bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 487: ITI-1020, a novel PDE type 1 inhibitor, reduces tumor growth in triple negative breast cancer (TNBC) mouse models
Authors: Voisin Maud , Kogan Aksinija A. , Goding Stephen , Snyder Gretchen L. , Davis Robert E. 
Published: April 2023

Abstract
Breast cancer is the most common cancer in women. Unfortunately, some patients do not benefit from most therapies and may even develop resistance to previously effective treatments leading to disease progression. Therefore, treatment resistance remains a significant challenge and new treatments are needed to overcome this problem.
ITI-1020 is a potent and highly selective inhibitor of the phosphodiesterase 1 (PDE1) enzyme. Given the role of PDE1 in the regulation of essential cellular functions, including among others the transition of monocytes to macrophages and potentially the infiltration of macrophages into the tumor microenvironment (TME), we hypothesize that ITI-1020 will alter macrophage infiltration and polarization, as well as improve T cell function and recruitment into the TME, thereby promoting antitumor immunity in murine cancer models.
We tested this hypothesis by studying the effect of ITI-1020 given, alone or in combination a PD-1 immune checkpoint inhibitor, on tumor growth, and TME composition of E0771 and 4T1 tumor-bearing mice, two syngeneic models of TNBC.
Mice treated with ITI-1020 alone or in combination with anti-PD-1 antibody showed significant inhibition of tumor growth compared to isotype controls in both type of tumors. Flow cytometry analysis of the tumor microenvironment showed a significant shift in the polarization of macrophages toward a more inflammatory phenotype, and/or a reduction in the number of exhausted T cells. Furthermore, scRNAseq analysis of tumors from mice treated with ITI-1020 in monotherapy showed altered expression of genes involved in inflammatory processes and cell proliferation within the tumor microenvironment and in the cancer cells.
These results suggest that ITI-1020 promotes antitumor immunity by a novel mechanism (PDE1 inhibition), leading to tumor growth inhibition in E0771 and 4T1 tumor models. Translating these findings to the clinic may provide a new hope for the treatment of refractory or resistant TNBC tumors.
Citation Format: Maud Voisin, Aksinija A. Kogan, Stephen Goding, Gretchen L. Snyder, Robert E. Davis. ITI-1020, a novel PDE type 1 inhibitor, reduces tumor growth in triple negative breast cancer (TNBC) mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 487.
Abstract 4914: Role of ClpP in the anti-cancer effects of imipridone ONC201 and ONC206
Authors: Lee Andrew , Maranto Cristina , Foster Scott , Morrow Sara , Allen Joshua E. , Lanier Randall , Sethna Phiroze , Prabhu Varun V. 
Published: April 2023

Abstract
ONC201 is the first bitopic dopamine receptor D2 (DRD2) antagonist and allosteric mitochondrial protease ClpP agonist. Downstream of target engagement, ONC201 activates the integrated stress response pathway resulting in selective tumor cell death. ONC201 is well tolerated and induces durable tumor regressions in H3 K27M-mutant glioma patients. ONC206, a derivative of ONC201 currently in Phase I trials for adult and pediatric brain tumors, is also a bitopic DRD2 antagonist and ClpP agonist with nanomolar potency. We further evaluated in vitro efficacy and mechanism of action specific to ClpP for ONC206 and investigated acquired resistance to ONC201 and ONC206. FITC-casein and peptide degradation assays confirmed that ONC206 acts as an agonist of human ClpP with enhanced potency relative to ONC201. Broad efficacy in the nanomolar range for ONC206 (GI50 &lt;78-889nM, 72h) was observed in 1,088 Genomics of Drug Sensitivity in Cancer (GDSC) cancer cell lines with increased sensitivity in cell lines exhibiting high ClpP mRNA expression. Among solid tumors, nervous system-related cell lines were particularly sensitive. Gene Expression Profiling Interactive Analysis (GEPIA) database analysis showed ClpP mRNA was overexpressed in glioblastoma cells relative to normal cells. GDSC observations were confirmed in glioblastoma (GBM) (T98G, A172, U87MG), H3.3 K27M mutant diffuse intrinsic pontine glioma (DIPG) (SF8628, SF7761) and astrocytoma (H4, U118MG) cell lines. ONC206 was more potent than ONC201 in cell viability assays for all glioma lines tested. SF8628 cells with a CRISPR-mediated ClpP knockout were shown to demonstrate resistance to both ONC201 and ONC206. Polyclonal resistant cell lines were generated through prolonged passaging in increasing concentrations of ONC201 or ONC206 (SF8628 and T98G cells). Cells with acquired resistance to ONC201 (ONC201Res) or ONC206 (ONC206Res) showed cross resistance to both imipridones. Time-stability of resistance was confirmed by removing drug for 2 to 4 weeks and retesting. RNAseq analysis revealed upregulation of the integrated stress response with imipridone treatment in T98G parental cells but not resistant clones. Whole genome sequencing revealed ClpP mutations in both ONC201Res and ONC206Res cells. Our results confirm the role of ClpP in the mechanism of action of ONC201 and ONC206 in tumor cells.
Citation Format: Andrew Lee, Cristina Maranto, Scott Foster, Sara Morrow, Joshua E. Allen, Randall Lanier, Phiroze Sethna, Varun V. Prabhu. Role of ClpP in the anti-cancer effects of imipridone ONC201 and ONC206. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4914.
Abstract 4941: Development of small molecule RPN13 inhibitors for treatment of glioblastoma
Authors: Chang Yung-Nien , Anchoori Ravi K. , Yamashita Alex Shimura , Rosa Marina da Costa 
Published: April 2023

Abstract
Glioblastoma (GBM) is an aggressive and deadly brain cancer with a one-year median survival due to the lack of effective targeted treatments. Our goal is to develop a small molecule inhibitor targeting RPN13 protein in the 19S proteasome complex as a new drug for GBM. RPN13 is a proteasome ubiquitin receptor that recognizes ubiquitin-conjugated proteins that are thus tagged for degradation via the 20S proteasome enzymatic complex. GBM is highly sensitive to proteasome inhibition due to its aggressive growth and accumulation of misfolded polyubiquitinated proteins that is insufficiently managed despite increased proteasome levels and enhanced proteasome activity (i.e. proteotoxic stress). Up Therapeutics judiciously designed drug-like RPN13 inhibitors to overcome limitations in the prototype RPN13 inhibitor RA190 identified at Johns Hopkins University. We selected Up284 as lead compound based upon our preliminary studies showing drug-like characteristics, specificity (binding to Cys88 of RPN13), and proteasome inhibition that produces a cytotoxic accumulation of polyUb proteins, ER stress, and reactive oxygen species. Up284 treatment selectively triggers apoptosis in solid tumor types including GBM cell lines and oncospheres. A suitable Up284 formulation was selected by measuring aqueous solubility, stability and on-target activity in mice imaged using a proteasome-dependent in vivo reporter. Up284 can be administered i.v. or orally, and it penetrates through the BBB. As a proof of concept for treatment of GBM, Up284 demonstrated on-target activity in intracranial syngeneic GL261 tumor model by inhibiting proteasome function in tumor tissues. Up284 also well tolerated and regressed tumors in syngeneic, xenograft and spontaneous models of ovarian and breast cancers with acceptable safety profile. Up284 also synergize with current frontline chemotherapeutics and can be used as a single agent or in combination for the treatment of wide range of cancers.
Citation Format: Yung-Nien Chang, Ravi K. Anchoori, Alex Shimura Yamashita, Marina da Costa Rosa. Development of small molecule RPN13 inhibitors for treatment of glioblastoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4941.
Abstract 4942: Heme targeting and its mechanistic role in triple-negative breast cancer suppression
Authors: Berisha Eranda , del Carmen Chacon Castro Maria , Ashrafi Adnin , Salamat Narges , Alemi Parinaz Sadat , Zhang Li 
Published: April 2023

Abstract
Breast cancer is the second leading cause of cancer-related deaths and comprises of approximately 30% of all cancer cases affecting women in the United States. There are three subtypes of breast cancer based on receptor profiles, with the third subtype being triple-negative breast cancer. TNBC accounts for about 10-15% of all breast cancers. The TNBC subtype lacks estrogen, progesterone, and HER2 receptors; it is associated with BRCA1 and BRCA2 mutations. This type of cancer has poor prognosis, tends to be more aggressive, and has limited treatment options compared to the other two subtypes. Heme is an essential molecule in the oxidative phosphorylation pathway and in the generation of reactive oxygen species (ROS). ROS generation causes oxidative stress and induces DNA damage in breast cancer. Therefore, targeting its activity potentially suppresses TNBC tumors. Heme-sequestering protein 2 (HeSP2) binds and sequesters heme. It has been shown that HeSP2 treatment of MDA-MB-231 cells inhibited cell proliferation and colony formation. Moreover, HeSP2 suppresses tumor growth in subcutaneously implanted TNBC MDA-MB-231 xenografts in NOD/SCID mice. Furthermore, in vitro studies using murine TNBC cell models 4T1-fluc Neo and EMT6-fluc Puro cells have also shown that cell proliferation and colony formation were inhibited after HeSP2 treatments of increasing concentrations. Thus, these results encourage the potential use of HeSP2 for breast tumor suppression. To further explore the effects of heme targeting and sequestration, we will determine heme flux in TNBC cell models by measuring the levels of heme uptake, export, synthesis, and degradation. Moreover, we will examine mitochondrial markers for OXPHOS complexes in HeSP2 treated TNBC xenografts using immunohistochemical analysis. Further studies are still underway to understand the role of heme in breast cancer, with preliminary results indicating that heme targeting, and sequestration effectively suppress triple-negative breast cancer and its progression.
Citation Format: Eranda Berisha, Maria del Carmen Chacon Castro, Adnin Ashrafi, Narges Salamat, Parinaz Sadat Alemi, Li Zhang. Heme targeting and its mechanistic role in triple-negative breast cancer suppression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4942.
Abstract 4982: The somatic mutation signature detected in gynecological mucosal melanoma
Authors: Li Zhongwu , Shen Lianyi , Liu Siyao 
Published: April 2023

Abstract
Background: Gynecological Mucosal Melanoma(GMM) is aggressive disease with a poor prognosis, where few studies focusing on its target drug and mutation signatures. Cancer as outcome of DNA mutagenesis process and can be inferred from somatic mutations signature by analyzing the genome sequence. Due to the rapid development of next-generation sequencing (NGS) and molecularly driven targeted therapy, discovering different mutation signature in cancer plays an important role in precision medicine.
Methods: The study was conducted at a high-volume melanoma center, the Peking University Cancer Hospital. We enrolled female patients with melanoma (n = 22) from 2017 to 2021. Subsequently, whole-exome sequencing performed on the Formalin-fixed paraffin-embedded (FFPE) specimens from 22 GMM patients and match normal tissues of patients. Tumor mutational burden (TMB) was measured as the number of nonsynonymous somatic mutations of whole-exome sequence coding region. Mutation signature detection base pair of six substitution subtypes: C&gt;A, C&gt;G, C&gt;T, T&gt;A, T&gt;C, and T&gt;G. NMF can be used to decompose matrix A into two nonnegative matrices.
Results: In all mutations of 22 GMM patients, we screen two mutation signatures. Signature 1 showed a strong correlation [0.77;cosine similarity value (CSV)] to the signature 3 from the COSMIC database, which represents failure of DNA double-strand break-repair by homologous recombination, which predominated in 55%(12/22) GMM patients. Signature 2 showed a strong correlation to Cosmic signature 1 (CSV = 0.791), which is has been found in all cancer types correlated with age cancer diagnosis. Patient-18 did not any treatment in our hospital, follow-up was lost. Kaplan-Meier revealed that Signature 2 was associated with longer overall survival in GMM patients and later recurrence or progression.
Conclusions: This study aimed to identify prognostic markers and the development of targeted therapy for the treatment of GMM.
Citation Format: Zhongwu Li, Lianyi Shen, Siyao Liu. The somatic mutation signature detected in gynecological mucosal melanoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4982.
Abstract 5022: Atypical protein kinase C inhibitors abrogate malignant breast cancer
Authors: Oishee Nuzhat Nowshin , Khalid Khandker Mohammad , Acevedo-Duncan Dr. Mildred 
Published: April 2023

Abstract
Breast cancer is the most common cancer type with expected cases of approximately 284,200 according to the National Cancer Institute. Atypical Protein Kinase C (aPKC) plays a significant role in many cancer types. A positive correlation between elevated PKC levels and both the invasive and chemotactic potential of human breast cancer cell lines has been suggested in in-vitro studies. In addition, the atypical protein kinase C isoforms (aPKC), PKC- and PKC- are involved in the increased proliferation of several cancer types, including breast cancer and ovarian cancer. Hence, this project focused on utilizing aPKC inhibitors, ICA-1S (5-amino-1-((1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide and - Stat (8-hydroxy-1,3,6- naphthalenetrisulfonic acid), on two malignant breast cancer cell lines (T47D and BT549) to observe the effect on cell proliferation. To observe the effects of the aPKC inhibitors on the malignant breast cancer cells, cell proliferation assays were conducted, where cells were treated with ICA-1S, and - Stat for 72 hours (about 3 days). Furthermore, to observe if ICA-1S induces apoptosis in the malignant breast cancer cells, both the cell lines were treated with ICA-1S for 120 hours (about 5 days), and western blotting techniques were utilized. The results indicated that in T47D cell line, treatment with ICA-1S (50uM) and - Stat (10uM) caused 52% and 75% reduction in cell proliferation, respectively. Moreover, with BT549 cell line, treatment with - Stat (1uM) decreased the cell proliferation by 40%. Additionally, it was observed by western blotting that ICA-1S induces apoptosis in BT549 cell line. This was shown by an increase in the cleavage of caspase 3 and PARP, along with a decrease in survivin, and phospho-BAD. However, ICA-1S did not induce apoptosis in T47D cell line. Further investigation will be conducted on determining the effect of aPKC inhibitors on the proliferation, invasion, and migration of the malignant breast cancer cell lines. In addition, siRNA treatment will be applied to knockdown PKC- and PKC- and subsequent effect will be observed. In conclusion, PKC- and PKC- plays a significant role on breast cancer, and further investigation will be conducted to analyze these roles, which will lead to the determination of a signaling pathway via which atypical protein Kinase C functions in breast cancer.
Citation Format: Nuzhat Nowshin Oishee, Khandker Mohammad Khalid, Dr. Mildred Acevedo-Duncan. Atypical protein kinase C inhibitors abrogate malignant breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5022.
Abstract 5030: Treatment of aromatase inhibitor-resistant cells with polyisoprenylated cysteinyl amide inhibitors stimulates the mitogen-activated protein kinase pathway enzymes, impedes cell proliferation and causes cell death
Authors: Lazarte Jassy Mary S. , Tilghman Syreeta L. , Lamango Nazarius S. 
Published: April 2023

Abstract
Overexpression and hyperactivity of the estrogen receptor drives 67-80% and 90% of breast cancer in women and men, respectively. Resistance to aromatase inhibitor (AI) therapies necessitates the continuous search for novel therapies. Previous studies demonstrate AI-resistance is associated with hormone-independence, enhanced motility, and increased growth factor signaling. Here, long-term letrozole-treated (LTLT-Ca) breast cancer cells were used to evaluate polyisoprenylated cysteinyl amide inhibitors (PCAIs) as potential alternative therapies for the treatment of aromatase inhibitor-resistant breast cancer. We determined the potency of PCAIs as anticancer agents by evaluating their effects on cell viability, phosphorylation of MAPK pathway enzymes, G-proteins levels, cell migration and apoptosis. Among the PCAIs tested, NSL-YHJ-2-27 showed significant potency against cell viability with an EC50 of 3.6 µM. MEK (p-MEK1/2), ERK (p-ERK1/2), and p90RSK (p-p90RSK) phosphorylation were significantly increased by 178, 119 and 125%, respectively, over controls. In addition, of the seven G-proteins evaluated, only KRAS and NRAS showed significant increases of 49% and 97%, respectively. Cell proliferation and colony formation were impeded by 82% and 74%, respectively, after PCAIs treatment. Migration of the LTLT-Ca cells was inhibited by 80% following treatment with 5 µM of NSL-YHJ-2-27. Lastly, the PCAIs also caused the degeneration of the spheroids after 10 µM PCAIs treatment, dead cells were very apparent after AO/EB staining. Our findings suggest that the PCAIs’ suppression of cell viability and activation of the MAPK pathway causes apoptosis possibly through the activation of the proapoptotic p-p90RSK isoforms. The results reveal the ability of the PCAIs to effectively cause a negative impact on several cancer hallmarks suggesting their potency as anticancer agents. These findings also support a potential role for PCAIs’ use in treating breast cancers that have become resistant to aromatase inhibitor therapies.
Citation Format: Jassy Mary S. Lazarte, Syreeta L. Tilghman, Nazarius S. Lamango. Treatment of aromatase inhibitor-resistant cells with polyisoprenylated cysteinyl amide inhibitors stimulates the mitogen-activated protein kinase pathway enzymes, impedes cell proliferation and causes cell death. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5030.
Abstract 505: Small molecule circadian clock compounds display therapeutic potential in targeting glioblastoma stem cells
Authors: Chan Priscilla , Wu Lian , Hovsepyan Anahit , Mkhitaryan Seda , Karapetyan Gevorg , Shah Khalid , Wakimoto Hiroaki , Kamenecka Theodore , Solt Laura A. , Cope Jamie , Moats Rex A. , Hirota Tsuyoshi , Rich Jeremy N. , Kay Steve A. 
Published: April 2023

Abstract
Glioblastoma multiforme (GBM) is the most common primary brain tumor, claiming the lives of roughly 10,000 Americans each year. Despite being the first cancer analyzed through the Cancer Genome Atlas, treatment success remains minimal, resulting average survival time of patients is 15 months following diagnosis and a five-year survival rate is 6.8%. One of the major challenges in treating GBM is the presence of GBM stem cells (GSCs) that are resistant to temozolomide (TMZ) chemotherapy and radiation, which is part of the current standard of care for GBM following maximal surgical resection. We found, however, that GSCs have a unique dependence on core circadian clock proteins, Brain and Muscle ARNTL-Like 1 (BMAL1) and Circadian Locomoter Output Cycles Protein Kaput (CLOCK), which is not observed in differentiated GBM cells or normal neuronal stem cells. Here we explore the use of novel small molecule circadian clock compounds that either lower BMAL1 transcription (REV-ERB agonists) or inhibit BMAL1::CLOCK heterodimer transcriptional activity (Cryptochrome (CRY) stabilizers or Casein Kinase (CK) 1/2 inhibitors) in targeting GSCs in in vitro patient derived cell lines and in in vivo GBM patient-derived xenograft (PDX) models. GSCs display increased sensitivity to clock compounds at single agent and combinations of clock compounds compared to non-cancerous cells, U2OS human osteosarcoma cells, and differentiated GSCs. Additionally, clock compounds are significantly more effective in targeting GSCs than TMZ. The clock compound SHP1705 increased over survival and delayed tumor growth in GBM PDX models. These results highlight the therapeutic potential small molecule circadian clock compounds have against GBM as both a single agent and adjuvant to existing therapies by specifically targeting the GSC population.
Citation Format: Priscilla Chan, Lian Wu, Anahit Hovsepyan, Seda Mkhitaryan, Gevorg Karapetyan, Khalid Shah, Hiroaki Wakimoto, Theodore Kamenecka, Laura A. Solt, Jamie Cope, Rex A. Moats, Tsuyoshi Hirota, Jeremy N. Rich, Steve A. Kay. Small molecule circadian clock compounds display therapeutic potential in targeting glioblastoma stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 505.