bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B036: Treatment modalities in KRAS-driven cancer
Authors: Tyson Darren R. , Singh Neetu , Bhavar Prashant K. , Sarma Partha Pratim , Surampudi Uday Kumar , Katike Sathish 
Published: May 2023

Abstract
KRAS is the most common RAS isoform, found to be altered in 22% of RAS-mutated cancers. The mutant protein is found most prevalently in pancreatic cancer followed by colorectal, non-small cell lung cancer and other solid tumors. Due to its structural complexity, KRAS remained “undruggable” for several decades. Recently, the discovery of a specific protein binding pocket has led to the development of small molecule inhibitors that potently bind and inhibit KRAS downstream signalling. The accelerated FDA approval of sotorasib and adagrasib for treatment of NSCLC patients harbouring KRASG12C-mutation and further clinical evaluation of several other inhibitors of KRASG12C are under investigation, however emergence of resistance and limited efficacy beyond non-small cell lung cancer is a major concern. Targeting KRAS mutations other than KRASG12C (i.e., without a mutant-specific cysteine residue) with small molecules, has been considered much more challenging, especially for developing covalent inhibitors. Small molecule targeting of KRASG12D (e.g. MRTX1133), is under active preclinical investigation and small molecule drugs that target other KRAS-activating mutations (G12S, G12R and G12V) are being intensely explored. A variety of novel alternative approaches are also being investigated to target tumors driven by mutant KRAS, such as (i) targeting complementary signalling pathways (ii) enhancing mutant KRAS protein degradation using PROTACS, (iii) developing pan-KRAS small molecules inhibitors, (iv) anti-KRAS immune cell-based therapies, (v) small interfering RNAs to block mutant KRAS expression and (vi) anti-KRAS vaccines. Here, we aim to provide a comprehensive overview of current status and future prospect of these modalities, in the context of RAS-mutated cancers.
Citation Format: Darren R. Tyson, Neetu Singh, Prashant K. Bhavar, Partha Pratim Sarma, Uday Kumar Surampudi, Sathish Katike. Treatment modalities in KRAS-driven cancer [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr B036.
Abstract B038: Preclinical efficacy of KRASG12C inhibitors in models of pediatric cancer
Authors: Price Hannah , Stauffer Stacey , Powell Katie , Baker Andrew , Perciaccante Andrew , Hernandez Edjay Ralph , Odeniyide Patience , Pratilas Christine , Burgan William , Jenkins Lisa , Rossman Kent L. , Yohe Marielle 
Published: May 2023

Abstract
Directly targeting RAS is a desirable approach for treating RAS-mutated tumors because direct RAS inhibitors block all RAS effector pathways simultaneously. Recently, several groups have developed agents that directly target KRAS by covalently modifying KRASG12C. KRAS is commonly altered in adult malignancies such as lung, pancreatic, and colorectal adenocarcinoma, but is less commonly altered in pediatric cancer. However, rare pediatric tumors harboring K-, H-, or NRASG12C are observed. The efficacy of KRASG12C inhibitors in pediatric malignancies is currently unknown, and the ability of these drugs to modify H- and NRASG12C has been incompletely characterized. Here we show that the KRASG12C inhibitors AMG 510, MRTX849, and ARS-1620 slow the release of GDP from H-, N-, and KRASG12C in vitro. Using RASless MEFs, we show that the activity of AMG 510 is specific for H-, N- or KRASG12C, while MRTX849 has both G12C and RAS-independent effects on cell viability. The KRASG12C inhibitors decreased cell viability in KRAS-mutant cell lines derived from patients with the pediatric solid tumor neuroblastoma. MRTX849 was more potent than AMG 510 in neuroblastoma cell lines but was less efficacious and less G12C-specific. The KRASG12C inhibitors also decreased cell viability in an NRASG12C-mutant T-cell ALL cell line derived from an adolescent patient but only MTRX849 decreased cell viability in an HRASG12C-mutant rhabdomyosarcoma cell line. These results suggest that KRASG12C inhibitors may be a treatment option for pediatric patients with H-, N- or KRASG12C mutant solid tumors or leukemia. Future studies will be aimed at testing the efficacy of these inhibitors in xenograft models of pediatric cancer and identifying non-RAS targets of MRTX849.
Citation Format: Hannah Price, Stacey Stauffer, Katie Powell, Andrew Baker, Andrew Perciaccante, Edjay Ralph Hernandez, Patience Odeniyide, Christine Pratilas, William Burgan, Lisa Jenkins, Kent L. Rossman, Marielle Yohe. Preclinical efficacy of KRASG12C inhibitors in models of pediatric cancer [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr B038.
Abstract B040: Designed sensors reveal normal and oncogenic Ras signaling in endomembranes and condensates
Authors: Zhang Jason Z. , Nguyen William H. , Rose John C. , Ong Shao-En , Maly Dustin J. , Baker David 
Published: May 2023

Abstract
While Ras is known to dynamically shuttle around the cell, the activity, mechanism of activation, and function of non-plasma membrane-localized Ras is unclear due to lack of suitable tools. To address these questions, we used the Latching Orthogonal Cage-Key pRotein (LOCKR) switch platform to generate first-in-class intracellular sensors for endogenous Ras activity (Ras-LOCKR-S) and signaling-dependent proximity labelers (Ras-LOCKR-PL). We find that: 1) Receptor activation leads to endogenous Ras signaling at endomembranes, which is enhanced by golgi-localized guanine exchange factors. 2) Recruitment of SAM68 and MARCKS to oncogenic condensates fuels local Ras signaling and cell growth. 3) Major Vault Protein drives RasG12C inhibitor resistance by enhancing signaling at the golgi and altering mitochondrial metabolism. Together, these results highlight the importance of non-plasma membrane Ras signaling (endomembranes and condensates), and our new sensors should accelerate the discovery of new therapeutic targets.
Citation Format: Jason Z. Zhang, William H. Nguyen, John C. Rose, Shao-En Ong, Dustin J. Maly, David Baker. Designed sensors reveal normal and oncogenic Ras signaling in endomembranes and condensates [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr B040.
Abstract IA09: Allelic specificity: The key to NRAS-mutant melanoma initiation?
Authors: Burd Christin E. 
Published: May 2023

Abstract
The reason why different NRAS mutants are enriched in each tumor type is unclear. We made a suite of conditional, Nras knock-in models (LSL-Q61R, -K, -L, -H, -P, -Q; G12D and G13D, -R) to test whether melanocyte transformation is dependent upon functions specific to the NRAS mutants found in human melanoma (Q61R and K). Spontaneous melanomas were rare in mice expressing Nras mutants infrequently observed in human melanoma (G12D, G13D, G13R, Q61H, or Q61P). However, melanocyte-specific Nras Q61R or Q61K expression induced rapid melanoma onset with high penetrance. Cohorts of mice carrying one LSL-Nras Q61R and one LSL-Nras Q61K, -L, -H, -P, or -Q allele were used to evaluate potential interactions between Nras mutants. These combinations initiated tumors with kinetics intermediate to those of mice homozygous for either allele (Nras Q61R or 61X) except in the case of Nras Q61Q/Q61R mice, which rarely developed tumors. Genomic and in vitro analyses revealed that the melanoma-initiating potential of each NRAS mutant directly correlated with enhanced MAPK signaling. Together, these data establish that functions specific to the most common NRAS mutants in human melanoma are needed to initiate the disease.
Citation Format: Christin E. Burd. Allelic specificity: The key to NRAS-mutant melanoma initiation? [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA09.
Abstract IA20: The impact of RAS inhibition on tumor immune evasion
Authors: Downward Julian 
Published: May 2023

Abstract
The approval of two KRAS G12C mutant-specific inhibitory drugs, sotorasib and adagrasib, has markedly improved the treatment of lung cancer patients harbouring KRAS G12C oncogenic mutations. However, development of acquired drug resistance is very common after initial responses, and impact on overall survival is small. Additional therapies will therefore need to be combined with KRASG12C inhibitors if long-term cures are to be achieved. Due to the immunosuppressive nature of the signaling network controlled by oncogenic KRAS, targeted KRAS G12C inhibition can indirectly affect anti-tumour immunity. This has served as a rationale for combination with immune checkpoint blockade (ICB), which we have shown leads to additional therapeutic benefit in immunogenic/hot, but not immune evasive/cold, pre-clinical lung tumour models. However, in clinical trials in KRAS G12C mutant lung cancer, combination of KRAS G12C inhibitors with PD-(L)1 blockade has yet to show improved outcome, either due to toxicities or lack of efficacy, possibly linked to prior progression on immunotherapy. Study of the response of KRAS G12C mutant lung tumours to KRAS G12C inhibitory drugs using spatial and multi-omic technologies has highlighted the role of particular populations of immune cells in the tumor microenvironment in impeding immune attack on the tumor. In immune evasive lung cancer, following KRAS G12C inhibitor treatment a community of cells is identified within the tumor containing dendritic cells, CD8+ T cells and dying tumor cells, which appears to function as an antigen presentation hub. This community is restrained by T reg cells, whose coordinate targeting markedly improves the impact of KRAS G12C inhibitors. In an immunogenic/hot mouse model of KRAS G12C mutant lung cancer, tertiary lymphoid structures are seen along with tumor-binding antibodies, which target endogenous retrovirus (ERV) envelope glycoproteins on the tumor cells. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted KRAS G12C inhibition in the murine model. ERV-reactive antibodies exert anti-tumour activity that extend survival in the murine model and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Rational, mechanism-based exploitation of the impact of KRAS inhibition on tumor immune evasion provides opportunities for successful combination therapy of RAS mutant cancers.
Citation Format: Julian Downward. The impact of RAS inhibition on tumor immune evasion [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA20.
Abstract IA25: Systematic interrogation of KRAS function
Authors: Hahn William C. 
Published: May 2023

Abstract
Oncogenic mutations of KRAS occur frequently in pancreas, lung and colon cancers. Recent efforts to target particular KRAS alleles or RAS effector pathways has led to clinical responses but resistance to therapy limits the effectiveness of these therapies. To understand the role of KRAS in tumor initiation and maintenance, we have used systematic approaches to understand dependencies in KRAS-driven cancers. Specifically, we have used genome scale gain and loss of function screens to interrogate pathways necessary for the survival of KRAS-driven cancers. We have identified genes that required for the survival of KRAS-driven cancers and that canonical RAS signaling proteins have multiple functions. Together these on-going approaches provide new insights into KRAS signaling and identify potential targets for combination therapies for KRAS driven cancers.
Citation Format: William C. Hahn. Systematic interrogation of KRAS function [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA25.
Abstract PR07: Oncogenic Kras signaling shapes the tumor microenvironment in lung adenocarcinoma
Authors: Baliira Rachael K. , Opsahl Emily Lasse , McLintock Elyse , Donahue Katelyn L. , Barravacchia Ivana , Magliano Marina Pasca di , Galbán Stefanie 
Published: May 2023

Abstract
Despite advancements in targeted therapy and immunotherapy, lung cancer remains the leading cause of cancer-related deaths in both men and women worldwide, with an estimated 2.2 million deaths each year. At 85%, non-small cell lung cancer (NSCLC) is by far the most common subtype, comprising adenocarcinomas and lung squamous cell carcinoma. Mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS), epidermal growth factor receptor (EGFR) and anaplastic lymphoma receptor tyrosine kinase (ALK) genes are common, with the worst overall survival in KRAS mutant adenocarcinoma patients. About 40% of lung tumors with KRAS mutations also harbor mutations in tumor protein p53 gene (TP53), a tumor suppressor gene. KrasG12C and KrasG12D are both prevalent mutations in lung cancer. Sotorasib, a KrasG12C inhibitor, was recently approved for treatment of NSCLC. However, only 37% of patients have an objective response to Sotorasib, with a median duration of just 11 months. The KrasG12D inhibitor MRTX1133 is entering clinical trials; elucidating the mechanism of action for potential resistance is imperative to design combination treatment approaches. While cell-intrinsic mechanisms of resistance in epithelial oncogenic KRASG12D (Kras*) are well studied, our group and others have shown that KRASG12D also extrinsically regulates the tumor microenvironment (TME) in pancreatic cancer. Whether and how this oncogene regulates the TME of lung cancer is less understood. To study the crosstalk between epithelial lung cells expressing oncogenic KRAS and the surrounding TME, we have established a triple transgenic murine model of Kras*-driven NSCLC, wherein both lung epithelial-specific expression of Kras* and expression of mutant TP53R172H (Tp53*) can be controlled in an inducible and reversible manner. Our preliminary data show that expression of Kras* drives tumor growth, while Kras* depletion results in regression, even in the presence of Tp53*. Here we interrogate how Kras* modulates the TME in lung adenocarcinomas. Harnessing scRNA sequencing, immunohistochemistry, and multiple biochemical approaches, we will provide insight into changes in stromal and immune contexture upon Kras* depletion in mice.
Citation Format: Rachael K. Baliira, Emily Lasse Opsahl, Elyse McLintock, Katelyn L. Donahue, Ivana Barravacchia, Marina Pasca di Magliano, Stefanie Galbán. Oncogenic Kras signaling shapes the tumor microenvironment in lung adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr PR07.
Abstract A12: Androgen receptor inhibition is involved in Finasteride-reduced AML cell proliferation
Authors: Cheng Pang-Ting , Teng Chieh-Lin Jerry , Cheng Yu-Chiao , Chen Mei-Chih , Lin Ho 
Published: May 2023

Abstract
Acute myeloid leukemia (AML) is a top priority type of hematological malignancies to be studied and treated. Androgen receptor (AR) plays important roles in various cancers, such as types of the prostate, breast, liver, and lung. However, the role of AR in leukemia is so far uncertain. Finasteride is a 5 alpha-reductase inhibitor for reduction of cellular 5 alpha-dihydrotestosterone production and commonly used to treat benign prostatic hyperplasia for decades. Here, the data showed that Finasteride treatment significantly decreased the proliferation of AML cell lines, including KG-1 and HL-60. More specific to its impact on androgen’s actions, the authors found that Finasteride inhibited the phosphorylation and activation of AR, while the cell cycle-related proteins such as CDK1, Cyclin A, and p21 were unaffected. Interestingly, the increase of AKT phosphorylation was observed after Finasteride treatment, which is correspondent to the previous findings of mutual correlations between AR inhibition and AKT activation in prostate cancer cells. It implies that AR might play a physiological role in AML cells for proliferation, in which AR closely collaborates with AKT for a balance of regulation. In summary, these results suggest that Finasteride might reduce the proliferation of AML cell lines through AR inhibition. These findings could be helpful to uncover novel AML treatments in the future.
Citation Format: Pang-Ting Cheng, Chieh-Lin Jerry Teng, Yu-Chiao Cheng, Mei-Chih Chen, Ho Lin. Androgen receptor inhibition is involved in Finasteride-reduced AML cell proliferation [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A12.
Abstract A15: Computational modeling of methylation impact of AML driver events
Authors: Gurun Burcu , Tyner Jeffrey W. , Demir Emek , Druker Brian J. , Spellman Paul T. 
Published: May 2023

Abstract
Decades before its clinical onset, epigenetic changes start to accumulate in the progenitor cells of Acute Myelogenous Leukemia– caused by tumor intrinsic driver mutations and tumor extrinsic environmental factors. There are millions of cancer-associated epigenetic changes that are persistent and stable throughout the leukemogenesis and at relapse. By grouping correlated loci into “epigenetic signatures”, we can gain insights on the AML etiology, dynamics as well as mechanisms around the methylation pathways of driver events. We approached this problem in two parts: First, we computationally constructed and analyzed methylation signatures that are associated with DNMT3A and TET2 mutations. Both of them are frequently mutated in AML and they are major causes of changes in the methylation landscape of healthy individuals, conferring a broad risk of transformation to a myeloid malignancy with the serial acquisition of an additional cooperating mutation. We built highly accurate ridge regression models that can differentiate the wild type vs mutant genotypes for DNMT3A and TET2 based on their downstream epigenetic impacts (AUROC 0.9 and 0.8, respectively). It suggests that despite the complicated genetic and epigenetic make-up of post-diagnosis samples, epigenetic regulator mutations’ signatures are distinguishable, and these distinctive marks remain stable over time. We further evaluated methylation loci selected by the models and showed that known downstream targets of DNMT3A such as EVI1/MECOM and AEBP2 (polycomb repressive complex member) were frequently selected by the models. We also identified multiple novel recurrent sites that were previously unassociated with DNMT3A and TET2. Second, we modeled different sources of variations in epigenetic patterns with Topic Modeling. Topic Modeling maps the sparse and high dimensional space of methylation profiles to a small and non-sparse latent space of small number of factors (topics). Each sample is represented as a combination of few topics in that latent space. We annotated these topics with biological and clinical features such as mutation status, prior malignancy, age and gender to shed light on the prevalence and combination of the mutations and other extrinsic factors present at the time of diagnosis. In the future, we aim to identify the etiologies of new signatures to inform detection, monitoring, risk stratifying and drug response studies for AML patients and track these changes throughout leukemogenesis in early detection cohorts.
Citation Format: Burcu Gurun, Jeffrey W. Tyner, Emek Demir, Brian J. Druker, Paul T. Spellman. Computational modeling of methylation impact of AML driver events [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A15.
Abstract A32: Exemestane inhibits survival and cell cycle regulators and retards AML cell proliferation
Authors: Chen Mei-chih , Cheng Pang-Ting , Cheng Yu-Chiao , Lin Ho , Teng Chieh-Lin Jerry 
Published: May 2023

Abstract
Acute myeloid leukemia (AML) is the most common type of leukemia with poor prognosis. Although estrogen plays important roles in female cancers, the recent reports indicate that estrogen and its receptors also attribute to the development of non-gender cancers and AML is one of those. Therefore, the inhibition of estrogen production becomes a potential strategy for AML treatment. Exemestane is an aromatase inhibitor and commonly used for reducing estrogen production in breast cancer patients. Our data showed that Exemestane treatment significantly decreased the proliferation of both KG-1 and HL-60 AML cell lines. Since STAT3 and AKT closely collaborate with estrogen receptor in breast cancer cells, their activations are next to be monitored. In KG-1 cells, the phosphorylations of STAT3 (Y705 and S727) and AKT (S473) were both inhibited by Exemestane treatment. Regarding the cell cycle control, p21 was increased by Exemestane in KG-1 cells in which Cyclin E was reduced. It suggests that CDK2 might be inactivated by Exemestane-reduced Cyclin E and therefore p21 escaped from the CDK2-dependent degradation. Although the signaling findings of Exemestane in KG-1 were interesting, no similar results were found in HL-60 cells except the growth inhibition, suggesting the distinct regulation mechanisms between two cell lines. In summary, these results not only suggest, again, the importance of estrogen demand for AML cells, but also show the novel and potential treatment of AML using blockade of estrogen supply, which could be helpful to uncover novel AML treatments in the future.
Citation Format: Mei-chih Chen, Pang-Ting Cheng, Yu-Chiao Cheng, Ho Lin, Chieh-Lin Jerry Teng. Exemestane inhibits survival and cell cycle regulators and retards AML cell proliferation [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A32.
Abstract IA09: Epigenomic landscapes of MDS
Authors: Figueroa Maria E. 
Published: May 2023

Abstract
While significant progress has been made to understand the genetic landscape of MDS, less is known about the epigenetic makeup of this disease and how this may impact biology and response to azacitidine (AZA). To address this, we performed genomic, epigenomic and transcriptomic analysis on CD34+ cells from a multicenter cohort of 94 intermediate or higher risk MDS patients treated with AZA who had documented responses. DNA methylation (DNAme) by ERRBS, gene expression (GE) by RNA-seq, mutational profiling, and detailed clinical, cytogenetic and laboratory data were documented. Supervised and unsupervised analyses revealed that aberrant DNAme in MDS is not distributed randomly but rather is highly correlated with disease phenotypes, capturing clinically relevant heterogeneity, beyond what is identified by methodologies used in the past that focused solely on promoter regions. Moreover, this epigenetic information can be harnessed for the development of robust biomarkers predictive of AZA response and integrative approaches combining GE and DNAme data can further improve the predictive performance of these biomarkers, with an AUC score=0.92.
Citation Format: Maria E. Figueroa. Epigenomic landscapes of MDS [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr IA09.