tbuckley/cabot-search huggingface dataset:
Abstract 4816: Racial disparities in adjunctive supportive care medication use in pancreatic cancer patients
Authors: Olga M. Trejos Kweyete, Yi Guo, Sherise C. Rogers, Lisa Scarton, David L. DeRemer, Chardae L. Whitner, Diana J. Wilkie, John M. Allen
Journal: Cancer Research (2024)

Abstract Background: Beyond its well-known lethality, pancreatic cancer (PC) is associated with a wide variety of physical and psychological complications. These complications collectively lead to an increase in symptom burden experienced by patients with PC, as compared to other cancer types, leading to lower health-related quality of life (HRQoL) and worsened clinical outcomes. Reducing symptom burden is often achieved through the use of supportive care medications (SCM). Racial disparities have been described in the use of pain and psychiatric medications but limited research has explored potential disparities in access to and utilization of other SCM among diverse racial and ethnic groups. The goal of this study was to illustrate the presence of racial/ethnic disparities in the treatment patterns of supportive care medications in end-of-life care of PC patients Methods: We used data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database from 2005 to 2017. Participants were identified using ICD9 and ICD10 diagnostic codes. Patients diagnosed with PC and have died in 2005-2007 with more than 1 year of Medicare enrollment before death were included. Logistic regression models to assess the association between use of supportive care medications and race, adjusting for covariates (sex, race, age, marital status, education, income, residence, CCI, year of diagnosis of PC, cancer stage). Results: After the application of the inclusion/exclusion criteria, 74,309 patients were included in the final analysis (White: 72.53%, Black 11.01%, Hispanic 9.60%, Asian/Pacific Islander 6.58%) Racial and ethnic disparities in the use of multiple SCM drug classes were identified. The results are summarized in Table 1. Conclusion: Disparities in the use of SCM were found in patients with PC. Minorities had significantly less use of sleep aids and headache aids, and increased use of cognitive aids and appetite stimulants. AAs also had lower uses of anti-emetics. AA Hispanic Asian SCM Drug Class aOR 95% CI aOR 95% CI aOR 95% CI Anti-emetics 0.77 (0.73, 0.81) 0.98 (0.93, 1.03) 1.01 (0.95, 1.08) Appetite stimulants 1.06 (1.01, 1.11) 1.01 (0.96, 1.06) 1.28 (1.20, 1.36) Cognitive aids 1.38 (1.25, 1.53) 1.04 (0.93, 1.17) 1.11 (0.97, 1.26) Headache aids 0.68 (0.63, 0.74) 0.81 (0.74, 0.87) 0.85 (0.77, 0.93) Sleep aids 0.71 (0.67, 0.75) 0.87 (0.82, 0.92) 0.87 (0.81, 0.93) Citation Format: Olga M. Trejos Kweyete, Yi Guo, Sherise C. Rogers, Lisa Scarton, David L. DeRemer, Chardae L. Whitner, Diana J. Wilkie, John M. Allen. Racial disparities in adjunctive supportive care medication use in pancreatic cancer patients [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 4816.
Abstract 4511: Discovery of the first-in-class G9a/GLP PROTAC degrader
Authors: Julia Velez, Yulin Han, Kwang-Su Park, Md Kabir, Peiyi Yang, Yan Xiong, H. Umit Kaniskan, Jian Jin
Journal: Cancer Research (2024)

Abstract G9a and GLP are lysine methyltransferases that catalyze dimethylation of histone H3 lysine 9 (H3K9me2), a transcriptionally repressive mark. Aberrantly expressed G9a/GLP has been implicated in numerous cancers, including prostate, lung, and leukemia. The oncogenic activity of G9a/GLP is attributed to both its catalytic and non-catalytic functions, such as forming co-activator complexes with p300, CARM1, GRIP1, and Mediator to positively regulate gene transcription. As such, current G9a/GLP enzymatic inhibitors display limited anti-cancer activity. As an alternative therapeutic strategy, PROTAC degraders harness the ubiquitin-proteasome system (UPS) to effectively eliminate oncoproteins and abrogate all catalytic and non-catalytic functions. Here, we present the first-in-class G9a/GLP PROTAC degrader, MS8709, which potently degrades G9a and GLP in a time-, concentration-, and UPS-dependent manner. Moreover, MS8709 induces superior cell growth inhibition compared to its parent inhibitor in prostate, lung, and leukemia cell lines. Overall, MS8709 is a useful chemical tool to investigate G9a/GLP biology and offers a novel approach for the treatment of G9a/GLP-dependent cancers. Citation Format: Julia Velez, Yulin Han, Kwang-Su Park, Md Kabir, Peiyi Yang, Yan Xiong, H. Umit Kaniskan, Jian Jin. Discovery of the first-in-class G9a/GLP PROTAC degrader [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 4511.
Abstract 4501: First reported PIM kinase degraders: Design, profiling &amp; optimization
Authors: Celine Legros, Paul Ratcliffe, Vanessa Porkolab, Michele Modugno, Olivier Mirguet
Journal: Cancer Research (2024)

Abstract The PIM serine/threonine kinases (PIM1/PIM2/PIM3) are downstream effectors of ABL, JAK2 and Flt-3 oncogenes and are required for tumorigenesis. Overexpression has been reported in hematological and solid tumors, myeloma, lymphoma, leukemia and adenocarcinoma. The first generation of PIM inhibitors to make it to the clinic, including SGI-1776, AZD1208 and PIM447, are known to be pan-PIM inhibitors, while the aim of this project was to identify novel &amp; selective PIM3 inhibitors. To this end, several Hit-finding approaches were employed to rapidly generate novel chemical matter, which were then assessed for their activity against PIM3 using a robust ADP-Glo™ assay. In parallel to this Hit-findings activity, we used AZD1208 scaffold as a starting point to generate PIM3 bifunctional protein degraders and designed a specific screening cascade in order to profile such modalities. The PIM degrader library, synthetized using Automated Robotics Lab, was characterized using ADP-Glo assays. It was then screened on our binding and activity kinase platforms, KINOMEscan® and KinaseProfiler™, and then fully profiled including ternary complex formation with biophysics and in vitro Safety Pharmacology Profiling Panels. One example is the AZD1208 derivate degrader, i.e. EC108154-1, which showed nanomolar range affinity for PIM3 and the E3-ligase CRBN-DDB1, and its affinity range was also confirmed with the ternary complex in SPR and MST-TRIC. This comprehensive screening cascade ensures an in-depth characterization and optimization of protein degraders, with the possibility of monitoring the ternary complex formation with biophysics methods. It is a good illustration of how this combination of tests can be instrumental in selecting the best degraders to progress to the next step of drug discovery. Citation Format: Celine Legros, Paul Ratcliffe, Vanessa Porkolab, Michele Modugno, Olivier Mirguet. First reported PIM kinase degraders: Design, profiling &amp; optimization [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 4501.
Abstract 4502: Design, synthesis, and evaluation of next-generation EGFR degraders to overcome osimertinib-resistance
Authors: Mohammad Hassan Baig, Juhan Bok, Dongmin Kim, Sagar Dattatraya Nale, Yun Sung Jo, Changjoong Kim, Taehhwan Park, Jaejune Dong, Byoung Gon Moon
Journal: Cancer Research (2024)

Abstract The occurrence of C797S mutation in epidermal growth factor receptor (EGFR) is a leading mechanism of clinically acquired resistance to third-generation EGFR inhibitors, including Osimertinib. L858R/T790M/C797S and del19/T790M/C797S are commonly observed tertiary EGFR mutants identified in Osimertinib-resistant tumors. As of now, no clinically approved treatment exists that specifically targets these mutants. Here, we report the design and synthesis of a series of highly effective next-generation EGFR degraders effectively degrading EGFR C797S-containing triple mutants. Most compounds demonstrated antiproliferation activity in the subnanomolar range when tested on Ba/F3L858R/T790M/C797S and del19/T790M/C797S cells. Not only C797S but our designed degraders also degraded a wide range of EGFR mutants, including Exon19Del and L858R/T790M (DC50 &amp;lt;100nM). One representative Compound, HDBNJ2812, strongly degrades L858R/T790M/C797S and del19/T790M/C797S with DC50 of 34 nM (Dmax 88.5%) and 14 nM (Dmax 99.7%), respectively. This compound potently inhibits the proliferation of Ba/F3L858R/T790M/C797S (GI50 64 nM) and del19/T790M/C797S (GI50 40 nM). HDBNJ2812 demonstrated high inhibitory potential on HCC827 (del19) and H1975 (L858R/T790M) cell lines (GI50 18.9 and 85 nM, respectively). Furthermore, this degrader demonstrates weak cytotoxicity on non-mutant EGFR-expressing cells, such as A431, WI-26 (human lung fibroblast cells), and CHO-K1 (Chinese hamster ovary cells). Additionally, the in vivo PK/PD findings complement this compound's potential to be considered further. HDBNJ2812 may serve as a lead compound to render the greater therapeutic window for treating resistant non-small cell lung cancer patients with EGFR C797S mutants. Citation Format: Mohammad Hassan Baig, Juhan Bok, Dongmin Kim, Sagar Dattatraya Nale, Yun Sung Jo, Changjoong Kim, Taehhwan Park, Jaejune Dong, Byoung Gon Moon. Design, synthesis, and evaluation of next-generation EGFR degraders to overcome osimertinib-resistance [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 4502.
Abstract 5911: <i>In vivo</i> efficacy of a novel peptide-conjugated drug in patient-derived xenograft models of breast cancer
Authors: Mitchell J. Elliott, Meghan Mcguire, Jennifer Silvester, Chantal Tobin, Samah El Ghamrasni, Francine Lui, Andrew Zhai, Ozge Yoluk, Aron Broom, Tracy Stone, Glenn Butterfoss, Serban Popa, Tianyu Lu, Chris Ing, David White, David W. Cescon
Journal: Cancer Research (2024)

Abstract Introduction: Antibody and peptide-conjugated drugs are rapidly entering the clinic for the treatment of patients with early and advanced breast cancer. These drugs are designed to achieve more targeted delivery of cytotoxic agents to tumor cells with robust clinical activity. ARB-1-6, a sortilin (SORT1) targeted peptide conjugated to the cytotoxic agent MMAE, has demonstrated pre-clinical activity and tolerability in cell line xenografts of breast cancer. To further characterize its spectrum of antitumor activity and biomarker correlates we evaluated ARB-1-6 in a collection of clinically and genomically annotated breast cancer patient-derived xenografts (PDX). Methods: Breast cancer PDX models were generated and propagated under IRB approved protocols [14-8358]. ARB-1-6 was dosed in tumor-bearing SCID mice by tail vein injection at 3 mg/kg weekly x 4 doses. Tumor volume was measured twice weekly until day 35 or until models reached humane endpoints, after which tumors were collected. Animals were weighed regularly and assessed for treatment-related toxicity. Results: 7 models (5 TN and 2 HR) have completed efficacy assessment to date. 3/7 models were derived from treatment naïve patients while 4/7 were derived from pre-treated patients (Table 1). Complete response (mRECIST) was seen in 5/7 (71.4%) models with stable disease occurring in 2/7 (28.6%). ARB-1-6 was well tolerated with no weight loss observed. Complete tumor regression was seen in a PDX derived from a patient with clinical resistance to a TROP2 antibody drug conjugate (ADC). Antitumor activity was observed in models with low SORT1 RNA expression; SORT1 IHC and other correlatives studies are underway. Conclusion: ARB-1-6 demonstrates substantial preclinical activity in PDX models at doses that are well tolerated in mice. Treatment of additional models is ongoing. Full results and correlative analyses including relationships between antitumor activity and target protein expression will be presented. PDX Model Characteristics and Patient Treatment PDX Subtype Pt. Treatment 1 TN AC-T 2 TN FEC-D, Gem+Carbo 3 TN AC-T 4 TN No 5 TN No 6 HR No 7 HR TC, ET, Cape, Gem+Cis, TROP2-ADC Citation Format: Mitchell J. Elliott, Meghan Mcguire, Jennifer Silvester, Chantal Tobin, Samah El Ghamrasni, Francine Lui, Andrew Zhai, Ozge Yoluk, Aron Broom, Tracy Stone, Glenn Butterfoss, Serban Popa, Tianyu Lu, Chris Ing, David White, David W. Cescon. In vivo efficacy of a novel peptide-conjugated drug in patient-derived xenograft models of breast 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 5911.
Abstract 6340: Novel conditionally active tetravalent B7-H3 x CD3 T-cell engagers targeting solid tumors
Authors: Ana Paula Cugnetti, PhD, Haizhen Liu, Patricia McNeeley, Kathryn Woodard, Cathy Chang, Gerhard Frey, William J. Boyle, Jay M. Short
Journal: Cancer Research (2024)

Abstract B7-H3, also known as CD276, is an immune-checkpoint molecule and a type 1 transmembrane protein that exerts a variety of biological functions. In cancer biology, the overexpression of B7-H3 is correlated with tumor cell invasion and metastasis, decreased T-cell infiltration and function, poor prognosis, and resistance to therapy. As B7-H3 is expressed in multiple solid tumors and plays an important role in modulating anti-tumor immune response as well as promoting cancer cell formation, it became an important target for the development of antibody-based immunotherapy. Many forms of bispecific antibodies targeting B7-H3 have shown antitumor response in preclinical studies. However, bispecific T-cell engagers (TCE) targeting B7H3 and CD3 have been correlated with cytokine release syndrome and hepatic adverse events, a common toxicity observed using TCEs which has limited the development of this immunotherapeutic in clinic. We leveraged BioAtla’s Conditionally Active Biologic (CAB) platform (1) to develop a DualCAB T-cell engager targeting B7-H3 and CD3. This DualCAB-TCE molecule, BA3142, was engineered to bind with high affinity to both recombinant B7-H3 and CD3 receptor/antigens under conditions that mimic the acidic tumor microenvironment, but with low affinity in alkaline physiological conditions. In vitro and in vivo efficacy and toxicity data for the clone BA3142 will be presented. Our data demonstrated that BA3142 promotes cytotoxicity of B7-H3-expressing cancer cells in vitro and induces significant tumor regression in vivo. In Non-Human Primates BA3142 bispecific antibody was tolerated up to 25 mg/kg with minimal cytokine release and no clinical and histopathological signs of toxicities. The CAB technology offers the opportunity to expand the number of targets suitable for drug development in a new class of DualCAB TCEs with superior safety margin and potency in the clinic. (1) Chang HW, Frey G, Liu H, Xing C, Steinman L, Boyle WJ, and Short, J.M. Generating tumor-selective conditionally active biologic anti-CTLA4 antibodies via protein-associated chemical switches. Proc Natl Acad Sci U S A 2021;118. Citation Format: Ana Paula Cugnetti, PhD, Haizhen Liu, Patricia McNeeley, Kathryn Woodard, Cathy Chang, Gerhard Frey, William J. Boyle, Jay M. Short. Novel conditionally active tetravalent B7-H3 x CD3 T-cell engagers targeting solid tumors [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 6340.
Abstract 6242: A workflow execution system in a data fabric for integrative cancer analyses
Authors: Aarti Venkat, Pauline Ribeyre, Jawad Qureshi, Sai Shanmukha Narumanchi, J Montgomery Maxwell, Bill Winslow, Sara Volk Garcia, Chris Meyer, Tzintzuni Garcia, Peter Vassilatos, Clinton Malson, Zhenyu Zhang, Robert Grossman
Journal: Cancer Research (2024)

Abstract Cancer researchers are increasingly conducting multi-omic research and performing integrative analyses on combinations of genomic, proteomic, transcriptomic, imaging, single cell and other data modalities. However, it is quite challenging for a researcher to effectively access, aggregate and analyze data and metadata from different data sources in a scalable and reproducible manner, as the individual datasets may be disconnected from each other, and have separate authentication and authorization requirements. We developed a workflow execution system in a data fabric called the Biomedical Research Hub (BRH) to overcome these challenges for academic researchers. The BRH is powered by the Gen3 technology, an open-source Kubernetes based software stack that allows cancer researchers to create their own data fabric and interoperate with data from multiple data sources. The workflow execution system utilizes nextflow and allows researchers to run containerized applications in the cloud in a secure and isolated environment. Data from multiple resources can be combined for analysis using convenient pay models including NIH STRIDES. We plan to demonstrate the application of our system on a scientific use case involving Clonal Hematopoiesis of Indeterminate potential (CHIP), a phenomenon that has been associated with aging, cancer, cardiovascular diseases, infection and all-cause mortality. We run containerized CHIP workflows on the cloud, utilizing two datasets accessible through BRH: i) The Genomic Data Commons, the world’s largest source of harmonized cancer data and ii) BioDataCatalyst, an NHLBI ecosystem that drives discovery and innovation for heart, lung, blood and sleep disorders. Our system is ideally suited for machine learning on large aggregated cancer datasets and federated learning tasks. Citation Format: Aarti Venkat, Pauline Ribeyre, Jawad Qureshi, Sai Shanmukha Narumanchi, J Montgomery Maxwell, Bill Winslow, Sara Volk Garcia, Chris Meyer, Tzintzuni Garcia, Peter Vassilatos, Clinton Malson, Zhenyu Zhang, Robert Grossman. A workflow execution system in a data fabric for integrative cancer analyses [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 6242.
Abstract 6785: KIYA-PREDICT™ XPDX: An <i>ex vivo</i> 3D spheroid platform for modeling <i>in vivo</i> responses to multiple classes of oncology therapeutics
Authors: Aaron L. Carlson, Natalie W. Dance, Kimberly J. Burgess, Danielle Y. Nadeau, Melissa Millard, Alyssa Simonson, Armando Diaz, Michael Wick, Teresa M. DesRochers
Journal: Cancer Research (2024)

Abstract Patient-derived xenografts (PDX) are a powerful and commonly used tool in preclinical drug development as they represent an in vivo platform for screening drug response in human tumors that recapitulate many molecular and histological features of the original patient tumor. However, these models are costly and time-intensive, necessitating the development of ex vivo platforms for assessing drug response to PDX-derived tumors to de-risk in vivo studies by aiding in model selection and reducing the number of animals and costs associated with in vivo experimentation. The KIYA-PREDICT™ platform is a clinically validated, ex vivo 3D cell culture platform with demonstrated ability to predict patient response to chemotherapy in high grade glioma and ovarian cancer. Here, we apply this platform to profiling XPDX from XenoSTART’s comprehensive library of well-characterized models as a tool for assessing drug response and mechanism of action ex vivo while also aiding in model selection for in vivo studies. Over 100 XPDX models have been profiled ex vivo for response to several classes of cancer therapeutics, including chemotherapy, targeted therapy, and antibody-drug conjugates (ADCs), demonstrating robust concordance with in vivo drug response. CDK4/6 inhibitors palbociclib and ribociclib evaluated ex vivo in breast XPDX display strong correlation to in vivo response and recapitulate palbociclib resistance. Similarly, G12C inhibitors sotorasib (AMG-510) and adagrasib (MRTX849) screened against a panel of non-small cell lung cancer XPDX ex vivo match in vivo response and drug resistance. Finally, ex vivo and in vivo responses to FDA approved ADC enfortumab vedotin were evaluated in a panel of bladder cancer PDX, with ex vivo and in vivo responses showing good concordance and expected modulation based on Nectin-4 expression levels. The combination of the KIYA-PREDICT™ platform with XenoSTART’s XPDX catalogue is a flexible and powerful tool that can be utilized for streamlining preclinical drug development for a wide range of therapeutic classes. Citation Format: Aaron L. Carlson, Natalie W. Dance, Kimberly J. Burgess, Danielle Y. Nadeau, Melissa Millard, Alyssa Simonson, Armando Diaz, Michael Wick, Teresa M. DesRochers. KIYA-PREDICT™ XPDX: An ex vivo 3D spheroid platform for modeling in vivo responses to multiple classes of oncology therapeutics [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 6785.
Abstract 6779: Modality agnostic tumor models of cancer which can more accurately define drug efficacy and mechanism to help develop more effective therapeutics
Authors: Preethi Samuel, Damieanus Odour Ochola, Huckie Del Mundo, Bhuvanesh Dave
Journal: Cancer Research (2024)

Abstract Introduction: In the path to clinic, researchers require robust tools to effectively evaluate the capacity of novel therapeutic modalities to generate anti-tumor responses. Using human-relevant, translational ex-vivo models is widely considered to reduce attrition during drug discovery and development for a more effective prediction of clinical outcomes during preclinical testing of drug candidates. Methods: The three levels of our patient derived tumoroid model platform, COMPASS (Custom Organoid Modeling Platform for Accurate SolutionS) was built to be versatile modality-agnostic human on human model system for pre-clinical testing. COMPASS 1 has stroma with epithelium; COMPASS 2 has stroma, epithelium, and immune components (from PBMCs) and COMPASS 3 has stroma, epithelium, immune components, and oxygenation. For widespread adaptation and utilization of our COMPASS platform we encourage extensive characterization by articulating the context of use to help build confidence in cases where limited knowledge and only few real-life cases exist. Results: Our proof-of-concept examples articulating the context of use demonstrate the modality-agnostic adaptability our COMPASS platform brings to the field of preclinical testing. We encourage a collaborative approach with researchers to support their testing needs to build confidence in our model to enable transition from existing screens, assays, and animal models. We envision preclinical use of COMPASS to help stratify patients for clinical trials, identify subpopulations that need dose modification and predict the response of patients and/or their risk of adverse effects. Conclusion: Due to its greater physiological relevance and ability to encompass downstream processes in a time and cost-efficient way, industry and academia should deliberate the impact platform such as COMPASS would have on their workflow and consider adapting to using these models routinely. Citation Format: Preethi Samuel, Damieanus Odour Ochola, Huckie Del Mundo, Bhuvanesh Dave. Modality agnostic tumor models of cancer which can more accurately define drug efficacy and mechanism to help develop more effective therapeutics [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 6779.