bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 396: Role of PHF8 in resistance to melanoma targeted therapies
Authors: Gómez-Muñoz María de los Ángeles , Eskow Nicole , Delclaux Ines , Moubarak Rana , Hernando-Monge Eva 
Published: April 2023

Abstract
Melanoma is a highly prevalent cancer with increasing incidence worldwide. While immune checkpoint inhibitors have drastically improved outcomes for about half of metastatic melanoma patients, many are still resistant to these treatments or develop life-threatening toxicities. Around 50% of melanomas carry BRAF mutations that result in constitutive activation of the MAPK pathway. Therapeutic combinations of BRAF and MEK inhibitors (MAPKi) have proven very efficient against these tumors, but responses are not durable and treatment-resistant recurrence almost inevitably occurs. Our group recently uncovered a role for the histone demethylase PHF8 in melanoma metastasis, and demonstrated that PHF8 directly controls the expression of key components of the TGFβ pathway. Given that TGFβ signaling crosstalks with the MAPK pathway and contributes to resistance to therapy in various tumors, we decided to investigate a potential role for PHF8 in response and resistance to MAPKi therapy in melanoma. To test our hypothesis, we assessed the effect of modulating PHF8 expression in BRAFV600E-mutant cells and their matched MAPKi-resistant derivatives. PHF8 silencing did not affect cell survival or proliferation of parental, MAPKi-sensitive melanoma cell lines, but it re-sensitized resistant cells to MAPKi treatment. Conversely, PHF8 overexpression in melanoma cell lines did not affect their proliferation rate but increased the emergence of resistant clones in BRAFV600E-mutant melanoma cells treated with BRAFi (Dabrafenib) and MEKi (Trametinib) combinations. Next, we assessed the dynamics of PHF8 expression and TGFβ signaling in melanoma cells exposed to MAPKi. Treatment of MAPKi-sensitive cells leads to a fast and complete downregulation of PHF8 protein expression without a change in mRNA levels, paralleled by reduced TGFβ signaling, as evidenced by decreased SMAD2 phosphorylation. However, PHF8 protein expression is restored in MAPKi resistant clones. Therefore, based on our preliminary data, we postulate that PHF8 suppression by the MAPK pathway plays a critical role in melanoma response to targeted therapy and that its restoration contributes to acquisition of resistance. We are currently investigating MAPK-dependent mechanisms controlling PHF8 stability, and testing novel PHF8 inhibitors for their ability to bypass or overcome melanoma resistance to MAPKi. Our studies might provide basis for a novel epigenetic therapy as a strategy to maximize the potential of MAPKi therapy in melanoma treatment.
Citation Format: María de los Ángeles Gómez-Muñoz, Nicole Eskow, Ines Delclaux, Rana Moubarak, Eva Hernando-Monge. Role of PHF8 in resistance to melanoma targeted therapies [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 396.
Abstract 3968: Conophylline-target ARL6ip1 regulates Ran-mediated cellular migration and invasion in human colorectal cancer cells
Authors: Lin Yinzhi , Karnan Sivasundaram , Ito Hideaki , Umezawa Kazuo 
Published: April 2023

Abstract
Introduction: Conophylline is an alkaloid isolated from the leaves of Ervatamia microphylla. We isolated conophylline as an inhibitor of K-Ras functions. It is known to ameliorate various disease models in animals, including cancer, diabetes mellitus, NASH, and hepatic cirrhosis. On the other hand, its molecular target was determined to be ADP-ribosylation factor-like 6-interacting protein 1 (ARL6ip1) using a conophylline-biotin conjugate. ARL6ip1 is located in the endoplasmic reticulum (ER) membrane, and the conophylline-binding domain was determined by deletion mutation analysis. Known functions of ARL6ip1 include inhibition of apoptosis, inhibition of glutamate transporter, and modulation of the ER structure. However, whether ARL6ip1 is involved in the mechanisms of various biological activities of conophylline has not been proven, since knockdown of ARL6ip1 has often failed to change the cellular phenotypes. Therefore, in the present research, we knocked out ARL6ip1 in human colon carcinoma cells by CRISPR-Cas9 and studied the involvement and mechanism of ARL6ip1 in the anticancer activity of conophylline. Ran activity was measured by a pull-down assay with Ran-GTP antibody.
Materials and Methods: Conophylline was isolated from the leaves of Ervatamia microphylla. We employed HCT116 and DLD1 cells as human colorectal cancer cells. Tumorigenicity was measured by soft agar colony formation. Cellular migration was measured by a wound healing assay and cell tracking analysis. Cellular invasion was measured by a Matrigel chamber assay.
Results: Conophylline inhibited soft agar colony formation in HCT116 and DLD1 cells. It inhibited migration and invasion in HCT116 and DLD1 cells at nontoxic concentrations. Knockout of ARL6ip1 also decreased tumorigenicity, migration, and invasion in HCT116 and DLD1 cells. The mechanistic study was carried out with HCT116 cells. ARL6 and Ran are both G-proteins and are reported to interact with ARL6ip1. Although knockdown of ARL6 did not change the cell migratory activity, knockdown of Ran inhibited the migration. Conophylline inhibited the interaction of ARL6ip1 to Ran in the proximity ligation assay. Moreover, conophylline inhibited the Ran activity.
Conclusion: CRISPR-Cas9 knockout of ARL6ip1 showed a similar anticancer activity as treatment with conophylline. It is likely that the anticancer activity of conophylline would be mediated by the ARL6ip1-Ran system. Thus, ARL6ip1 would be a useful molecular target for the treatment of cancer.
Citation Format: Yinzhi Lin, Sivasundaram Karnan, Hideaki Ito, Kazuo Umezawa. Conophylline-target ARL6ip1 regulates Ran-mediated cellular migration and invasion in human colorectal 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 3968.
Abstract 3995: Trastuzumab deruxtecan, antibody-drug conjugate targeting HER2, effectively inhibits growth of patient-derived xenograft model with CIC-rearranged sarcoma
Authors: Kojima Yuki , Yagishita Shigehiro , Sudo Kazuki , Shimoi Tatsunori , Iwata Shintaro , Watanabe Shun-ichi , Ogawa Chitose , Yoshida Akihiko , Yatabe Yasushi , Yonemori Kan , Hamada Akinobu 
Published: April 2023

Abstract
Background: Capicua-double homeobox 4 (CIC-DUX4)-rearranged sarcomas (CDS) are extremely rare and highly aggressive sarcomas. There is no standard therapy for the patients with advanced CDS, and therapeutic development is needed. We evaluated preclinical efficacy of trastuzumab deruxtecan (T-DXd), a humanized monoclonal HER2-targeting antibody conjugated to a topoisomerase 1 inhibitor, DXd, in patient-derived xenograft (PDX) models with CDS.
Methods: Patient-derived tumor tissue was transplanted into subcutaneous around the flank of female NOG mice, which were treated with vehicle or T-DXd (3 mg/kg, intravenous, Day0) when the mean tumor volume reached 200 mm3. Tumor volume was assessed twice weekly for 3 weeks to assess the efficacy of T-DXd.
Results: This study included 3 CDS-derived PDXs. HER2 expression was low in one PDX and not expressed in two PDXs. One PDX was established from a specimen at initial diagnosis, two were established from specimens after prior-chemotherapy. T-DXd demonstrated significant tumor growth delay compared to vehicle in all PDX models investigated. One PDX with no efficacy was HER2-negative and had a treatment history of topoisomerase I inhibitor. In contrast, PDX of HER2-negative topoisomerase I inhibitor-resistant Ewing sarcoma was also administered T-DXd under the same conditions and was found to be refractory.
Conclusion: The present study showed that a therapeutic potential of T-DXd in CDS patients, including HER2-negative.
Citation Format: Yuki Kojima, Shigehiro Yagishita, Kazuki Sudo, Tatsunori Shimoi, Shintaro Iwata, Shun-ichi Watanabe, Chitose Ogawa, Akihiko Yoshida, Yasushi Yatabe, Kan Yonemori, Akinobu Hamada. Trastuzumab deruxtecan, antibody-drug conjugate targeting HER2, effectively inhibits growth of patient-derived xenograft model with CIC-rearranged sarcoma. [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 3995.
Abstract 400: TIP60-mediated regulation of DNp63a is associated with cisplatin resistance
Authors: Hira Akshay , Stacy Andrew J. , Zhang Jin , Kemp Mike , Kadakia Madhavi P. 
Published: April 2023

Abstract
About 5.4 million basal and squamous cell skin cancers are diagnosed each year in the US. The chemotherapeutic drug, Cisplatin is often used to treat squamous cell carcinoma (SCC) patients, but low response rates and disease recurrence is common. ΔNp63α, a member of the p53 family of transcription factors, is overexpressed and considered oncogenic in non-melanoma skin cancer where it regulates cell survival, promotes proliferation and inhibits cell apoptosis. ΔNp63α has also been shown to promote resistance to cisplatin by transcriptionally regulating several DNA damage response (DDR) genes. A previous study from our lab showed that the histone acetyltransferase (HAT) TIP60 promotes SCC proliferation by positively regulating ΔNp63α protein levels in manner dependent on the catalytic activity of TIP60. This finding suggested that TIP60 may contribute to the failure of platinum-based drugs in SCC and led us to hypothesize that TIP60-mediated acetylation of ΔNp63α regulates its stability and transcriptional activity to promote chemoresistance. Silencing endogenous TIP60 led to a decrease in ΔNp63α transcript and protein levels in multiple SCC cell lines, indicating the positive regulation of ΔNp63α by TIP60 is not cell-line specific. Further, TIP60 levels positively correlated with ΔNp63α stability, protein levels and cisplatin resistance. Stable expression of TIP60 or ΔNp63α individually promoted resistance to cisplatin and reduced cell death, whereas loss of ΔNp63α and TIP60 induced G2/M arrest, increased cell-death and sensitized cells to cisplatin. Moreover, pharmacological inhibition of TIP60 reduced acetylation of ΔNp63α and sensitized resistant cells to cisplatin. Finally, we demonstrated that ΔNp63α and TIP60 levels positively correlated with DNA repair capacity and negatively correlated with cisplatin-DNA adduct formation. Silencing of either TIP60 or ΔNp63α enhanced cisplatin-DNA adduct formation and significantly reduced expression of genes involved in DDR. Taken together, our data indicate that TIP60-mediated stabilization of ΔNp63α increases cisplatin resistance and provides critical insights into the mechanisms by which ΔNp63α confers cisplatin resistance through regulation of genes involved in DNA damage repair. Our findings suggest that inhibition of TIP60 may be therapeutically advantageous in overcoming cisplatin resistance in SCC other epithelial cancers.
Citation Format: Akshay Hira, Andrew J. Stacy, Jin Zhang, Mike Kemp, Madhavi P. Kadakia. TIP60-mediated regulation of DNp63a is associated with cisplatin resistance [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 400.
Abstract 4016: Discovery of a small-molecule EGFR inhibitor that can potently target various EGFR mutants, including C797S mutant, in vitro and in vivo
Authors: Jeon Yeejin , Lee Kiram , Jang Anna , Kim Miyeon , Yoon Kyeong Jin , Lee Yeri , Kim Dongsu , Kim Donggeon , Park Dohyun , Lim Sang Kyun , Choi Sung Pil 
Published: April 2023

Abstract
EGFR is one of receptor tyrosine kinases (RTKs) and, upon ligand binding, turns on the downstream signals that include oncogenic RAS/MEK/ERK, PI3K/AKT/mTOR, and JAK/STAT pathways. EGFR gene mutations, such as Exon 19 deletion (Del19) and L858R mutations, induce abnormal activation of the EGFR protein even in the absence of the ligand leading to various cancers. EGFR mutations are found in non-small cell lung cancer (NSCLC) patients with 10-15% frequency (approximately 50% in Asian patients).
Starting from Del19 and L8585R mutations, additional mutations in the EGFR gene occur during the treatment with 1st/2nd/3rd generation EGFR inhibitors, resulting in Del19/T790M, L858R/T790M, Del19/T790M/C797S, L858R/T790M/C797S, Del19/C797S, and L858R/C797S mutations. While double mutations that include the T790M mutation have been efficaciously treated with Osimertinib, there are currently no approved therapies that can effectively target the C797S-containing mutants.
Here we present preclinical data showing a small-molecule inhibitor that effectively disables EGFR mutants, including Del19/T790M/C797S, L858R/T790M/C797S, Del19/C797S, and L858R/C797S mutants. High potency and selectivity were confirmed by in vitro kinase assays and cellular assays. Outstanding anti-cancer activity was observed in mouse xenograft models with various EGFR mutations and, importantly, it was inactive in the EGFR wild-type model. With confirmed brain penetrance through in vivo studies, our potent EGFR inhibitor may provide a great therapeutic potential for patients with EGFR mutation-driven NSCLC.
Citation Format: Yeejin Jeon, Kiram Lee, Anna Jang, Miyeon Kim, Kyeong Jin Yoon, Yeri Lee, Dongsu Kim, Donggeon Kim, Dohyun Park, Sang Kyun Lim, Sung Pil Choi. Discovery of a small-molecule EGFR inhibitor that can potently target various EGFR mutants, including C797S mutant, in vitro and in vivo. [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 4016.
Abstract 4017: TAS2940 inhibits intracranial tumor growth and prolongs survival in HER2-aberrant and EGFR-amplified patient-derived xenograft models
Authors: Han Jing , Mahendra Mikhila , Gandhi Poojabahen , Daniele Joseph R. , Carrillo Caroline C. , Bivona Benjamin J. , Feng Ningping , Heymach John V. , Meric-Bernstam Funda , Oguchi Kei , Mizuarai Shinji , Heffernan Timothy P. , Vellano Christopher P. , Marszalek Joseph R. 
Published: April 2023

Abstract
Patients with brain tumors and metastases have poor prognosis and overall survival rates despite the advancements in neurosurgery, radiotherapy, and chemotherapy. Genomic alterations in HER2 are present in brain metastases of breast cancer (BC; ~20%) and non-small cell lung cancer (NSCLC; 13-20%), and EGFR alterations occur frequently in glioblastoma multiforme (GBM; &gt;50%). Despite the advancements in standard of care options, optimal treatment management for these patients remains an unmet medical need. Recent evidence suggests activity of systemic therapy for immune and targeted therapies in the brain, including agents targeting HER2/EGFR. HER2-targeted tyrosine kinase inhibitors lapatinib, neratinib, and tucatinib and the HER2-targeted antibodies trastuzumab and pertuzumab, in combination with chemotherapy, have been shown to improve survival of patients with HER2 overexpressing BC in the presence of brain metastases. The limited penetration of these compounds into the CNS, however, limits their efficacy. TAS2940 is an irreversible pan-ErbB inhibitor with greater brain-penetrability than poziotinib, tucatinib, and neratinib. Here, we demonstrate that TAS2940 induces downregulation of phosphorylated HER2/EGFR, reduces tumor burden, and promotes a significant increase in survival in intracranial xenograft mouse models with HER2-amplification (BC), HER2-Exon20 insertion mutation (NSCLC), and EGFR-amplification (GBM). These promising preclinical data highlight potential novel therapeutic strategies for patients with EGFR-aberrant GBM and brain metastases harboring HER2/EGFR alterations, and may help support the advancement of the ongoing first-in-human clinical trial (NCT04982926) for TAS2940 in solid tumors with EGFR and/or HER2 alterations.
Citation Format: Jing Han, Mikhila Mahendra, Poojabahen Gandhi, Joseph R. Daniele, Caroline C. Carrillo, Benjamin J. Bivona, Ningping Feng, John V. Heymach, Funda Meric-Bernstam, Kei Oguchi, Shinji Mizuarai, Timothy P. Heffernan, Christopher P. Vellano, Joseph R. Marszalek. TAS2940 inhibits intracranial tumor growth and prolongs survival in HER2-aberrant and EGFR-amplified patient-derived xenograft 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 4017.
Abstract 4067: RNA primed SMAR-TTMcells against multiple driver mutations, all HLA's, designed for first line therapy
Authors: Muzaffar Farzonai , Ryan David , Barry Walter , Abera Abenezer , Slanetz Alfred E. 
Published: April 2023

Abstract
Immune checkpoint inhibitors, such as anti-PD1 antibodies, have revolutionized cancer immunotherapy. Their success demonstrates that a patient’s own T cells recognize and treat cancer. However, anti-PD1 therapy is most effective in the treatment of cancers with high mutational burden, ~5% of all malignancies. Therefore, an alternative strategy is necessary to target cancer with lower mutational burden (the other ~95%). Importantly, the efficacy of PD-1 blockade is associated with the recruitment of new T cells from the blood rather than the activation of pre-existing tumor infiltrating lymphocytes (Yost K.E., et al. Nat. Med. 2019). Our approach is to use RNA to prime and expand T cells from the blood to cancer-specific mutations ex vivo. We can generate T cell populations reactive to as few as 8 and as many as 40 cancer-specific mutant proteins in a single production run. In vitro, these T cells have mutation-specific cytotoxicity and do not kill the normal cells. These T cells express homing receptors that allow them to infiltrate the tumor and express high levels of TNFα and IFNγ, both of which are associated with effective tumor cytotoxicity and pro-inflammatory modification of the tumor microenvironment (TME). The predominant immunophenotype of these cells is consistent with central and effector memory, CD4+ and CD8+ T cells, with almost no regulatory or exhausted T cells. We believe these T cells can be used as a cellular therapy in conjunction with, or as an alternative to, immune checkpoint inhibitors to treat lower mutational burden cancers that comprise most patients’ tumors.
Citation Format: Farzonai Muzaffar, David Ryan, Walter Barry, Abenezer Abera, Alfred E. Slanetz. RNA primed SMAR-TTMcells against multiple driver mutations, all HLA's, designed for first line therapy. [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 4067.
Abstract 4072: Class I HLA-independent lysis of immunotherapy-resistant melanoma by CD8 T cells
Authors: Xie Hongyan , Jiang Aiping , Jenney Anne , Sun Yi , Sharova Tatyana , Sade-Feldman Moshe , Revach Or-yam , Cicerchia Angelina , Rasmussen Martin Q. , Hacohen Nir , Manguso Robert T. , Jenkins Russell W. 
Published: April 2023

Abstract
Cancer immunotherapy with immune checkpoint blockade (ICB) has transformed the treatment of melanoma, although intrinsic or acquired resistance develops in nearly half of patients. Tumor-infiltrating CD8+ T lymphocytes (TILs) are key determinants of anti-tumor immunity in melanoma and other cancers, and single-cell RNA-sequencing has identified T cell states associated with improved clinical response to ICB, as well as adoptive T cell therapy (ACT). Despite these advances, strategies to identify and analyze tumor-reactive TILs in ICB-resistant patients remain limited. Here, we demonstrate that TILs from ICB-resistant melanoma patients can recognize and eliminate autologous tumor cells independent of class I HLA-TCR interactions. TILs eliminated matched melanoma cells in a time and dose-dependent fashion associated with secretion of effector cytokines. Strikingly, the deletion of B2M (resulting in loss of class I HLA surface expression) did not alter the activity of these TILs. Immunophenotyping studies confirmed that TILs are largely (&gt;95%) effector memory (Tem) CD8 T cells (CD45RA-CD45RO+CCR7-) and give rise to terminal effector cells after co-culture with matched melanoma cells. Further, the elimination of melanoma cells by TILs required intact JAK1/2 signaling, although interferon-gamma (IFNγ) was neither necessary nor sufficient for tumor cell elimination. Together, these findings demonstrate that expanded TILs from ICB-resistant melanoma patients are capable of eliminating melanoma cells via a novel, class I MHC-independent mechanism.
Citation Format: Hongyan Xie, Aiping Jiang, Anne Jenney, Yi Sun, Tatyana Sharova, Moshe Sade-Feldman, Or-yam Revach, Angelina Cicerchia, Martin Q. Rasmussen, Nir Hacohen, Robert T. Manguso, Russell W. Jenkins. Class I HLA-independent lysis of immunotherapy-resistant melanoma by CD8 T 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 4072.
Abstract 4122: TIL-containing patient-derived explant cultures reveal role of metformin on antigen presenting cell activation
Authors: Turpin Rita J. , Liu Ruixian , Munne Pauliina , Peura Aino , Rannikko Jenna , Philips Gino , Salmelin Natasha , Hurskainen Elina , Suleymanova Ilida , Mutka Minna , Meretoja Tuomo , Mattson Johanna , Mustjoki Satu , Saavalainen Päivi , Lambrechts Diether , Pouwels Jeroen , Hollmén Maija , Klefström Juha 
Published: April 2023

Abstract
Globally, breast cancer is among the most diagnosed cancer types for women. Current and upcoming breast cancer therapies are being investigated in combination with compounds that stimulate an immune response, but whether the therapeutic agents themselves have unexpected immunomodulatory effects is often overlooked. Here, we have developed a method to grow 3D cultures of intact fragments of patient-derived tissue (Patient-Derived Explant Cultures; PDECs) to assess the preclinical potential of studying human tumor cells and immune cells simultaneously ex vivo
Single cell sequencing, flow cytometry, gene expression profiling and cytokine profiling data show that the tumor immunocontexture is conserved in PDECs and that these resident immune cells respond to distinct immune stimulus
We performed gene expression profiling, flow cytometry, and cytokine profiling of drug-treated human explants and found that metformin has antitumor potential through the activation of antigen presenting cells. We further validated in vitro that metformin-mediated APC activation is largely through mitochondrial respiration inhibition irrespective of the presence of tumor cells. Our PDEC platform highlights the preclinical potential of ex vivo explants by simultaneously offering information of tumor and immune cell toxicity and mechanism.
Citation Format: Rita J. Turpin, Ruixian Liu, Pauliina Munne, Aino Peura, Jenna Rannikko, Gino Philips, Natasha Salmelin, Elina Hurskainen, Ilida Suleymanova, Minna Mutka, Tuomo Meretoja, Johanna Mattson, Satu Mustjoki, Päivi Saavalainen, Diether Lambrechts, Jeroen Pouwels, Maija Hollmén, Juha Klefström. TIL-containing patient-derived explant cultures reveal role of metformin on antigen presenting cell activation. [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 4122.