bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LBA011: Discovery of combination targets of CDK inhibitors from CRISPR screens
Authors: Kim Kimberly H , Almaden Jonathan , arunachalam vinu , VanArsdale Todd , liu chaoting 
Published: December 2021

Abstract
CRISPR/Cas9 functional genetic screens are a powerful tool to discover drug targets in cancer. While many screens have been performed for identification of intrinsic cancer vulnerabilities, synthetic lethalities of targeted therapies remain largely unexplored, despite the fact that they may provide a potential targets and pathways for potential combination therapies, advance understanding of target biology, and hone patient selection strategies. To discover novel combination targets of Palbociclib, a CDK2 inhibitor, and a CDK2,4,6 inhibitor, we have screened a genome-wide CRISPR library in priority tumors with genetic background of interest, including ER+ breast cancer (HCC1428, MCF7), cyclin E amplified breast (HCC1806) and/or ovarian cancer (OVCAR4), and pancreatic cancer cell lines (MIAPACA2, Hs766T, SU8686). We analyzed the samples by condition and compared using MAGeCK-MLE for gene-level drop out and enrichment to identify common sensitizers and resistors to different CDK inhibitors. Differential genes, complexes, and pathways were assessed, and we have found that genes involved in G1/S transition (CyclinE/CDK2) are top Palbo sensitizers and CDK1/CyclinA, CDC25A/B, MuvB complex (MYBL2 and FOXM1) are major CDK2 sensitizing genes. In addition to sensitizers, we have identified genes with strong signals of resistance to CDK inhibitors. Furthermore, we highlighted major mechanisms influencing response to CDK2 inhibitors; 1) Regulation of DREAM may influence response to CDK inhibitors, 2) Regulation of cell cycle check points mediated by CDC25. Our targeted CRISPR KO screens in different CDKi combinations have identified common sensitizers and mediators of resistance to CDK inhibitors, and highlighted biology worthy of deeper consideration and offers opportunities to consider new directions for therapeutic intervention into the cancer cell cycle
Citation Format: Kimberly H Kim, Jonathan Almaden, vinu arunachalam, Todd VanArsdale, chaoting liu. Discovery of combination targets of CDK inhibitors from CRISPR screens [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA011.
Abstract LBA015: Accelerating clinically-translatable discoveries using a network-and RNA-based precision-oncology framework
Authors: Vasciaveo Alessandro , Zou Min , Arriaga Juan Martín , De Almeida De Almeida Francisca Nunes , Douglass Eugene , Shen Michael , Califano Andrea , Abate-Shen Cory 
Published: December 2021

Abstract
Despite recent advances, prioritizing therapy at the individual patient level remains challenging. In fact, inter-patient tumor heterogeneity remains one of the major challenges in cancer therapy, making it difficult to optimize available treatments on an individual patient basis. Likewise, the systematic prediction of drug sensitivity in vivo is still a major challenge in translational biology, where targeted therapeutics are currently selected based on the presence of either actionable oncogene dependencies or aberrant cellular mechanisms. A further challenge is the limited availability of models that faithfully recapitulate the biology, complexity, and heterogeneity of human tumors, including their interaction with a competent immune system. To address these challenges, we introduce OncoLoop, a highly-generalizable, network-based precision medicine framework to triangulate between available mouse models, human tumors, and large-scale drug perturbational assays with in vivo validation to predict personalized treatment. OncoLoop requires only transcriptomic data (i.e., RNA-seq profiles) and leverages regulatory network analysis to (a) identify cognate models based on conservation of patient-specific Master Regulator (MR) proteins and (b) prioritize drugs based on their ability to invert the activity of MR proteins (MR-inverters), using drug perturbation profiles in cognate cell lines. As proof-of-concept, we applied OncoLoop to prostate cancer using a series of genetically engineered mouse models (GEMMs) that capture a broad range of phenotypes, including metastatic, castration-resistant and neuroendocrine disease. Indeed, ~70% of patients in published cohorts had at least one high-fidelity matched GEMM. Drugs targeting shared Master Regulator dependencies of a patient and its cognate GEMM(s) were predicted using perturbational profiles of &gt;300 drugs in MR-matched cell lines, resulting in an 80% validation rate in GEMM allografts and human xenografts. This network-based approach is highly generalized and can be applied to both cancer and non-cancer-related contexts.
Citation Format: Alessandro Vasciaveo, Min Zou, Juan Martín Arriaga, Francisca Nunes De Almeida De Almeida, Eugene Douglass, Michael Shen, Andrea Califano, Cory Abate-Shen. Accelerating clinically-translatable discoveries using a network-and RNA-based precision-oncology framework [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA015.
Abstract LBA022: IMM20324, a first-in-class, anti-interleukin-38 monoclonal antibody, rescues myeloid cell activation in vitro and induces robust anti-tumor responses in vivo
Authors: Dowling John P , Nikitin Pavel A , Shen Fang , Finn James P , Patel Nirja , Swider Cezary , Steele Jamie , Shukla Halley , Robinson Matthew K , Lundgren Karen , Harman Benjamin C 
Published: December 2021

Abstract
Immune checkpoint inhibitors that overcome T cell suppressive mechanisms in tumors have revolutionized the treatment of cancer. However, therapies targeting innate immune cell subsets that orchestrate adaptive immune responses could significantly improve the incidence of clinical response by more effectively activating a multi-lineage response to the tumor. Here, we show that IMM20324, an antibody that binds and neutralizes IL-38, enhances innate immune cell function in vitro and inhibits tumor growth in vivo. IMM20324 binds human, mouse and cynomolgus IL-38 and inhibits the binding of IL-38 to its putative receptors, IL1RAPL1 and IL-36R. In vivo, IMM20324 administration leads to inhibition of tumor growth and improved survival in two different syngeneic tumor models. Importantly, while IMM20324 targets innate immune cells, antibody treatment leads to the induction of immunological memory responses that induce tumor rejection following tumor rechallenge. Together, our data support the hypothesis that IL-38 plays an important role in tumor immunity and that therapies targeting IL-38 could reverse suppressive mechanisms in tumor microenvironment. IMM20324 demonstrated favorable in vitro potency and in vivo efficacy and therefore represents a promising development candidate with the potential to treat multiple cancers.
Citation Format: John P Dowling, Pavel A Nikitin, Fang Shen, James P Finn, Nirja Patel, Cezary Swider, Jamie Steele, Halley Shukla, Matthew K Robinson, Karen Lundgren, Benjamin C Harman. IMM20324, a first-in-class, anti-interleukin-38 monoclonal antibody, rescues myeloid cell activation in vitro and induces robust anti-tumor responses in vivo [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA022.
Abstract LBA041: Identification and characterization of potent RAD51 inhibitors targeting RAD51-BRCA2 interaction
Authors: Sasmal Sanjita , Patra Sukanya , Boorgu Venkatesham , Yanamandra Mahesh , Chithaluri Shankar , Pathange Hema Sankar , Hiremath Deepika , Girme Sandeep M , Pawar Amit Kumar 
Published: December 2021

Abstract
The DNA damage response (DDR) is a complex cellular network that acts as a cell defense mechanism and exerts signal for repair of DNA lesions. It repairs different types of DNA damage such as single-strand (ssDNA) breaks, DNA inter-strand crosslinks and double strand breaks (DSB) caused by endogenous and exogenous factors. These damages are mainly repaired by homologous recombination (HR) repair, and non-homologous end joining (NHEJ). DNA double-strand breaks (DSBs) are the most severe DNA damage and predominantly repaired by HR. As the DDR pathway is critical for tumorigenesis, a high degree of interest has been generated in the recent past to target this network. RAD51 is one of the pivotal enzymes for DNA double-strand break repair by the HR pathway. While PARP inhibitors are extensively used for BRCA2 mutated cancers, their responses in BRCA2 WT is limited. Targeting RAD51 will open a new avenue to treat BRCA2 WT cancer patients. BRCA2 interaction with RAD51 is a prerequisite for RAD51 nuclear translocation to exert its function by binding to DNA. The disruption of this interaction leads to inhibition of DNA repair and in turn inhibits proliferation and tumor growth. As this leads to BRCAness in an otherwise BRCA2 WT background, it is expected to have synergy with PARP1 inhibitors. We report the identification of novel and potent RAD51 inhibitors which disrupt the RAD51:BRCA2 interaction. Our hit compounds show anticancer activity in relevant cancer cell lines across various indications. Further, our compounds inhibit RAD51 nuclear translocation upon induction of exogenous DNA damage. Multiple series have been identified, with a good SAR trend and correlating well with cell based and PD activity. Further profiling of these compounds is ongoing.
Citation Format: Sanjita Sasmal, Sukanya Patra, Venkatesham Boorgu, Mahesh Yanamandra, Shankar Chithaluri, Hema Sankar Pathange, Deepika Hiremath, Sandeep M Girme, Amit Kumar Pawar. Identification and characterization of potent RAD51 inhibitors targeting RAD51-BRCA2 interaction [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA041.
Abstract P002: Metabolomic credentialling of murine chemical carcinogenesis model of urothelial cancer
Authors: Said Neveen A. 
Published: December 2021

Abstract
Bladder cancer (BCa) is the most common malignancy of urinary system with increasing incidence and mortality and limited treatment options. Therefore, it is imperative to validate preclinical models that faithfully represent BCa cellular, molecular, and metabolic heterogeneity to develop new therapeutics. We performed metabolomic profiling of premalignant and non-muscle invasive bladder cancer (NMIBC) that ensued in chemical carcinogenesis N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model. We identified the enriched metabolic signatures that associate with premalignant and NMIBC. We found that enrichment of lipid metabolism is the forerunner of carcinogen-induced premalignant and NMIBC lesions. Cross-species analysis revealed the prognostic value of the enzymes associated with carcinogen-induced enriched metabolic in human disease. To date, this is the first study describing the global metabolomic profiles associated with early premalignant and NMIBC and provide evidence that these metabolomic signatures can be used for prognostication of human disease.
Citation Format: Neveen A. Said. Metabolomic credentialling of murine chemical carcinogenesis model of urothelial cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P002.
Abstract P008: myc Gene and cancer variant analysis and network interaction: An in-silico analysis
Authors: Kabrah Saeed 
Published: December 2021

Abstract
The myc is a proto-oncogene that regulates the cellular process like cell growth, proliferation, metabolism, apoptosis and malignancy pathologies. myc deregulation occurs in several cancers and plays a significant role in disease development, metastatic potential, and therapeutic resistance. Drug targeting myc in cancer remains highly desirable with substantial challenges, delaying the direct myc targeted drugs’s development. These drugs target the myc transcriptions deregulations in tumours cell by compound inhibiting the inducing of epigenetic silencing or regulation of G-quadruplex structures within the myc promoter. Proteins involved in myc's post-translational modulation have been identified as significant surrogate targets for lowering myc activity downstream of aberrant cell stimulatory signals.
Citation Format: Saeed Kabrah. myc Gene and cancer variant analysis and network interaction: An in-silico analysis [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P008.
Abstract P012: Genomic and clinical correlates of overall survival (OS) in men with newly diagnosed metastatic castration-sensitive prostate cancer (mCSPC) undergoing intensified androgen deprivation therapy (ADT)
Authors: Sayegh Nicolas , Peterson Bennet , Nussenzveig Roberto , Kessel Adam , McFarland Taylor Ryan , Hahn Andrew Warren , Sirohi Deepika , Kohli Manish , Maughan Benjamin Louis , Swami Umang , Yandell Mark , Agarwal Neeraj 
Published: December 2021

Abstract
Background: Despite recent advancements in systemic therapy in men with mCSPC, disease remains fatal. Identification of novel genomic and clinical correlates of survival in this setting remain a significant unmet need. Methods: Newly diagnosed mCSPC undergoing intensified ADT i.e., ADT plus docetaxel or novel hormonal therapy and available tumor comprehensive genomic profiling (CGP) were included in the analysis. CGP was performed by a CLIA certified Next Generation Sequencing panel (Foundation Medicine) and involved the following genes: FAS, KDM6A, MYC1, PTEN, RB1, TMPRSS2, and TP53. All variants of unknown significance were removed, and mutated genes present in ≥5 % patients were included. Cox proportional hazards was used to assess relationships between OS and multiple variables (age at diagnosis, Gleason score, baseline PSA, de-novo disease, volume of disease, presence of visceral metastases and presence of genetic aberrations on CGP). Results: 127 patients were eligible and included. Higher baseline PSA (HR 1.45, 95% CI 1.09-1.9, P=0.0097), presence of visceral metastases (HR 4.41, 95% CI 1.26-15.39, P=0.0199) and genomic aberrations in MYC1 (HR 5.23, 95% CI 1.05-26.04, P=0.0433) and RB1 (HR 32.72, 95% CI 5.35-200.2, P=0.0002) were significantly associated with inferior OS. High volume disease trended to associate with poor OS, but was not statistically significant (HR 1.63, 95% CI 0.56-4.71, P=0.367). PTEN loss and other genomic aberrations were not associated with OS. See Table. Conclusions: In this real-world patient population of men with mCSPC undergoing intensified ADT we identify clinical and genomic markers associated with poor OS. This study has limitations as expected in a retrospective analysis. These data, upon external validation, may aid with development of a risk stratification model, counseling of patients, treatment decision making in the clinic, as well as further drug development.
Citation Format: Nicolas Sayegh, Bennet Peterson, Roberto Nussenzveig, Adam Kessel, Taylor Ryan McFarland, Andrew Warren Hahn, Deepika Sirohi, Manish Kohli, Benjamin Louis Maughan, Umang Swami, Mark Yandell, Neeraj Agarwal. Genomic and clinical correlates of overall survival (OS) in men with newly diagnosed metastatic castration-sensitive prostate cancer (mCSPC) undergoing intensified androgen deprivation therapy (ADT) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P012.
Abstract P050: Trial in progress: A phase 2 multicenter study of autologous tumor-infiltrating lymphocyte (TIL, LN-145) cell therapy in patients with metastatic non-small cell lung cancer (mNSCLC)
Authors: Massarelli Erminia , Samakoglu Selda , Gontcharova Viktoria , Chen Guang , Jagasia Madan , Finckenstein Friedrich Graf , Sukari Ammar 
Published: December 2021

Abstract
Patients with mNSCLC without actionable driver mutation(s) who have progressed after cytotoxic chemotherapy plus immune checkpoint inhibitors (ICI) ± bevacizumab have limited treatment options and represent an unmet need. The safety and efficacy of TIL cell therapy for patients with mNSCLC who failed to respond or progressed on nivolumab has been evaluated in a Phase 1 clinical trial (Creelan B. AACR 2020), demonstrating an objective response rate (ORR) of 25% including 17% durable CR. This provides a clear rationale for initiation of IOV-LUN-202 study, evaluating TIL cell therapy with LN-145 in patients with mNSCLC without actionable driver mutation(s), who have progressed on or following a single line of approved systemic therapy consisting of combined ICI + chemotherapy ± bevacizumab. Trial Design IOV-LUN-202 (NCT04614103) is a prospective, open-label, multi-cohort, non-randomized, multicenter Phase 2 study. Cohorts 1 and 2 (each, n=40) are enrolling patients with mNSCLC based on tumor proportion score (TPS; Cohort 1, TPS &lt;1%; Cohort 2, TPS ≥1%) at metastatic diagnosis prior to ICI use. Cohort 3 (TPS &lt;1%; n=15) uses core biopsies for tumor acquisition in patients unable to undergo a surgical harvest, and Cohort 4 is designated for patients requiring retreatment. LN-145 is a cryopreserved infusion product generated at centralized GMP facilities in a 22 day manufacturing process. All patients receive TIL therapy consisting of nonmyeloablative lymphodepletion with cyclophosphamide (60 mg/kg × 2) + fludarabine (25 mg/m2 × 5), followed by a single infusion of autologous LN-145 (Day 0) and up to 6 doses of IL-2 (600,000 IU/kg). Key eligibility criteria include age ≥ 18 y, 1 prior line of therapy, ≥1 lesion(s) available for TIL generation and a remaining RECIST-measurable lesion, and ECOG PS 0–1. For each cohort the primary endpoint is ORR per RECIST 1.1. Secondary endpoints are safety, complete response rate, duration of response, disease control rate, progression-free survival, overall survival, and efficiency of generating LN-145 from tumor core biopsies (Cohort 3).
Citation Format: Erminia Massarelli, Selda Samakoglu, Viktoria Gontcharova, Guang Chen, Madan Jagasia, Friedrich Graf Finckenstein, Ammar Sukari. Trial in progress: A phase 2 multicenter study of autologous tumor-infiltrating lymphocyte (TIL, LN-145) cell therapy in patients with metastatic non-small cell lung cancer (mNSCLC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P050.
Abstract P063: Novel prodrugs coupled with albumin nanoparticle encapsulation improves antitumor effects of the nucleoside analog gemcitabine
Authors: Raheja Neil , Kahana Jason , Jackman Robin , Monnig Curtis 
Published: December 2021

Abstract
Nucleoside analogs such as gemcitabine have been widely used to treat many solid tumors. Despite their near universal use and well understood mechanisms of action, this class of chemotherapeutic agents has notable shortcomings including rapid metabolism, limited systemic exposure, acquired resistance, and dose-limiting toxicities. Albumin-based nanoparticles offer several advantages for drug delivery including direct tumor targeting, low risk of immunogenicity, and ease of synthesis and manufacturing. We have modified numerous nucleoside drugs of clinical significance to form new prodrugs and use nanoparticle encapsulation in an attempt to improve the therapeutic index of the parent drugs. Different prodrugs of gemcitabine were designed to evade drug resistance mechanisms, and methods were developed to form stable lyophilized nanoparticle formulations. Nanoparticles were characterized by particle size (~40-65 nm) and polydispersity, and dose-dependent effects on the proliferation of human tumor cell lines were compared to the response to the parent drug gemcitabine. To evaluate effects in vivo, nanoparticle formulations were dosed intravenously (IV) to immunocompromised mice bearing patient-derived xenografts (PDx). The prodrug JTX-836 (IC50=0.46 nM) was ~10x more potent against BxPC-3 pancreatic adenocarcinoma cells than the parent gemcitabine (IC50 = 5.2 nM) in vitro. IV dosing of JTX-836 albumin nanoparticle formulation improved tumor growth inhibition in PDx models of both pancreatic ductal adenocarcinoma (CTG-0282 TumorGraft, Champions Oncology) and ovarian cancer (CTG-1180, Champions Oncology) when compared to IV gemcitabine dosing. These results demonstrate the potential for nanoparticle encapsulation of prodrugs to improve the antitumor activity of existing nucleoside analog therapeutics and support continued development of albumin-based delivery of gemcitabine for the treatment of human cancer.
Citation Format: Neil Raheja, Jason Kahana, Robin Jackman, Curtis Monnig. Novel prodrugs coupled with albumin nanoparticle encapsulation improves antitumor effects of the nucleoside analog gemcitabine [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P063.