bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5817: pH responsive delivery of gemcitabine/pirarubicin co-loaded biodegradable polymeric nanoparticles for synergistic anti-cancer therapy
Authors: Gupta Priya , Kharbanda Surender M. , Singh Harpal 
Published: March 2024

Abstract
Gemcitabine, a nucleoside antimetabolite, is a widely known chemotherapeutic agent being used as a first line treatment alone or in combination with other chemo drugs for different types of cancer. However, due to its extremely short half-life in the body caused by enzymatic degradation and poor pharmacokinetics, the I.V. dosage of administration is quite high i.e., &gt;1000 mg/m2 for metastatic breast cancer treatment. Moreover, gemcitabine in combination with anthracyclines imparts synergy but free anthracyclines are reported to be associated with long term cardiac toxicity. Nanoparticle-based drug delivery systems have provided a befitted solution for improving the poor pharmacokinetic properties and systemic toxicity caused by the chemo drugs because of their ability to improve bioavailability of the drugs at the desired site as well as overcoming multi-drug resistance (MDR).In the present work, PLA-based biodegradable block copolymeric nanoparticles have been employed to co-load Gemcitabine and Pirarubicin for improved anti-cancer activity. Gemcitabine and Pirarubicin have been chemically conjugated to the amphiphilic block copolymer mPEG PLA via a pH responsive Schiff’s Base linkage using a linker molecule Levulinic acid. The prepared PIRA/GEM co-loaded nanoparticles exhibited an optimum size, zeta potential and polydispersity index i.e., 187 ± 3.5 nm, -10 ± 2.0 and &lt; 0.1 PDI respectively. Further, in the drug release experiments, these Nps displayed sustained and higher drug release in lysosomal pH (pH 5.0) than in the physiological buffer environment (pH 7.4) attributed to the pH sensitive bonding. The co-loaded Nps were prepared in multiple ratios (Pira: Gem - 1:1, 1:3, and 3:1) and investigated for in-vitro cellular inhibition studies in comparison to singly loaded drug Nps and corresponding free drug formulations in various breast cancer cell lines. Additionally, apoptotic studies revealed significant enhancement in synergistic activity in the case of PIRA/GEM co-loaded Nps in comparison to conventional free drug formulations. In conclusion, this nano-formulation demonstrated excellent anti-cancer activity against breast cancer cells therefore it may be used as a potential candidate for therapeutic use.
Citation Format: Priya Gupta, Surender M. Kharbanda, Harpal Singh. pH responsive delivery of gemcitabine/pirarubicin co-loaded biodegradable polymeric nanoparticles for synergistic anti-cancer therapy [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 5817.
Abstract 583: Spatiotemporal analyses of longitudinal specimens reveal mechanisms of response and resistance to immune checkpoint blockade in metastatic melanoma
Authors: Zhang Gao , Coussens Lisa , Herlyn Meenhard , Flaherty Keith T. , Boland Genevieve , Mills Gordon 
Published: March 2024

Abstract
Although durable responses to immune checkpoint blockade (ICB) therapies exhibit by a subgroup of patients with metastatic melanoma, most of patients have no response or develop to acquired resistance to ICB therapies within few years. Molecular mechanisms of primary and acquired resistance to ICB therapies are still elusive, which warrants further elucidation. Here, we used a holistic approach to profile 35 longitudinal tumor specimens at pre-, on-, and post-treatment time points which were derived from 7 patients (3 responders and 4 non-responders) with metastatic melanoma who progressed on sequential ICB therapies, including anti-PD-1 and anti-CTLA-4 therapies. We integrated analyses of RNA sequencing, Whole-exome Sequencing (WES), NanoString nCounter vantage 3D, Cyclic Immunofluorescence (Cyc-IF), NanoString Digital Spatial Profiling (DSP) and Multiplex Immunohistochemistry (mIHC) data of these longitudinal tumor specimens to elucidate evolutionary trajectories that occurred in both the tumor and the tumor immune microenvironment (TiME) that may have orchestrated response and resistance to ICB therapies. Simultaneous analyses of genomic, transcriptomic and proteomic data identified the re-activation of MAPK-RAS as well as PI3K pathway upon or after ICB therapies, which may elucidate the mechanism of resistance to ICB therapies. Spatially-resolved, image-based immune monitoring analysis at single cell resolution revealed that the activation status of T cell markers and T-cell checkpoint is conversely associated with potential mechanism of resistance to ICB therapies. In summary, integrated analyses of muti-oics and spatially image-based data from longitudinal tumor specimens allow us not only to reveal the dynamic co-revolution of both tumor and immune cells in TiME following sequential ICB therapies but also to provide a comprehensive perspective to molecular mechanisms of response and resistance to ICB therapies in patients with metastatic melanoma.
Citation Format: Gao Zhang, Lisa Coussens, Meenhard Herlyn, Keith T. Flaherty, Genevieve Boland, Gordon Mills. Spatiotemporal analyses of longitudinal specimens reveal mechanisms of response and resistance to immune checkpoint blockade in metastatic 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 583.
Abstract 5830: A first-of-its-kind model that reconstitutes targeted drug-induced cellular transdifferentiation
Authors: Gopal Priyanka , Abazeed Mohamed 
Published: March 2024

Abstract
Introduction: Lung tumors treated with targeted therapies ultimately relapse due to intra-genic resistance mutations, bypass pathway activation, or cellular lineage changes. Newer precision therapies have higher selectivity and potency against both resistant and activating gene mutations, resulting in a significant increase in incidence of cellular transdifferentiation. The most common form of transdifferentiation is the change from lung adenocarcinomas (LUADs) to small cell lung cancer (t-SCLC) upon drug treatment which remains very poorly understood.
Methods: We have combined patient derived xenografts (PDX) and ex vivo lines with multi-omic characterization, high-content image-based morphometry and fluorescence tracking, and single-cell barcode tracing to better understand the process of lung tumor transdifferentiation.
Results: We have developed a first-of-its-kind t-SCLC model that reconstitutes ex vivo LUAD to SCLC transdifferentiation. Genomic and transcriptomic analyses of our NSCLC PDX collection identified tumors with mutation in TP53 and RB1, two genes that are altered in virtually all de novo SCLCs. PDX sample CBX336 was identified as having mutations in both TP53 and RB1, in addition to expressing the KRASG12C oncogene. Upon treatment with Sotorasib, CBX336 tumors initially demonstrated slow tumor growth, followed by a dramatic increase in the growth after prolonged drug exposure. Our experimental and computational data suggest a highly coordinated procession toward transdifferentiation with the parallel upregulation of the neuroendocrine transcription factor NEUROD1 across numerous epithelial cellular clones.
Conclusions: Our new experimental system allows characterization at the single-cell level. Ongoing work includes the integration of new resources to study lineage reprogramming, and advancing new therapeutic strategies.
Citation Format: Priyanka Gopal, Mohamed Abazeed. A first-of-its-kind model that reconstitutes targeted drug-induced cellular transdifferentiation [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 5830.
Abstract 5851: Dysregulated RNA splicing promotes AML quiescence and chemoresistance
Authors: Wang Eric , Han Cuijuan , Calderon Alexander , Lawal Abimbo , Hariramani Nidhi , Crosse Edie , Bradley Robert 
Published: March 2024

Abstract
Chemotherapy is the first-line treatment for patients with acute myeloid leukemia (AML). Although most achieve initial remission, an estimated 50% of patients will relapse with poor clinical outcome. The paucity of genetic lesions in AML patients that relapse from chemotherapy implicate non-genetic alterations that mediate chemoresistance. In this study, we conducted a longitudinal analysis of alternative splicing changes in a cohort of 19 AML patients at diagnosis and relapse post-chemotherapy treatment. We found that the long isoform of the transcription factor-encoding gene RUNX1 (also known as RUNX1C) is upregulated in AML relapse cohorts and conferred chemotherapy resistance. Mechanistically, we show that B cell translocation gene 2 (BTG2) is an RUNX1C isoform-specific transcriptional target that promote transition into a quiescent and treatment-resistant state. Direct targeting of RUNX1C mRNA augments chemotherapy response in AML patient-derived xenograft (PDX) models in vivo. These findings uncover an isoform-specific functionality that influences chemotherapy responsiveness and offers a therapeutic strategy to sensitize leukemic cells to conventional chemotherapy treatments.
Citation Format: Eric Wang, Cuijuan Han, Alexander Calderon, Abimbo Lawal, Nidhi Hariramani, Edie Crosse, Robert Bradley. Dysregulated RNA splicing promotes AML quiescence and chemoresistance [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 5851.
Abstract 586: Tumor cell-intrinsic PD-1 activation drives therapeutic resistance in colorectal cancer cells
Authors: Mok Ho Kit , Yapp Donald , Tai Isabella 
Published: March 2024

Abstract
Background/Aim: Despite advancements in diagnosis and treatment, advanced CRC remains a formidable treatment challenge with limited therapeutic options because these tumors are resistant to chemo-, radio- and targeted-therapies. Emerging research shows that the presence of tumor cell-intrinsic PD-1 (ciPD-1) in various tumor types is involved in tumorigenicity and therapy-refractory disease. For example, ciPD-1 promotes tumor growth in melanoma and liver cancer, but in lung cancer, ciPD-1 exhibits tumor-suppressive behavior. These findings highlight the intriguing possibility that ciPD-1 may exert context specific functions within the tumor, beyond its well-known role in immune response suppression. Consequently, the present study addressed the pressing need to explore the effects of immune checkpoint inhibitors within broader tumor context and tumor microenvironment. We have established drug-resistant CRC cells and found that ciPD-1 was upregulated in these cells. This, together with an observation that ciPD-1-mediated survival signaling pathways was activated in CRC patient populations, prompted us to investigate the role of ciPD-1 in regulation of therapeutic resistance in CRC in the absence of immune cells.
Methods: We evaluated the clinicopathological relevance of ciPD-1 and its correlation with disease progression in CRC samples from clinical cohorts. Monoclonal antibody inhibition and siRNA interference methods were used to characterize the functional roles of ciPD-1 in regulating therapeutic resistance in CRC. The gene expression profiles of PD-1-High and PD-1-Low patient groups retrieved from clinical cohorts were compared to identify ciPD-1-medatied survival pathways in CRC patients.
Results: We found that ciPD-1 had a critical role in regulating CRC tumorigenicity and survival outcomes. Tumors with high expression levels of ciPD-1 also showed higher mutation rate and levels of microsatellite instability. Exposing CRC cells to chemotherapy, radiation, and nutrient deprivation increased ciPD-1 levels. In line with these observations, drug-resistant CRC cells also expressed higher levels of ciPD-1. The inhibition of ciPD-1 in CRC cells by monoclonal antibody or siRNA interference decreased cell proliferation and self-renewal rates, while enhancing treatment efficacy.
Conclusion: Our studies reveal that CRC cells increase ciPD-1 expressions in response to drug treatment and targeting ciPD-1-mediated survival pathways can delay the onset of drug resistance and promote therapeutic sensitiveness in CRC cells.
Citation Format: Ho Kit Mok, Donald Yapp, Isabella Tai. Tumor cell-intrinsic PD-1 activation drives therapeutic resistance in colorectal 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 586.
Abstract 5869: Investigation of molecular alterations associated with double resistance to BRAF and MEK inhibition in melanoma
Authors: Isaak Armond J. , Clements GeGe R. , Huang Lei , Qin Yifei , Zho Qiang , Merlino Glenn , Yu Yanlin 
Published: March 2024

Abstract
More than 50% of melanomas harbor activating BRAF kinase mutations, with BRAFV600E representing more than 90% of BRAF mutations. Inhibition of mutant BRAF by BRAF inhibitors (BRAFi) in patients with advanced melanoma yields a remarkable initial clinical response. Limited duration response and disease recurrence of inhibitors occurs due to acquired drug resistance. Recently identified mechanisms of MAPK hyperactivation in acquired resistance to BRAFi have encouraged clinicians to employ a combination of BRAF and MAPK inhibitors to block the MAPK signaling pathway more effectively. However, most patients treated with this combination therapy still relapse due to de novo drug resistance. Therefore, innovative strategies are still necessary to improve the precision and durability of anti-melanoma therapies. To investigate the mechanism of both BRAFi and MEKi resistance (double resistance, DR) in mutant BRAF melanomas, we have developed models from four human melanoma cell lines to explore the hypothesis that molecular alterations are related to double resistance to BRAFi and MEKi in melanoma. We have found that BRAFi-MEKi double-resistant models exhibit distinct differences in morphology and growth kinetics. Specifically, BRAFi-MEKi double-resistant human melanomas express a higher level of FGFb and PAI-1 expression. We confirmed that overexpression of FGFb and PAI-1 in parental cells could increase the ability to resist BRAF and MEK inhibition. Additionally, we discovered that decreased expression of FGFb and PAI-1, via knock-down, inhibition, or CRISPR in double resistant cells, can restore cell sensitivity to treatments of BRAFi and MEKi. To further elucidate the role of FGFb and PAI-1 on resistant melanoma, we have extended our scope to in vivo mouse xenograft models. Our findings uncovered the mechanism of how melanoma cells can escape BRAFi and MEKi attacks and offer a rational strategy to guide future clinical treatments.
Citation Format: Armond J. Isaak, GeGe R. Clements, Lei Huang, Yifei Qin, Qiang Zho, Glenn Merlino, Yanlin Yu. Investigation of molecular alterations associated with double resistance to BRAF and MEK inhibition in 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 5869.
Abstract 5876: ALDH3A1 as a predictive marker for gemcitabine treatment in pancreatic cancer
Authors: Kim Jin Su , Keum Ji Young , Park Chan Hee , Bang Seungmin 
Published: March 2024

Abstract
Background: Pancreatic cancer is one of the incurable cancer. The currently preferred chemotherapy regimens, including gemcitabine, do not extend patient survival by more than a year, and studies on drug resistance mechanisms or biomarkers for the drug sensitivity are very limited. Aldehyde dehydrogenase (ALDH) is a family of enzymes that play an essential role in cell survival and protection. In cancer cells, it is thought that overexpression of the ALDHs confers a survival advantage to the cells, which is associated with a poor prognosis. In this study, we analyzed the drug sensitivity between ALDH3A1 expression and gemcitabine in PDAC cells.
Method: In this study, we investigated the relationship between ALDH3A1 expression and gemcitabine sensitivity using 8 pancreatic cancer cell line. We observed changes in the pattern of ALDH3A1 expression in established gemcitabine resistance pancreatic cancer cell line. Following this, we functionally inhibited ALDH3A1 to determine its impact on gemcitabine sensitivity using shRNA method. To elucidate the molecular mechanisms related with ALDH3A1, we performed multi-omics analysis such as transcriptomics and proteomics.
Results: As a results, there was a negative correlation between ALDH3A1 expression (Protein & mRNA) and gemcitabine resistance 8 pancreatic cancer cell lines. However, in established gemcitabine resistance BxPC3 cells compared to control cells, gemcitabine resistance increased more than 1000 fold while the protein expression was decreased. In these results correlated with inhibition of ALDH3A1 expression using shALDH3A1 experiments both change ALDH3A1 expression and gemcitabine resistance. In biological phenotype experiments, cell proliferation and migration increased in the ALDH3A1 inhibition groups. When using combination treatment of gemcitabine and CB29, a known ALDH3A1 inhibitor, drug resistance increased by more than 2,000 fold in the combination treatment groups. In RNAseq analysis, Adherens junction, Ras signaling, Axon guidance, and JAK-STAT signaling pathway related genes were up regulated in shALDH3A1 treatment group compared control.
Conclusion: In this study, we demonstrated the negative correlation between ALDH3A1 and gemcitabine resistant in pancreatic cancer cell lines and suggesting that it may serves as a predictive marker for gemcitabine treatment in pancreatic cancer patients.
Keywords: Pancreatic ductal adenocarcinoma (PDAC), Aldehyde dehydrogenase 3 family member A1 (ALDH3A1), Gemcitabine sensitivity.
Citation Format: Jin Su Kim, Ji Young Keum, Chan Hee Park, Seungmin Bang. ALDH3A1 as a predictive marker for gemcitabine treatment in 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 5876.
Abstract 5881: Upregulation of TET2 expression by DNA methyltransferase (DNMT) inhibitors is associated with resistance in DNMT1 knockout colorectal cancer cells
Authors: Laranjeira Angelo B. , Nguyen Dat , Pelosof Lorraine C. , Doroshow James H. , Yang Sherry X. 
Published: March 2024

Abstract
Ten-eleven-translocation 2 (TET2) is a member of the TET family proteins (TET1-3) that convert 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC) in DNA and causes site-specific DNA demethylation. The effects of DNMT1 on TET2 phenotype following DNMT inhibitor treatment is unclear in human cancer. In colorectal cancer HCT116 cells with DNMT1 gene intact (DNMT1+/+) and deletion (DNMT1−/−) status, we found that TET2 expression was robustly increased in DNMT1−/− cells after treatment with 0.5 µM and 5 µM decitabine for 72 h, 96 h, and 120 h. The augmentation in TET2 expression was accompanied by a dose-dependent re-expression of p16ink4A in DNMT1−/− cells. Particularly, TET2 upregulation was associated with resistance to DNMT inhibitors, showing a lack of induction of DNA damage, cell-cycle arrest and apoptosis after drug exposure in DNMT1−/− compared to DNMT1+/+ cells. The treatment with 4’-thio-5-aza-2’-deoxycytidine (aza-T-dCyd) only up-regulated TET2 and re-expressed p16ink4A at the lower dose of 0.5 µM, which was consistent with our previous findings that high dose of aza-T-dCyd at 5 µM predominantly eliminates the cancer cells with severe DNA damage by undergoing apoptosis and cell death (Scientific Reports, 13:5964, 2023). Moreover, both decitabine and aza-T-dCyd had minimal effects on TET2 upregulation and p16ink4A re-expression in cells with intact DNMT1 gene. The data suggest that the absence of DNMT1 gene made the cells prone to TET2 upregulation upon DNMT inhibitor challenges. Future study is needed to investigate the interactive relationship between DNMT1 and TET2 as well as demethylation, and its impact on cancer treatment with DNMT inhibitors.
Citation Format: Angelo B. Laranjeira, Dat Nguyen, Lorraine C. Pelosof, James H. Doroshow, Sherry X. Yang. Upregulation of TET2 expression by DNA methyltransferase (DNMT) inhibitors is associated with resistance in DNMT1 knockout colorectal 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 5881.
Abstract 5902: Targeting MAPK-driven tumors via inhibition of MAP2K4
Authors: Wade Mark , Tamanini Emiliano , Unbekandt Mathieu , Wallis Nicola , Lyons John , Munck Joanne , Woodhead Andrew , Schopf Patrick , Stow Jessie , East Charlotte , Clark Mellissa , Denis Jeffrey St. , Pathuri Puja 
Published: March 2024

Abstract
MAPK pathway activation is a feature of multiple tumor types. Drugging KRAS and BRAF, the two main oncogenic drivers in the MAPK pathway, has proven successful in the clinic. Inhibition of the downstream effectors, MEK and ERK, can also induce tumor regression. Despite this, many tumors are intrinsically resistant to MAPK pathway inhibitors, or acquire resistance under selective pressure to drug treatment. This creates a need for combination treatments to improve clinical responses. A synthetic lethal (SL) interaction between inhibition of the MAPK pathway and blockade of JNK-JUN signaling has recently been described1. Specifically, data from yeast genetics and CRISPR knockout experiments in human cells have identified MAP2K4 as a potential therapeutic target that could be combined with MAPK inhibitors. To date, however, no potent MAP2K4 inhibitors with in vitro and cellular selectivity against key anti-targets have been reported. Here, we describe the development of potent covalent inhibitors of MAP2K4 kinase activity. Biochemical and cell-based assays show that the compound(s) are selective for MAP2K4 versus anti-targets including MAP2K7 and ERK kinases. The combination of MAP2K4 and MEK/ERK inhibitors was effective in cell lines driven by MAPK signaling. These data provide the rationale for further development of MAP2K4 inhibitors to advance our understanding of this novel drug combination.
References: 1. Xue Z, Vis DJ, Bruna A, Sustic T, van Wageningen S, Batra AS, et al. MAP3K1 and MAP2K4 mutations are associated with sensitivity to MEK inhibitors in multiple cancer models. Cell Res. 2018; 28:719-29.
Citation Format: Mark Wade, Emiliano Tamanini, Mathieu Unbekandt, Nicola Wallis, John Lyons, Joanne Munck, Andrew Woodhead, Patrick Schopf, Jessie Stow, Charlotte East, Mellissa Clark, Jeffrey St. Denis, Puja Pathuri. Targeting MAPK-driven tumors via inhibition of MAP2K4 [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 5902.