bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5495: Combination therapy with poly (ADP-ribose) polymerase inhibitor in endometrial cancer
Authors: Xu Conway , Hou Xiaonan , Jessen Erik , Wang Chen , Weroha S. John 
Published: April 2023

Abstract
Objective: Endometrial cancer (EC) is the most common gynecologic malignancy and serous histology is the second most common subtype. It is associated with poorer outcomes as recurrent disease tends to be resistant to chemotherapy. Given the dearth of proven targeted therapies in this setting and the tendency for serous ECs to have homologous recombination deficiency (HRD), this study aimed to test the synergy between poly (ADP-ribose) polymerase inhibitors (PARPis) and SN38, an active metabolite of DNA topoisomerase I, irinotecan. PARPis are currently FDA approved in ovarian cancer and have their greatest efficacy in tumors with HRD while topoisomerase inhibitors are a standard chemotherapy option for recurrent cancer.
Methods: A genomic instability score (GIS) was derived from low-pass whole genome sequencing-based bioinformatics analysis according to three previously reported HRD metrics: telomeric allelic imbalance, large state transitions, and loss of heterozygosity. GIS was calculated for 34 patient derived xenograft (PDX) tumors, of which eight had serous histology. PARPi, rucaparib, and SN38 were used to treat EC PDX tumors in ex vivo 3D cell culture experiments using RealTime Glo for viability after 4-5 days of drug exposure. Synergy was assessed by calculating the combination index (CI) using Chou-Talalay method.
Results: GIS ≥ 42 was noted in 62.5% (5/8) of serous EC PDX tumors and only 19.2% (5/26) of non-serous EC PDX tumors. Synergy (CI &lt; 1.0) between rucaparib and SN38 was demonstrated in 85.7% (6/7) of serous EC PDX ex vivo 3D cell culture experiments, but only 62.5% (10/16) of non-serous EC PDX tumors.
Conclusions: Most serous EC PDX tumors had a high GIS, consistent with HRD, when compared to a minority of non-serous histologies. Furthermore, combination therapy of rucaparib and SN38 had a synergistic effect in almost all serous EC PDX models, while still being effective in a majority of non-serous models. Additional PDX tumors need to be assessed to establish the predictive value of a GIS on synergy between rucaparib and SN38. Further in vivo studies are also needed to confirm these ex vivo findings of synergy. Ultimately, the hope is to generate preclinical data which justifies the use of PARPis in serous ECs as monotherapy or in combination with other anticancer therapies.
Citation Format: Conway Xu, Xiaonan Hou, Erik Jessen, Chen Wang, S. John Weroha. Combination therapy with poly (ADP-ribose) polymerase inhibitor in endometrial 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 5495.
Abstract 5747: A novel combination therapy of arenavirus vectors and PD1-IL2v strongly potentiates tumor specific T cell responses resulting in synergistic anti-tumor efficacy
Authors: Strauss Judith , Reckendorfer Diana , Pojar Kimberly , Deak Laura Codarri , Nicolini Valeria , Sutmuller Roger , Klein Christian , Umaña Pablo , Orlinger Klaus K. , Lauterbach Henning 
Published: April 2023

Abstract
It is undisputed that CD8 T cells play a critical role in controlling tumor growth and killing tumor cells, and that tumor specific T cells are essential for clinical responses to immune checkpoint inhibitors. Yet, the induction and maintenance of functional tumor antigen specific T cell responses represent still one of the greatest challenges in cancer immunotherapy.
Therapeutic cancer vaccines based on engineered arenavirus vectors have been shown preclinically to overcome self-tolerance to tumor associated antigens (TAA) and mount unprecedented T cell responses, both, in preclinical tumor models as well as HPV16+ cancer patients in an ongoing Phase 1/2 trial. The novel PD-1 targeted IL-2 variant (PD1-IL2v) was created to maximize the potency of IL-2R activation of effector T cells while overcoming the toxicities of wildtype IL-2. Cis binding of PD1-IL2v to PD-1 and IL-2Rβγ on the same cell was recently shown to promote differentiation of stem-like CD8 T cells into better effectors and was therefore identified as an ideal compound for combination therapies with arenavirus vectors. Combination of vectors encoding tumor associated foreign or self-antigens with PD1-IL2v lead to a massive, up to 60-fold, increase of peripheral tumor specific CD8 T cell numbers compared to vector treatment alone. Notably, frequency of peripheral regulatory T cells was not enhanced by this combination. The massive increase of TAA specific CD8 T cells was associated with synergistic anti-tumor efficacy in two independent tumor models, resulting in longer survival times and up to 60% complete responders. Complete tumor clearance resulted in a stable memory T cell population and protection against tumor re-challenge. Ongoing studies will address modifications of the tumor microenvironment and further characterization of tumor infiltrating T cells upon combination therapy.
These preclinical data establish the combination of arenavirus vectors and PD1-IL2v as a promising next generation cancer immunotherapy.
Citation Format: Judith Strauss, Diana Reckendorfer, Kimberly Pojar, Laura Codarri Deak, Valeria Nicolini, Roger Sutmuller, Christian Klein, Pablo Umaña, Klaus K. Orlinger, Henning Lauterbach. A novel combination therapy of arenavirus vectors and PD1-IL2v strongly potentiates tumor specific T cell responses resulting in synergistic anti-tumor efficacy. [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 5747.
Abstract 5860: ZEB1-driven reconstruction of the hyaluronan network establishes a pro-metastatic microenvironment in lung adenocarcinoma
Authors: Lee Sieun , Park Jihye , Kim Eun Ju , Park Sungsoo , Kurie Jonathan M. , Ahn Young-Ho 
Published: April 2023

Abstract
Hyaluronan, one of the major components of the extracellular matrix (ECM), surrounds and protects neighboring cells from diverse stresses. Hyaluronan promotes epithelial-to-mesenchymal transition (EMT) and metastasis in various epithelial cancers. However, the mechanism by which the hyaluronan network built up by cancer cells regulates cancer progression and metastasis in the tumor microenvironment has not been elucidated in detail. In this study, ITIH2, a hyaluronan-binding protein that participates in building a hyaluronan network, was confirmed to be secreted from mesenchymal-like lung cancer cells when co-cultured with cancer-associated fibroblasts. ITIH2 was transcriptionally upregulated by ZEB1, an EMT-inducing transcription factor. Hyaluronic acid synthase-2 (HAS2) was also up-regulated by ZEB1, and the expression of HAS2 and ZEB1 showed a positive correlation in the TCGA database. In addition, ZEB1 controlled alternative splicing and isoform expression of CD44, a hyaluronan receptor. Interestingly, ITIH2 knockdown and 4-methylumbelliferone (4-MU), a HAS inhibitor, reduced the formation of hyaluronan cables and inhibited the migration and invasion of lung cancer cells. Likewise, when lung cancer cells were treated with “Compound S,” an ITIH2 inhibitor predicted by a deep learning-based drug-target interaction algorithm, the formation of hyaluronan cables and cell migration were suppressed. In addition, the ITIH2 inhibitor prevented the growth of metastatic tumors in an orthotopic lung cancer mouse model. Collectively, the EMT signal controlled by ZEB1 establishes the pro-metastatic hyaluronan network in the tumor microenvironment, suggesting a novel strategy for targeting the hyaluronan network to suppress lung cancer progression and metastasis.
Citation Format: Sieun Lee, Jihye Park, Eun Ju Kim, Sungsoo Park, Jonathan M. Kurie, Young-Ho Ahn. ZEB1-driven reconstruction of the hyaluronan network establishes a pro-metastatic microenvironment in lung adenocarcinoma [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 5860.
Abstract 5869: The concordant disruption of B7/CD28 immune regulators predicts the prognosis of oral carcinoma
Authors: Chang Sih-Rou 
Published: April 2023

Abstract
Immune-escape is a critical factor determining the survival of malignancies including oral squamous cell carcinoma (OSCC). The immune escape of cancer cells may be driven by B7/CD28 family members and others on the tumor cells that form ligand-inhibitory receptor complexes with immune cells. Since the family members of B7/CD28 can functionally compensate, the concomitant disruption of multiple B7/CD28 family members in OSCC pathogenesis remains elusive. RNAseq performed on OSCC and paired oral mucosa retrieved the transcriptome of OSCC, and algorithms signified the general alterations of T cell population and the increase of macrophage population in tumors relative to controls. Upregulation of CD80, CD86, PD-L1, PD-L2, CD276 and CTLA4, and downregulation of L-ICOS in OSCC relative to normal mucosa was noted. In addition, there was a high concordance in the expression profile across the dysregulated regulators. The co-upregulation of CD276 and CTLA4 was associated with the decrease of T helper and NK cell population, and the increase of Treg and myeloid dendritic cell population. Interestingly, tumors harboring higher PD-L1 and/or PD-L2 expression accompany with lower ICOS or PD1 expression exhibited worse prognosis. In combination with these immunity features in primary tumors, the survival of patients with lymph node metastasis was further worsened. In the isografic models of murine OSCC cell lines, the decrease of CD4+T population in the lymph node and increase of myeloid dendritic cell population in the spleen were induced in the host mice. Many miRNAs are involved in the modulation of immune escape for malignancies. With the treatment of inhibitors against oncogenic miRNAs which enabled the OSCC suppression, the inhibitors of miR-146a and miR-211 also resulted in the down-regulation in the protein expression of multiple B7/CD28 members. This study concludes the eminent co-disruption of B7/CD28 members in OSCC tumors, which would confound the patient survival. The efficacy of miRNA inhibitors in abrogating oncogenicity and B7/CD28 members could be a therapeutic strategy.
Citation Format: Sih-Rou Chang. The concordant disruption of B7/CD28 immune regulators predicts the prognosis of oral carcinoma. [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 5869.
Abstract 5876: Sorafenib and Lenvatinib induce vascular responses in patient derived HCC on-Chip models
Authors: Mocellin Orsola , Robinson Abbie , Olczyk Aleksandra , Treillard Stephane , Olivier Thomas , Ng Chee , Heijmans Jeroen , Goubert Désiréé , Stok Arthur , van Tienderen Gilles , Verstegen Monique , Trietsch Sebastian , Lanz Henriëtte , Vulto Paul , Joore Jos , Queiroz Karla S. 
Published: April 2023

Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Its incidence is increasing, and is closely related to advanced liver disease. Interactions in the HCC microenvironment between tumor cells and the associated stroma actively regulate tumor initiation, progression, metastasis, and therapy response. In the present study, we used the OrganoPlate graft to establish a co-culture system consisting of dissociated HCC tumors (HCC 1-8) and cell lines, HCC derived fibroblasts and vasculature. Cultures were prepared and validated by assessing their response to Sorafenib and Lenvatinib (72 hours). Cultures had their viability (alamar blue assay), and chemokine/cytokine levels in the supernatant (Luminex) determined. In addition, the organization of the vasculature in the tumor compartment was studied through immunostainings, confocal imaging, and subsequent morphological analyses. HCC models were characterized by a range of specific markers, tumor (albumin), endothelial (CD31 and VE-Cadherin) and stromal (aSMA) cells. CD31 immunostained cultures were imaged, and morphology changes quantified. Sorafenib and Lenvatinib induced changes in the tumor vasculature area and organization. Hereby, we present vascularized patient-derived HCC models that include relevant cellular players of the HCC microenvironment. These co-cultures are highly suitable for studying specific cell types as well as patient-specific responses. We envision that this patient derived model will evolve to become a platform for understanding the interplay between angiogenesis, stroma and immune infiltrate in HCC.
Citation Format: Orsola Mocellin, Abbie Robinson, Aleksandra Olczyk, Stephane Treillard, Thomas Olivier, Chee Ng, Jeroen Heijmans, Désiréé Goubert, Arthur Stok, Gilles van Tienderen, Monique Verstegen, Sebastian Trietsch, Henriëtte Lanz, Paul Vulto, Jos Joore, Karla S. Queiroz. Sorafenib and Lenvatinib induce vascular responses in patient derived HCC on-Chip 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 5876.
Abstract 5975: Discovery of mechanisms that modulate the hippo pathway and CDK6 expression in CDK4/6 inhibitor resistant breast cancer cells
Authors: Yu Chung-Jen , Zhuang Yong-Ji , Lin Ting-Yi , Chao Ta-Chung , Liu Chun-Yu , Tseng Ling-Ming , Lai Jiun-I 
Published: April 2023

Abstract
Hormone positive (HR+) breast cancer is the most common subtype in this population. The current standard of care in advanced HR+ breast cancer includes endocrine therapy (tamoxifen, aromatase inhibitors, etc) and CDK4/6 inhibitors. CDK4/6 inhibitors significantly prolong survival and is now the general accepted choice of drug in first line. Despite the enormous clinical benefit, there remains a substantial portion of patients who ultimately develop resistance against CDK4/6 inhibitors. Many mechanisms have been proposed for CDK4/6 inhibitor resistant, including upregulation of CDK4, CDK6, Cyclin E, and others. Recently studies have linked the hippo pathway to CDK6 upregulation and resulting in CDK4/6 inhibitor resistance. We have set up a kinase library screen for kinase inhibitors that downregulate CDK6 amplification and further assess for reversal of resistance. We discovered staurosporine and the PI3K inhibitor PIK-75 as small molecules that potently downregulate CDK6 expression in breast cancer cells. We further confirmed that these compounds reverse the resistance towards CDK4/6 inhibitors in CDK6 amplification cells. By kinase profiling combined with a small hairpin RNA (shRNA) screen, we discovered the mechanisms that resulted in CDK6 downregulation and modulation of the hippo pathway to reverse the CDK4/6 inhibitor resistance. Our discovery has implications for therapeutic development in this group of patients posing a huge unmet need.
Citation Format: Chung-Jen Yu, Yong-Ji Zhuang, Ting-Yi Lin, Ta-Chung Chao, Chun-Yu Liu, Ling-Ming Tseng, Jiun-I Lai. Discovery of mechanisms that modulate the hippo pathway and CDK6 expression in CDK4/6 inhibitor resistant breast cancer 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 5975.
Abstract 5977: Evaluation of the potential combination regimens for q901, a clinical stage selective cdk7 inhibitor, as a DNA damage repair inhibitor
Authors: Yu Donghoon , Jeon Yeejin , Lee YoonJi , Lee Seung-Joo , Kim Jaeseung , Jung Hyerim , Kim Tae-Kyung , Nam Kiyean 
Published: April 2023

Abstract
Background; Q901 is an extremely selective CDK7 inhibitor with potent single agent activity in the multiple in vivo tumor models including small cell lung cancer, cholangiocarcinoma, colon cancer, pancreatic cancer, hormone receptor positive breast cancer, castrate-resistant prostate cancer, and ovarian cancer. Q901 is currently in Phase 1/2 clinical trial for patients with selected advanced solid tumors (ClinicalTrials.gov: NCT05394103). In the preclinical models, Q901 treatment induces DNA damage response (DDR) impairment markers, particularly ones involved in the double-strand break repair mechanisms. This opens up broad range of possibilities for new combination regimen that could benefit from the accumulated DNA damages caused by Q901 treatment.
Methods: Various combinations have been tested to evaluate potential clinical regimens in multiple solid tumor models. Two different BRCA wild-type ovarian cancer A2780 and OVCAR3 models, an estrogen receptor positive MCF7 breast cancer model, or a syngeneic RENCA mouse renal cancer model was tested with Q901 in combination with poly ADP-ribose polymerase (PARP) inhibitor, selective estrogen receptor degrader (SERD), an estrogen receptor (ER) PROTAC degrader, or an anti-PD-1 antibody, respectively.
Results: In the A2780 model, the PARPi alone group showed 15% TGI (tumor growth inhibition), but significant tumor regression (104% TGI) was observed in the Q901 and PARPi combination. In the OVCAR3 model, the Q901 and PARPi combination group showed 105% TGI, whereas the PARPi alone group showed 38% TGI. In the MCF7 model, SERD alone showed 64% TGI and Q901 combination with SERD showed 94% TGI. Remarkable tumor regression (111% TGI) was observed in the MCF7 model combining ER PROTAC and Q901, whereas ER PROTAC alone group showed 55% TGI. In the RENCA model, the anti-PD-1 antibody alone group showed 13.2% TGI and the combination of Q901 and anti-PD-1 antibody showed 66% TGI. In summary, these preclinical model studies demonstrated significant additive/synergistic effects of the Q901 combination on tumor growth inhibition.
Conclusion: The non-clinical data demonstrate that Q901 not only has a potential as a single agent,but can also be used in combination with other therapeutic strategies to develop next-generation cancer therapeutics to potentially address unmet medical needs.
Citation Format: Donghoon Yu, Yeejin Jeon, YoonJi Lee, Seung-Joo Lee, Jaeseung Kim, Hyerim Jung, Tae-Kyung Kim, Kiyean Nam. Evaluation of the potential combination regimens for q901, a clinical stage selective cdk7 inhibitor, as a DNA damage repair inhibitor [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 5977.
Abstract 6002: Characterizing dynamic landscape of DNA methylation in ovarian high-grade serous carcinoma
Authors: Lahtinen Alexandra , Marchi Giovanni , Afenteva Daria , Holmström Susanna , Huhtinen Kaisa , Virtanen Anni , Hynninen Johanna , Häkkinen Antti , Hautaniemi Sampsa 
Published: April 2023

Abstract
Dysregulated DNA methylation (DNAm) is a hallmark of all cancer types, though the precise role of these aberrations in tumor progression and treatment response remains elusive. Advances in whole-genome bisulfite sequencing (WGBS) have enabled profiling methylomes at full resolution and stimulated interest to explore dynamics of DNAm across tumor sites and cancer treatment. A major challenge in the analysis of patient data is that a surgically removed tumor sample represents a mixture of cancer cells and microenvironment, and that the insights on DNAm changes are intertwined due to mixed effects from patient epigenomic background, tissue context, and treatment pressure. By using a computational approach, these effects can be decomposed into patient background, tissue site, and treatment phase specific changes, and controlled for natural microenvironment variation. retion, and action, as well as in several oncogenic signaling cascades. The analysis of the tissue profiles indicated that the progression of HGSC from the tissues-of-origin to the metastatic deposits is accompanied by drastic changes in DNAm profiles. Thus, when comparing ovaries and peritoneum, intra-abdominal tissues mesentery and omentum featured prominent change of promoter DNAm: loss in 10% and gain in 20% of genes. Interestingly, the genes with aberrant DNAm included ABC transporters implicated in pumping drugs across the cell membrane, as well as the members of MAPK and PI3K signaling cascades. The joint analysis of both treatment and tissue contributions suggests that the overall modest effect of NACT is further reduced in metastases, mediated via DNAm changes in genes involved in multidrug resistance.
Citation Format: Alexandra Lahtinen, Giovanni Marchi, Daria Afenteva, Susanna Holmström, Kaisa Huhtinen, Anni Virtanen, Johanna Hynninen, Antti Häkkinen, Sampsa Hautaniemi. Characterizing dynamic landscape of DNA methylation in ovarian high-grade serous carcinoma [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 6002.