM of TMZ, greater ATF4 expression was observed with the dual treatments than with the monotherapies. Subsequent western blots were conducted using three GBM cell lines (U251MG, T98G, and SNB19-GFP) at three time points (8, 24, and 48 hours). All cell lines were treated with 0 and 5uM of ONC201 alone or in combination with 0 and 200uM of TMZ. For all three cell lines, ATF4 expression increased in the combined presence of TMZ and ONC201. However, the effects of TMZ on ONC201-induced ATF4 expression were most pronounced in U251MG and least conclusive in T98G. Additionally, the time points in which this increase in ATF4 expression occurred varied among cell lines. CHOP expression was also probed and was seen to increase with the combination treatment in U251MG. These observations suggest a potential synergistic relationship between chemotherapeutics ONC201 and TMZ in the ATF4 integrated stress response pathway in GBM. By exploring the effects of this dual treatment on upstream and downstream factors in the pathway, we can identify, characterize, and potentially target the root cause of this synergy. Citation Format: Josephine Chen, Tyler J. Roady, Lanlan Zhou, Wafik S. El-Deiry. Synergy between ONC201 and temozolomide on ATF4 integrated stress response 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 7226.
Abstract 5716: CDK7 as a drug target in advanced stage uveal melanoma
Authors: Francis J. Waltrich
Journal: Cancer Research (2024)

Abstract Uveal melanoma (UM) metastasizes predominantly to the liver, and most metastatic UM are BAP1-deficient. Targeted therapies, such as MEK inhibitors, have failed clinically. There are few FDA-approved therapies for metastatic UM, but these therapies are limited to only a subset of patients and have modest survival benefits. Hence, there is a need to identify novel and effective treatment strategies. Due to the low mutational burden in UM, targeting transcriptional may be an effective strategy. Here, we identified Cyclin Dependent Kinase 7 (CDK7), a key regulator of transcription, as an essential and druggable target in UM. CDK7 directly phosphorylates RNA polymerase II and is expressed in all UMs. siRNA-mediated knockdown of CDK7 decreased the growth of three BAP1-deficient UM cell lines. We tested a clinically relevant, highly specific CDK7 inhibitor, SY-5609, developed by Syros Pharmaceuticals and similarly showed that the cell lines were sensitive to the growth inhibitory effects of SY-5609. Furthermore, we observed synergistic effects on cell growth inhibition when combined with a MEK inhibitor (Trametinib). We performed RNA sequencing and identified several Hallmark Genesets to be positively enriched, including interferon-gamma response, TGF-beta signaling, and NFκB signaling after treatment with SY-5609. These results are validated using a multi-omic approach, utilizing Reverse Phase Protein Array (RPPA) data to validate transcriptome to proteome expression of these enriched pathways. Overall, our studies indicate that targeting CDK7 in uveal melanoma is a potential treatment strategy for BAP1-deficient UM and enhances MEK inhibitor efficacy. Citation Format: Francis J. Waltrich. CDK7 as a drug target in advanced stage uveal melanoma [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 5716.
Abstract 7240: Intratumor delivery of plasmid DNA encoding immune stimulating agents induces both local and systemic responses
Authors: Richard Heller, Loree C. Heller, Guilan Shi, Jody Synowiec, Julie Singh, Alex Otten, Mark J. Jaroszeski
Journal: Cancer Research (2024)

Abstract Immune checkpoint inhibitors (ICIs) have significant clinical benefits, but are limited by both primary and acquired resistance. The absence of T cells within the tumor microenvironment (TME) is a significant hurdle, reducing the efficacy of ICIs against solid tumors. Multiple studies have been initiated to modify the TME to enhance the effectiveness of ICIs. We previously demonstrated that the intratumor delivery of a plasmid encoding interleukin-12 (pIL-12) using gene electrotransfer (GET) resulted in a significant increase in T effector cells and a reduction in T regulatory cells and myeloid derived suppressor cells within the TME, inducing a robust immune response. Combining pIL-12 GET with ICIs resulted in local and systemic responses in both preclinical and clinical studies. While encouraging results were obtained, improvements were possible. For example, the established GET technology requires high applied voltage for plasmid delivery. In addition, satisfactory delivery cannot be immediately detected. Our current research has focused on developing the next generation GET technology to overcome these issues. This new system includes a pulse generator, a heat source and a tissue impedance measuring device. An array that incorporates independently addressable electrodes was also developed. A moderate elevation of the tissue temperature coupled with the electrode array enabled a 75% reduction in the applied voltage. We tested the approach in the B16.F10 mouse melanoma model. Delivery of pIL-12 with the new system resulted in 100% long-term complete regression and 100% protection from challenge. In addition, monitoring impedance within each independent section of the electrode array revealed different pulse numbers were needed to achieve delivery in each section. We next evaluated a combination therapy, pIL-12 plasmid combined with a plasmid encoding a PD1 peptide, delivered with the next-gen device. In a multi-tumor model, the plasmids were delivered to the subcutaneous tumor; tumors generated with an intraperitoneal injection were untreated. This new therapy induced complete regression of the subcutaneous tumor and blockage of peritoneal tumor growth as assessed via in vivo imaging. Peritoneal tumor growth was not affected by single plasmid delivery or when both plasmids were delivered with the established GET technology. Work is ongoing to translate this approach to clinical evaluation. Citation Format: Richard Heller, Loree C. Heller, Guilan Shi, Jody Synowiec, Julie Singh, Alex Otten, Mark J. Jaroszeski. Intratumor delivery of plasmid DNA encoding immune stimulating agents induces both local and systemic responses [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 7240.
Abstract 2394: Significance of regional lymph node dissection in patients with clear cell sarcoma and epithelioid sarcoma
Authors: Toshiyuki Takemori, Eisuke Kobayashi, Shintaro Iwata, Koichi Ogura, Shuhei Osaki, Suguru Fukushima, Akira Kawai
Journal: Cancer Research (2024)

Abstract Objective Clear cell sarcoma (CCS) and epithelioid sarcoma (ES) are common as soft-tissue sarcoma subtypes causing lymph node metastasis (LNM), but the role of regional lymph node dissection is still unclear especially in these patients without imaging evidence of LNM. Here we retrospectively investigated the significance of lymph node dissection for patients with CCS and ES. Methods Forty-one patients (CCS: 13, ES: 28) with no distant metastasis other than in the regional lymph nodes were enrolled in this study. Of these 41 patients, those without LNM on imaging findings were categorized into two groups: "with dissection (WD)" group and "no dissection (ND)" group, respectively. Overall survival (OS), lymph node metastatic-free survival (LNMFS), progression-free survival (PFS), and post-operative LNM rate were compared between two groups. Results There were 26 patients who had undergone regional lymph node dissection and 15 patients who had not undergone regional lymph node dissection (ND group). Histopathological examination revealed metastasis to the lymph nodes in 9 of the 26 patients (38.5%). 9 patients were suspected of having LNM based on preoperative imaging findings such as CT or FDG PET/CT. Among the remaining 17 patients (WD group) in whom LNM was not suspected based on preoperative imaging findings, 6 patients (35.3%) had LNM. OS (p=0.03), LNMFS (p&amp;lt;0.01), and PFS (p&amp;lt;0.01) were all significantly better in the WD group. The postoperative LNM rate was significantly lower in the WD group than in the ND group (p=0.03), and there were no significant differences in OS, LNMFS, or PFS between the CCS and ES groups in terms of histological type. Discussion Even in cases where LNM was not suspected on preoperative imaging, LNM was present in more than 30% of cases. The possibility of regional LNM should be borne in mind in soft-tissue sarcomas, which frequently present with LNM, regardless of imaging findings. We also suggested that simultaneous dissection of the regional lymph nodes at the time of resection of the primary tumor improves the prognosis. Although ES and CCS are ultra-rare sarcomas, further validation with the accumulation of case series is desirable. Citation Format: Toshiyuki Takemori, Eisuke Kobayashi, Shintaro Iwata, Koichi Ogura, Shuhei Osaki, Suguru Fukushima, Akira Kawai. Significance of regional lymph node dissection in patients with clear cell sarcoma and epithelioid sarcoma [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 2394.
Abstract 3331: Preclinical combination of ONC206 with radiotherapy and temozolomide in a GBM mouse orthotopic model
Authors: Lanlan Zhou, Leiqing Zhang, Jun Zhang, Shengliang Zhang, Wafik S. El-Deiry
Journal: Cancer Research (2024)

Abstract Glioblastoma multiforme (GBM) is the most common form of primary malignant brain tumor in adults. It is also the most aggressive and lethal. Standard of care therapy comprises maximal safe surgical resection followed by adjuvant alkylating agent temozolomide (TMZ) and radiotherapy (RT). There have only been five drugs and one device ever approved by the FDA for the treatment of GBM. The five-year survival rate for GBM patients has shown no notable improvement in the last three decades. We previously reported that the first-in-class imipridone small-molecule Dordaviprone (ONC201) decreases protein chaperone ClpX to unleash mitochondrial protease ClpP activity, integrated stress response and cell death. Preclinical combination of ONC201 (100 mg/kg weekly) with radiotherapy and Temozolomide in a GBM mouse orthotopic model results in reduced tumor burden and prolonged survival. The second generation imipridone ONC206 also activates integrated stress response and decreases ClpX in GBM cells but ONC206 is approximately 20 times more potent than its parent imipridone ONC201. ONC206 0.08 uM in combination with 12.5 uM TMZ and 2 Gy RT reduced the cell viability of GBM cells significantly compared to all single treatments and double treatments. During a short-term treatment of a GBM mouse orthotopic model, ONC206 (50 mg/kg weekly, half of ONC201 doses) synergizes with TMZ and RT to induce more tumor cell apoptosis and inhibits more tumor cell proliferation compared to other groups with single or double treatments. There are two ongoing clinical trials with ONC206: single weekly or multiple-day weekly dose regimens of single-agent, oral ONC206 in patients with recurrent, primary central nervous system (CNS) neoplasms (NCT04541082) and ONC206 alone or in combination with radiation therapy in treating patients with diffuse midline gliomas that is newly diagnosed or has come back (recurrent) or other recurrent primary malignant CNS tumors (NCT04732065). Future studies evaluating the role of immune function, mitochondrial metabolism, dopamine receptors, the ISR and TRAIL pathway in the synergistic effect would support further development of the triple combination regimen of ONC206, TMZ and radiation therapy for GBM clinical trial. Citation Format: Lanlan Zhou, Leiqing Zhang, Jun Zhang, Shengliang Zhang, Wafik S. El-Deiry. Preclinical combination of ONC206 with radiotherapy and temozolomide in a GBM mouse orthotopic model [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 3331.
Abstract 207: Tumor suppressive role of NKX2-1 in advanced thyroid cancer progression
Authors: Yo-Taro Shirai, Shioko Kimura
Journal: Cancer Research (2024)

Abstract NKX2-1 is a homeodomain transcription factor, known as a master regulator of thyroid development. NKX2-1 is also crucial for lung epithelium differentiation, and the involvement of NKX2-1 in lung carcinogenesis and cancer progression has been intensely investigated. However, the role of NKX2-1 in thyroid cancer progression remains elusive. The Cancer Genome Atlas (TCGA) dataset analysis demonstrated that papillary thyroid cancer (PTC) patients with low NKX2-1 mRNA expression had significantly poorer prognosis than those with a combination of intermediate and high mRNA expression of NKX2-1. Lentivirus-transduced tetracycline (Tet)-inducible system was used to achieve NKX2-1 overexpression in advanced follicular thyroid cancer (FTC) cell lines, FTC-238 and WRO, and an anaplastic thyroid cancer (ATC) cell line 8305C, in which NKX2-1 expression is barely/not detected. All these thyroid cancer cell lines showed significant suppression of cell proliferation with NKX2-1 overexpression. In addition, NKX2-1 overexpression inhibited migration of FTC-238 cells. The levels of mRNA and protein expression of mesenchymal markers, matrix metalloproteinase-2 (MMP-2) and fibronectin, were decreased by NKX2-1 overexpression in FTC-238 cells, suggesting a possibility that NKX2-1 partially inhibits epithelial-mesenchymal transition (EMT). SNAIL and SLUG are essential EMT transcription factors involved in metastasis in cancer progression. NKX2-1 mRNA expression was significantly lower in high SNAI1 (encoding SNAIL) expressing PTC in TCGA database. Indeed, suppression of SNAIL protein expression was found upon overexpression of NKX2-1 in FTC-238 cells which naturally express high level of SNAIL. These findings suggest that NKX2-1 may inhibit the migration of advanced thyroid cancer cells through SNAIL-induced EMT. Similarly, suppression of SLUG protein expression by overexpression of NKX2-1 was observed in WRO and 8305C cells which express high level of SLUG protein. Whether NKX2-1 overexpression inhibits migration and invasion of WRO and 8305C cells through SLUG-induced EMT is currently under examination. The Tet-inducible NKX2-1 expressing thyroid cancer cells will be used for in vivo evaluation of their metastatic ability using an immunocompromised mouse model. The findings so far suggest that NKX2-1 exerts a tumor suppressive activity in advanced thyroid cancers through suppression of cell proliferation, and cell migration presumably via suppression of EMT transcription factors. Citation Format: Yo-Taro Shirai, Shioko Kimura. Tumor suppressive role of NKX2-1 in advanced thyroid cancer progression [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 207.
Abstract 3328: Oridonin derivative compounds target STATs to inhibit triple-negative breast cancer
Authors: Gabrielle Vontz, Jun Li, Zhipin Liang, Ruixia Ma, Pingyuan Wang, Haiying Chen, Jia Zhou, Qiang Shen
Journal: Cancer Research (2024)

Abstract Breast cancer remains the second leading cause of cancer related deaths in women. Despite the development of targeted treatments and immunotherapies, triple-negative breast cancer (TNBC) continues to evade effective treatment. TNBC lacks sufficient expression of druggable markers, ER, PR, and Her2, and exhibits especially aggressive characteristics including later diagnosis, lower survival rate, and higher rates of metastasis and reoccurrence. Currently, cytotoxic chemotherapy and radiation remain the standard of care for TNBC. Our work utilizes compounds from nature to develop therapies for TNBC with improved efficacy and safety. Oridonin, a natural kaurene-type diterpenoid enriched in the medicinal herb Rabdosia rubescens, is a promising anticancer agent, but exhibits limited bioavailability and potency. Our team successfully developed oridonin derivative CYD0618 compound that exhibits significantly improved solubility and anticancer activity. This study aims to characterize the mechanism of action of CYD0618 on TNBC cells. We found that CYD0618 reduces the proliferation of TNBC cells in vitro with IC50s at the nanomolar level. We also found CYD0618 has high potency against TNBC in vivo. Within a xenograft mouse model, CYD0618 suppresses the growth of TNBC tumors and extends animal survival. Using Western blot to probe for putative targets, we found CYD0618 reduces activation of STAT3, a transcription factor critically involved in proliferation, survival, and transformation of epithelial cells. Because STAT3 is constitutively active in ~70% of human cancers, there has been a tremendous effort to develop STAT3 targeting therapies; however, none has achieved FDA approval. In addition to STAT3, we show CYD0618 also suppresses other STAT transcription factors. Compared to selective STAT3 degradation by PROTAC treatment, poly-STAT targeting by CYD0618 exhibits superior activity against TNBC cells. Our study identifies CYD0618 as a novel poly-STAT inhibitor with promising activity against TNBC. Citation Format: Gabrielle Vontz, Jun Li, Zhipin Liang, Ruixia Ma, Pingyuan Wang, Haiying Chen, Jia Zhou, Qiang Shen. Oridonin derivative compounds target STATs to inhibit 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 3328.