bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1074: Cellular uptake and metabolism of MT1-MMP-activated taxane prodrugs
Authors: Polykandritou Athina , Serre Alexandra , Spencer Hannah , Morais Goreti R. , Race Amanda , Shnyder Steven , Loadman Paul , Falconer Robert A. 
Published: June 2022

Abstract
ICT3205 is a targeted cytotoxic agent, comprised of an MT1-MMP-specific peptide and a paclitaxel warhead. Paclitaxel, originally approved in 1992, is one of the most commonly used chemotherapies for various cancer types, but is often characterized by its dose-limiting toxicity and low aqueous solubility. Tumor-targeted prodrugs are a promising strategy for the selective delivery of taxanes to prostate tumors, especially given the results of STAMPEDE trial1. Previous work has shown that ICT3205 is selectively metabolized in tumor tissue over the normal tissue, and that this is specifically mediated by MT1-MMP2. In vivo studies have demonstrated that when administered at an equimolar dose to paclitaxel, ICT3205 has a superior anticancer effect, with an absence of systemic toxicity. In this study we aim to further investigate the cellular uptake and metabolism of ICT3205 and other taxane analogues in MT1-MMP +ve (HT1080) and MT1-MMP -ve (MCF-7) cells in vitro. The compound will be also studied in the PC3 prostate cancer cell line, since it has been demonstrated before that there is a good correlation between MT1-MMP protein and mRNA expression. ICT3205 and analogues have been synthesized, and purified by semi-preparative HPLC. We report the tumor-specific metabolism of ICT3205 in prostate tumors ex vivo, and we are currently studying its cellular uptake and metabolism in MT1-MMP +ve and MT1-MMP -ve cancer cell-lines using HPLC, mass spectrometry and immunofluorescent microscopy. Moreover, ex vivo metabolism studies are performed on the analogues, while they will be also assessed for their metabolism and cellular uptake. These data will provide a better understanding of the mechanism of uptake and metabolism of this type of peptide prodrugs, and will provide the basis for the future synthesis and optimization of these prodrugs.
1.James ND et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomized controlled trial. Lancet. 2016;387(10024):1163-772.Loadman PM et al. Improved delivery of paclitaxel to prostate tumors: a membrane-type matrix metalloproteinase (MT-MMP)-targeted approach. Cancer Res. 2016;76:3
Citation Format: Athina Polykandritou, Alexandra Serre, Hannah Spencer, Goreti R. Morais, Amanda Race, Steven Shnyder, Paul Loadman, Robert A. Falconer. Cellular uptake and metabolism of MT1-MMP-activated taxane prodrugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1074.
Abstract 1104: Loss of SUV420H2 drives EGFR inhibitor resistance in EGFR mutant NSCLC cell lines
Authors: Agredo Alejandra , Pal Arpita , Lanman Nadia , Son Jihye , Kasinski Andrea L. 
Published: June 2022

Abstract
Although important advancements have been achieved in the treatment of cancer, lung cancer is still the leading cause of cancer-related deaths in both men and women, with an estimated 1.6 million deaths each year. Non-small cell lung cancer (NSCLC), which makes up ~85% of lung cancer cases, is mainly treated with radiotherapy, chemotherapies, and targeted agents. Epidermal growth factor receptor (EGFR) is commonly mutated in NSCLC patients and leads to increased proliferation and cell survival. The standard-of-care treatment for patients harboring activating mutations in EGFR is treatment with tyrosine kinase inhibitors (TKI), such as erlotinib. While tumors initially respond to TKIs, after 1-2 years most of the patients develop resistance. In ~60% of patients, TKI resistance is the results of a secondary mutation in EGFR, leading to sustained receptor activation. Whereas, in the remaining 20%, tumors turn on bypass tracks-signals to overcome inhibition of the EGFR pathway. However, in 15-20% of the cases the mechanisms underlying resistance are unknown. Hence, there is a need to identify additional mechanisms involved in TKIs resistance.
Our laboratory performed a genome-wide CRISPR Cas9 knock-out screen to identify genes that when knocked-out would drive erlotinib resistance. Fold enrichment analysis of sgRNAs, identified the protein coding gene SUV420H2 as a top candidate. SUV420H2 is a histone methyltransferase that trimethylates H4K20 (H4K20me3), enabling the establishment of constitutive and facultative heterochromatin. The process by which SUV420H2 is reduced in tumors is unknown, yet data from human samples suggests that SUV420H2 is globally downregulated in NSCLC. Additionally, loss of H4K20me3, the modification made by SUV420H2, in preneoplasia influences prognosis of NSCLC, indicating that loss of SUV420H2 function is a crucial mechanism in carcinogenesis.
SUV420H2 expression has historically been associated with generating constitutive heterochromatin. However, more recently SUV420H2 was found to silence euchromatin regions. Our recent data suggests that SUV420H2 leads to reduced transcription of the oncogene MET by silencing the oncogenic long non-coding RNA LINC01510 upstream of MET. These findings led us to hypothesize that loss of SUV420H2 leads to erlotinib resistance through to upregulation of oncogenes including MET. Moreover, we aim to identify genes that are dynamically regulated by SUV420H2 using chromatin immunoprecipitation in NSCLC cell lines to further understand SUV420H2-mediated gene regulation and its role in TKIs resistance.
Citation Format: Alejandra Agredo, Arpita Pal, Nadia Lanman, Jihye Son, Andrea L. Kasinski. Loss of SUV420H2 drives EGFR inhibitor resistance in EGFR mutant NSCLC cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1104.
Abstract 1108: Evaluation of heme inhibitory therapy in combination with chemotherapy drugs on SCLC progression
Authors: Ashrafi Adnin , Salamat Narges , Zhang Li 
Published: June 2022

Abstract
Lung cancer is the leading cause of cancer-related death in the US. It is mainly divided in two types: small cell lung cancer and non-small cell lung cancer. About 85-90% of cases are classified as non-small cell lung cancer (NSCLC). Small cell lung cancer (SCLC) is an aggressive neuroendocrine lung tumor representing 15% of lung cancers. Despite the advent of targeted therapies and chemotherapies, effective therapies for lung cancer are an unlikely outcome for most patients. SCLC is initially highly responsive to cisplatin and etoposide chemotherapy but, in almost every case, becomes rapidly chemo resistant. However, the mechanisms underlying initial sensitivity and subsequent resistance are not well investigated. Thus, alternative approaches and combination therapy is required for treating SCLCs. Recent studies in our lab show that NSCLC cells demonstrate elevated levels of heme via increased heme uptake and synthesis, and elevated oxidative phosphorylation (OXPHOS) and ATP generation which fuels NSCLC proliferation. Also, limiting heme via inhibition of heme uptake using heme sequestering peptides (HeSP2) can delay growth and progression of NSCLC tumors. This HeSP2 can also effectively inhibit angiogenesis, normalize tumor vasculature, and alleviate tumor hypoxia in NSCLC tumors and thereby inhibit lung tumor growth and progression. Tumor heterogeneity is critical for tumor growth, metastasis, and acquired therapeutic resistance. To understand if heme can effectively reduce tumor cell proliferation and growth and improve tumor microenvironment, we treated chemo resistant SCLCs with HeSP2 and in combination with commonly used chemo drugs cisplatin and etoposide. Our data shows that HesP2 can strongly inhibit cell proliferation and decreases oxygen consumption rate along with ATP generation in SCLCs. To gain insights into mechanism by which the heme sequestering peptides limit tumor growth and progression, we implanted subcutaneous or SCLC cell lines in NOD/SCID mice. Mice were treated with saline (control), HeSP2, HeSP2 and cisplatin, HeSP2 and etoposide. Tumor growth was monitored using caliper measurements. Tumors tissues were harvested, processed and paraffin embedded for immunohistochemistry (IHC) and histology experiments. These results indicate that heme sequestration can be a powerful strategy for suppressing lung tumors likely drug-resistant tumors that rely on oxidative phosphorylation for survival.
Citation Format: Adnin Ashrafi, Narges Salamat, Li Zhang. Evaluation of heme inhibitory therapy in combination with chemotherapy drugs on SCLC progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1108.
Abstract 1147: A novel anti-Galectin-3 antibody therapeutic for the treatment of triple negative breast cancer
Authors: Zhang Li , Wu Heng , Palopo Karyssa , Hu Jie , Cadiente Marvin , Nguyen Anh , Mirabella Teodelinda , Sun Dongxu 
Published: June 2022

Abstract
About 43,600 women in the U.S. are expected to die in 2021 from breast cancer. Triple negative breast cancer (TNBC), which accounts for approximately 15% of all breast cancers, is diagnosed by exclusion of expression and/or amplification of three biomarkers (estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor 2 [HER2]).Characterized by a high risk of relapse (one half of patients with early stages experience recurrence), short overall survival and progression-free survival (life expectancy of few months after failure of first-line chemotherapy), TNBC represents a high unmet medical need. Galectin-3 plays multiple roles in tumor initiation and development via a variety of cellular processes, spanning from angiogenesis to tumor migration. Galectin-3 (Gal3) expression is induced in TNBC patients and highly correlates with poor survival, as shown by our and others’ bioinformatics analysis from public database. We recently discovered and patented a series of antibodies with high specificity and affinity for Gal3, one of which is currently tested in human volunteers. This clinical candidate has shown superior pharmacokinetic properties and clean toxicity profile in GLP studies on non-human primates. Here, we show that anti-Gal3 inhibit both anchorage dependent and independent growth of TNBC cells, as well as Gal3-induced escape from NK cell killing. Also, anti-Gal3 proved to be efficacious in in vivo studies, where TNBC cells were implanted in mammary fat pads of mice and tumor progression, measured as growth of primary mass and presence of metastatic nodules in the lungs, was followed during the two months of treatment. The results presented herein support the conclusion that our therapeutic modality could offer an alternative promising treatment of TNBC.
Citation Format: Li Zhang, Heng Wu, Karyssa Palopo, Jie Hu, Marvin Cadiente, Anh Nguyen, Teodelinda Mirabella, Dongxu Sun. A novel anti-Galectin-3 antibody therapeutic for the treatment of triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1147.
Abstract 1185: Survey of genomic alterations in Merkel cell carcinoma (MCC) in the AACR Project Genie real-world database
Authors: Brazel Danielle , Kumar Priyanka , Doan Hung , Moyers Justin T. 
Published: June 2022

Abstract
Introduction: MCC is a rare and highly aggressive cutaneous neuroendocrine carcinoma with increasing incidence over the last few decades. Cytotoxic chemotherapy and checkpoint inhibitors have provided modest treatment options, however, there are no approved or standard of care targeted treatment options. Here we surveyed the presence of targetable alterations in the AACR Project Genie Database
Methods: Individual patient data were accessed from the cBioPortal. Variables of interest include demographic data, alterations annotated by OncoKB therapeutic evidence level, and TCGA PanCancer pathway alterations.
Results: A total of 295 patients with MCC were cataloged in the database. Patients included were 34.6% (n=102) female with a median age of 71. Patients identified race as 91.2% (n=269) white, 2.4% (n=7) African American, and 0.4% (n=2) Asian.
The median number of alterations was 3.00 (SD 21.4, Range 0-178). Oncogenic alterations represented 17.4% (n=660 of 3799) of mutations. Sampled tissue originated from primary tumor in 54% (n=161) verses metastases in 42.4% (n=125).
NGS identified 18.5% (n=55) with an FDA approved drug for use in a biomarker approved indication or approved drug in another indication (Level 1-3). An additional 13.9% (n=41) had a Level 4 (L4) mutation. The most common Level 3B gene mutations include PIK3CA (4.1%, n=12), and BRCA1/2 (4.1%, n=12), HRAS (1.7%, n=5), TSC1/2 (1.7%, n=5). The most common L4 mutations include PTEN (4.4%, n=13), ARID1A (3.7%, n=11), and CDKN2A (2.4%, n=7).
Only three fusions were identified; L3B fusions ATM-CDK12 and TSC2 along with Level 4 PTEN.
Copy number alterations were identified in a small subset of patients. L3B CNAs include ATM, CHEK1 (n=1), BARD1 (n=1), BRCA2 (n=1), RAD51B (n=1), RAD51D (n=1). Level 4 CNAs identified CDKN2A (n=4) and PTEN (n=1).
In 60.7% cases, PanCancer pathways were altered and 28.5% had alterations in multiple pathways. The most commonly altered pathways were RTK-RAS (37.6%, n=111), TP53 (33.9%, n=100), Cell Cycle (33.9, n=100), PI3K (32.2%, n=95) and NOTCH (30.8%, n=91). Additionally, oncogenic DNA damage repair gene alterations (BRCA1/2, CHEK1/2, ATM, PALB2, BRIP1, RAD51) were present in 7.5% (n=22) of cases.
Conclusions: Here we identified a subset of patients with targetable mutations in MCC. The majority of patients had oncogenic alterations in cancer pathways which may support the investigation of kinase inhibitors as single agent or in combination with immunotherapy or cytotoxic chemotherapy in Merkel Cell Carcinoma.
Citation Format: Danielle Brazel, Priyanka Kumar, Hung Doan, Justin T. Moyers. Survey of genomic alterations in Merkel cell carcinoma (MCC) in the AACR Project Genie real-world database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1185.
Abstract 1215: pVACsplice: Predicting neoantigens from tumor-specific alternative splicing events derived from cis-acting regulatory mutations using whole exome and RNA sequencing data
Authors: Richters Megan M. , Cotto Kelsy C. , Kiwala Susanna , Xia Huiming , Carreno Beatriz M. , Dunn Gavin P. , Ribas Antoni , Griffith Obi L. , Griffith Malachi 
Published: June 2022

Abstract
Neoantigens are tumor-specific peptides on the cell surface that can be recognized by the adaptive immune system. Personalized immunotherapies, such as cancer vaccines, rely on neoantigen prediction to identify sequences that can activate T cells to recognize and destroy the tumor. The majority of cancer vaccine trials have utilized neoantigens derived from missense mutations and small insertions and deletions. However, other mutation types could contribute to the overall neoantigen landscape, such as aberrantly spliced transcripts arising from cis-acting regulatory mutations. In this study, we explore the potential immunogenicity of alternative splicing events by creating pVACsplice, a tool to expand the capability of pVACtools, a suite of tools for neoantigen prediction (http://www.pvactools.org). pVACsplice assembles alternative transcripts from tumor-specific splicing patterns, identifies sequence changes by comparison to a reference, and predicts neoantigens from the novel regions. To verify the accuracy of alternative transcript assembly, we ran pVACsplice with HCC1395 cell line samples and performed long-read sequencing to detect the transcripts in vitro. Matched whole exome sequencing and RNA sequencing datasets from glioblastoma, melanoma, and colorectal cancer cohorts will also be analyzed with pVACsplice to obtain binding affinity estimates. We will compare these results to neoantigen predictions from other mutation sources and across cancer types to discover the prevalence of immunogenic splicing events. Finally, we will perform immunogenicity testing with a set of high quality candidates to validate our predictions. We hope to increase the number of candidates for patients’ vaccines by adding this functionality to our standard neoantigen prediction workflow. This tool could help generate a more accurate portrait of the neoantigen landscape in tumors, and in turn, enhance responses to personalized immunotherapies.
Citation Format: Megan M. Richters, Kelsy C. Cotto, Susanna Kiwala, Huiming Xia, Beatriz M. Carreno, Gavin P. Dunn, Antoni Ribas, Obi L. Griffith, Malachi Griffith. pVACsplice: Predicting neoantigens from tumor-specific alternative splicing events derived from cis-acting regulatory mutations using whole exome and RNA sequencing data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1215.
Abstract 1223: Accurate inference of genetic ancestry from cancer-derived data
Authors: Belleau Pascal , Deschênes Astrid , Tuveson David A. , Krasnitz Alexander 
Published: June 2022

Abstract
Introduction: For multiple cancer types, epidemiological data exhibit strong correlations between, on the one hand, the incidence of the disease, its severity when diagnosed, and its clinical outcome, and, on the other hand, the ancestral background of the patient. Recent studies point to genetic and phenotypic differences between tumors in patient populations with differing genetic ancestries, and to the need for more data collection to power research in this area. We sought to facilitate such analysis by developing computational tools for genetic ancestry inference from cancer-derived molecular data, without the need for the patient’s cancer-free genotype or self-declared race or ethnicity. The ability to perform such inference accurately would unlock vast amounts of such data for ancestry-oriented studies of cancer from two major sources. One is the body of data stored by similar massive digital repositories. The other is the body of archival tumor tissues from which molecular data may be generated.
Methods: We developed methods for genetic ancestry inference from cancer-derived whole exomes, transcriptomes and targeted gene panels, in the absence of matching cancer-free genomic data. These are adaptive, endowed with the ability to optimize their performance for each input cancer-derived molecular profile. As a result, these inference methods perform consistently, and with quantifiable accuracy, across a range of profiling depths and qualities, and mitigate cancer-related damage to the genome, such as somatic copy-number variation.
Results: We examined the performance of these tools with molecular data from three cancer types: pancreatic and ovarian cancers as representative of epithelial tumor types, and acute myeloid leukemia as an example of hematopoietic malignancy. Three molecular data types were considered: whole-exome sequences, exome sequences targeting a panel of cancer-related genes and RNA sequences. The inference accuracy was found to be consistently above 97% across the three cancers and the three data types.
Conclusion: Our study demonstrates the feasibility of accurate inference of genetic ancestry from cancer-derived data, with no need for matching cancer-free genotypes. Computational tools for this purpose will be made available as open-source software.
Citation Format: Pascal Belleau, Astrid Deschênes, David A. Tuveson, Alexander Krasnitz. Accurate inference of genetic ancestry from cancer-derived data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1223.
Abstract 1226: A genome wide pharmacological perturbation platform
Authors: Correia Cristina , Ung Choong Yong , Zhang Cheng , Kaufmann Scott H. , Li Hu 
Published: June 2022

Abstract
Background: Large scale genetic perturbations screens have been instrumental for many key discoveries. In the last decade sequence specific genetic perturbations created RNAi and CRISPR (PMID: 25446316). Recently, specific genome targeting approaches using single guide RNAs (sgRNAs) for the CRISPR-Cas9 system have been repurposed to induce sequence-specific repression or activation of gene expression at a genome-wide scale. Different perturbation approaches have different effects and encompass a trade-off between specificity and duration in establishing a measurable perturbation which can result in different biological readouts. However, bench-side strategies are time consuming and expensive. The method described here aims to build a systems-based computational platform to assess pharmacological and biological perturbations at genome-wide network level.Methods: Our network tool NetDecoder (Nucleic Acids Res. 2016; 44(10):e100) that models genome-wide information flow will be used to build context specific protein-protein interaction networks. These networks will be subsequently subjected to in silico perturbations and their impacts on network properties will be assessed. AVANA and Demeter datasets will be used during method validation procedures. Results: Using publicly available expression datasets we generated context specific Breast Cancer networks and individually manipulated nodes and edges of context-specific networks associated with pharmacological FDA approved targets. Our perturbation networks captured cellular rewiring by engulfing new gene players, alterations of the network size and its connectivity. Conclusions: Our in-silico genome wide perturbation platform provides a flexible approach to fine-tune single and tandem manipulations, allowing for inexpensively monitoring a range of pharmacological interventions using large omics data.
Citation Format: Cristina Correia, Choong Yong Ung, Cheng Zhang, Scott H. Kaufmann, Hu Li. A genome wide pharmacological perturbation platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1226.