bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Development of Resistance to Type II JAK2 Inhibitors in MPN Depends on AXL Kinase and Is Targetable
Authors: Codilupi Tamara , Szybinski Jakub , Arunasalam Stefanie , Jungius Sarah , Dunbar Andrew C. , Stivala Simona , Brkic Sime , Albrecht Camille , Vokalova Lenka , Yang Julie L. , Buczak Katarzyna , Ghosh Nilabh , Passweg Jakob R. , Rovo Alicia , Angelillo-Scherrer Anne , Pankov Dmitry , Dirnhofer Stefan , Levine Ross L. , Koche Richard , Meyer Sara C.
Published: February 2024

AbstractPurpose:
Myeloproliferative neoplasms (MPN) dysregulate JAK2 signaling. Because clinical JAK2 inhibitors have limited disease-modifying effects, type II JAK2 inhibitors such as CHZ868 stabilizing inactive JAK2 and reducing MPN clones, gain interest. We studied whether MPN cells escape from type ll inhibition.
Experimental Design:
MPN cells were continuously exposed to CHZ868. We used phosphoproteomic analyses and ATAC/RNA sequencing to characterize acquired resistance to type II JAK2 inhibition, and targeted candidate mediators in MPN cells and mice.
Results:
MPN cells showed increased IC50 and reduced apoptosis upon CHZ868 reflecting acquired resistance to JAK2 inhibition. Among >2,500 differential phospho-sites, MAPK pathway activation was most prominent, while JAK2-STAT3/5 remained suppressed. Altered histone occupancy promoting AP-1/GATA binding motif exposure associated with upregulated AXL kinase and enriched RAS target gene profiles. AXL knockdown resensitized MPN cells and combined JAK2/AXL inhibition using bemcentinib or gilteritinib reduced IC50 to levels of sensitive cells. While resistant cells induced tumor growth in NOD/SCID gamma mice despite JAK2 inhibition, JAK2/AXL inhibition largely prevented tumor progression. Because inhibitors of MAPK pathway kinases such as MEK are clinically used in other malignancies, we evaluated JAK2/MAPK inhibition with trametinib to interfere with AXL/MAPK-induced resistance. Tumor growth was halted similarly to JAK2/AXL inhibition and in a systemic cell line–derived mouse model, marrow infiltration was decreased supporting dependency on AXL/MAPK.
Conclusions:
We report on a novel mechanism of AXL/MAPK-driven escape from type II JAK2 inhibition, which is targetable at different nodes. This highlights AXL as mediator of acquired resistance warranting inhibition to enhance sustainability of JAK2 inhibition in MPN.
Data from Aneuploidy Landscape in Precursors of Ovarian Cancer
Authors: Wang Yeh , Douville Christopher , Chien Yen-Wei , Wang Brant G. , Chen Chi-Long , Pinto Andre , Smith Saron Ann , Drapkin Ronny , Chui M. Herman , Numan Tricia , Vang Russell , Papadopoulos Nickolas , Wang Tian-Li , Shih Ie-Ming
Published: February 2024

AbstractPurpose:
Serous tubal intraepithelial carcinoma (STIC) is now recognized as the main precursor of ovarian high-grade serous carcinoma (HGSC). Other potential tubal lesions include p53 signatures and tubal intraepithelial lesions. We aimed to investigate the extent and pattern of aneuploidy in these epithelial lesions and HGSC to define the features that characterize stages of tumor initiation and progression.
Experimental Design:
We applied RealSeqS to compare genome-wide aneuploidy patterns among the precursors, HGSC (cases, n = 85), and histologically unremarkable fallopian tube epithelium (HU-FTE; control, n = 65). On the basis of a discovery set (n = 67), we developed an aneuploidy-based algorithm, REAL-FAST (Repetitive Element AneupLoidy Sequencing Fallopian Tube Aneuploidy in STIC), to correlate the molecular data with pathology diagnoses. We validated the result in an independent validation set (n = 83) to determine its performance. We correlated the molecularly defined precursor subgroups with proliferative activity and histology.
Results:
We found that nearly all p53 signatures lost the entire Chr17, offering a “two-hit” mechanism involving both TP53 and BRCA1 in BRCA1 germline mutation carriers. Proliferatively active STICs harbor gains of 19q12 (CCNE1), 19q13.2, 8q24 (MYC), or 8q arm, whereas proliferatively dormant STICs show 22q loss. REAL-FAST classified HU-FTE and STICs into 5 clusters and identified a STIC subgroup harboring unique aneuploidy that is associated with increased proliferation and discohesive growth. On the basis of a validation set, REAL-FAST showed 95.8% sensitivity and 97.1% specificity in detecting STIC/HGSC.
Conclusions:
Morphologically similar STICs are molecularly distinct. The REAL-FAST assay identifies a potentially “aggressive” STIC subgroup harboring unique DNA aneuploidy that is associated with increased cellular proliferation and discohesive growth. REAL-FAST offers a highly reproducible adjunct technique to assist the diagnosis of STIC lesions.
Data from Phase I Study of Elraglusib (9-ING-41), a Glycogen Synthase Kinase-3β Inhibitor, as Monotherapy or Combined with Chemotherapy in Patients with Advanced Malignancies
Authors: Carneiro Benedito A. , Cavalcante Ludimila , Mahalingam Devalingam , Saeed Anwaar , Safran Howard , Ma Wen Wee , Coveler Andrew L. , Powell Steven , Bastos Bruno , Davis Elizabeth , Sahai Vaibhav , Mikrut William , Longstreth James , Smith Sheri , Weisskittel Taylor , Li Hu , Borden Brittany A. , Harvey R. Donald , Sahebjam Solmaz , Cervantes Andrés , Koukol Austin , Mazar Andrew P. , Steeghs Neeltje , Kurzrock Razelle , Giles Francis J. , Munster Pamela
Published: February 2024

AbstractPurpose:
The safety, pharmacokinetics, and efficacy of elraglusib, a glycogen synthase kinase-3β (GSK-3β) small-molecule inhibitor, as monotherapy or combined with chemotherapy, in patients with relapsed or refractory solid tumors or hematologic malignancies was studied.
Patients and Methods:
Elraglusib (intravenously twice weekly in 3-week cycles) monotherapy dose escalation was followed by dose escalation with eight chemotherapy regimens (gemcitabine, doxorubicin, lomustine, carboplatin, irinotecan, gemcitabine/nab-paclitaxel, paclitaxel/carboplatin, and pemetrexed/carboplatin) in patients previously exposed to the same chemotherapy.
Results:
Patients received monotherapy (n = 67) or combination therapy (n = 171) elraglusib doses 1 to 15 mg/kg twice weekly. The initial recommended phase II dose (RP2D) of elraglusib was 15 mg/kg twice weekly and was defined, without dose-limiting toxicity observation, due to fluid volumes necessary for drug administration. The RP2D was subsequently reduced to 9.3 mg/kg once weekly to reduce elraglusib-associated central/peripheral vascular access catheter blockages. Other common elraglusib-related adverse events (AE) included transient visual changes and fatigue. Grade ≥3 treatment-emergent AEs occurred in 55.2% and 71.3% of patients on monotherapy and combination therapy, respectively. Part 1 monotherapy (n = 62) and part 2 combination (n = 138) patients were evaluable for response. In part 1, a patient with melanoma had a complete response, and a patient with acute T-cell leukemia/lymphoma had a partial response (PR). In part 2, seven PRs were observed, and the median progression-free survival and overall survival were 2.1 [95% confidence interval (CI), 2–2.6] and 6.9 (95% CI, 5.7–8.4) months, respectively.
Conclusions:
Elraglusib had a favorable toxicity profile as monotherapy and combined with chemotherapy and was associated with clinical benefit supporting further clinical evaluation in combination with chemotherapy.
Supplementary figure 2 from Design and Evaluation of Phosphonamidate-Linked Exatecan Constructs for Highly Loaded, Stable, and Efficacious Antibody–Drug Conjugates
Authors: Schmitt Saskia , Machui Paul , Mai Isabelle , Herterich Sarah , Wunder Swetlana , Cyprys Philipp , Gerlach Marcus , Ochtrop Philipp , Hackenberger Christian P.R. , Schumacher Dominik , Helma Jonas , Vogl Annette M. , Kasper Marc-André
Published: February 2024

Analytical SEC chromatograms of trastuzumab-LP3 DAR8, trastuzumab-LP5 DAR8 and Enhertu at day 0 and after storage for four weeks at 4°C and 37°C in the dark.
Supplementary figure 1 from Design and Evaluation of Phosphonamidate-Linked Exatecan Constructs for Highly Loaded, Stable, and Efficacious Antibody–Drug Conjugates
Authors: Schmitt Saskia , Machui Paul , Mai Isabelle , Herterich Sarah , Wunder Swetlana , Cyprys Philipp , Gerlach Marcus , Ochtrop Philipp , Hackenberger Christian P.R. , Schumacher Dominik , Helma Jonas , Vogl Annette M. , Kasper Marc-André
Published: February 2024

Dose-response curves for the ADC synthesized from trastuzumab and LP1 and LP3-LP3 on SKBR-3, HCC-78 and MDA-MB-468
Organic synthesis from Design and Evaluation of Phosphonamidate-Linked Exatecan Constructs for Highly Loaded, Stable, and Efficacious Antibody–Drug Conjugates
Authors: Schmitt Saskia , Machui Paul , Mai Isabelle , Herterich Sarah , Wunder Swetlana , Cyprys Philipp , Gerlach Marcus , Ochtrop Philipp , Hackenberger Christian P.R. , Schumacher Dominik , Helma Jonas , Vogl Annette M. , Kasper Marc-André
Published: February 2024

Organic Synthesis procedures for the linker payloads and characterization of products and intermediates.
Supplementary methods S6 from Novel Methionine Aminopeptidase 2 Inhibitor M8891 Synergizes with VEGF Receptor Inhibitors to Inhibit Tumor Growth of Renal Cell Carcinoma Models
Authors: Friese-Hamim Manja , Ortiz Ruiz Maria J. , Bogatyrova Olga , Keil Marina , Rohdich Felix , Blume Beatrix , Leuthner Birgitta , Czauderna Frank , Hahn Diane , Jabs Julia , Jaehrling Frank , Heinrich Timo , Kellner Roland , Chan Katherine , Tong Amy H.Y. , Wienke Dirk , Moffat Jason , Blaukat Andree , Zenke Frank T.
Published: February 2024

Generation of rabbit monoclonal antibody against unprocessed human EF1a
Supplementary Table S7-2 from Novel Methionine Aminopeptidase 2 Inhibitor M8891 Synergizes with VEGF Receptor Inhibitors to Inhibit Tumor Growth of Renal Cell Carcinoma Models
Authors: Friese-Hamim Manja , Ortiz Ruiz Maria J. , Bogatyrova Olga , Keil Marina , Rohdich Felix , Blume Beatrix , Leuthner Birgitta , Czauderna Frank , Hahn Diane , Jabs Julia , Jaehrling Frank , Heinrich Timo , Kellner Roland , Chan Katherine , Tong Amy H.Y. , Wienke Dirk , Moffat Jason , Blaukat Andree , Zenke Frank T.
Published: February 2024

Top CRISPR hits that score as suppressors or sensitizers
Supplementary Table S3-1 from Novel Methionine Aminopeptidase 2 Inhibitor M8891 Synergizes with VEGF Receptor Inhibitors to Inhibit Tumor Growth of Renal Cell Carcinoma Models
Authors: Friese-Hamim Manja , Ortiz Ruiz Maria J. , Bogatyrova Olga , Keil Marina , Rohdich Felix , Blume Beatrix , Leuthner Birgitta , Czauderna Frank , Hahn Diane , Jabs Julia , Jaehrling Frank , Heinrich Timo , Kellner Roland , Chan Katherine , Tong Amy H.Y. , Wienke Dirk , Moffat Jason , Blaukat Andree , Zenke Frank T.
Published: February 2024

IC50 and efficacy of M8891 in cancer cell lines
Supplementary Figure S8-3 from Novel Methionine Aminopeptidase 2 Inhibitor M8891 Synergizes with VEGF Receptor Inhibitors to Inhibit Tumor Growth of Renal Cell Carcinoma Models
Authors: Friese-Hamim Manja , Ortiz Ruiz Maria J. , Bogatyrova Olga , Keil Marina , Rohdich Felix , Blume Beatrix , Leuthner Birgitta , Czauderna Frank , Hahn Diane , Jabs Julia , Jaehrling Frank , Heinrich Timo , Kellner Roland , Chan Katherine , Tong Amy H.Y. , Wienke Dirk , Moffat Jason , Blaukat Andree , Zenke Frank T.
Published: February 2024

Body weight curves of colon cancer PDX model CXF-1783-bearing mice treated with vehicle or M8891 (150 mg/kg, twice daily, per os) monotherapy
Supplementary Table1 from Effects of Combined Therapeutic Targeting of AXL and ATR on Pleural Mesothelioma Cells
Authors: Hirai Soichi , Yamada Tadaaki , Katayama Yuki , Ishida Masaki , Kawachi Hayato , Matsui Yohei , Nakamura Ryota , Morimoto Kenji , Horinaka Mano , Sakai Toshiyuki , Sekido Yoshitaka , Tokuda Shinsaku , Takayama Koichi
Published: February 2024

Supplementary Table1
Figure S4 from Effects of Combined Therapeutic Targeting of AXL and ATR on Pleural Mesothelioma Cells
Authors: Hirai Soichi , Yamada Tadaaki , Katayama Yuki , Ishida Masaki , Kawachi Hayato , Matsui Yohei , Nakamura Ryota , Morimoto Kenji , Horinaka Mano , Sakai Toshiyuki , Sekido Yoshitaka , Tokuda Shinsaku , Takayama Koichi
Published: February 2024

Figure S4
Supplementary Figure S11-4 from Novel Methionine Aminopeptidase 2 Inhibitor M8891 Synergizes with VEGF Receptor Inhibitors to Inhibit Tumor Growth of Renal Cell Carcinoma Models
Authors: Friese-Hamim Manja , Ortiz Ruiz Maria J. , Bogatyrova Olga , Keil Marina , Rohdich Felix , Blume Beatrix , Leuthner Birgitta , Czauderna Frank , Hahn Diane , Jabs Julia , Jaehrling Frank , Heinrich Timo , Kellner Roland , Chan Katherine , Tong Amy H.Y. , Wienke Dirk , Moffat Jason , Blaukat Andree , Zenke Frank T.
Published: February 2024

Body weight curves for RCC PDX model RXF-2796-bearing mice treated with vehicle, M8891 (100 mg/kg, daily, per os), sunitinib (40 mg/kg, daily, per os), or the combination are shown
Supplementary Figure S11-3 from Novel Methionine Aminopeptidase 2 Inhibitor M8891 Synergizes with VEGF Receptor Inhibitors to Inhibit Tumor Growth of Renal Cell Carcinoma Models
Authors: Friese-Hamim Manja , Ortiz Ruiz Maria J. , Bogatyrova Olga , Keil Marina , Rohdich Felix , Blume Beatrix , Leuthner Birgitta , Czauderna Frank , Hahn Diane , Jabs Julia , Jaehrling Frank , Heinrich Timo , Kellner Roland , Chan Katherine , Tong Amy H.Y. , Wienke Dirk , Moffat Jason , Blaukat Andree , Zenke Frank T.
Published: February 2024

Body weight curves for RCC PDX model RXF-2717-bearing mice treated with vehicle, M8891 (100 mg/kg, daily, per os), sunitinib (40 mg/kg, daily, per os), or the combination are shown
Table S2 from CD38 x ICAM-1 Bispecific Antibody Is a Novel Approach for Treating Multiple Myeloma and Lymphoma
Authors: Chen Xiaocheng , Wong Oi Kwan , Reiman Lauren , Sherbenou Daniel W. , Post Leonard
Published: February 2024

Patient Characteristics
Figure S7 from CD38 x ICAM-1 Bispecific Antibody Is a Novel Approach for Treating Multiple Myeloma and Lymphoma
Authors: Chen Xiaocheng , Wong Oi Kwan , Reiman Lauren , Sherbenou Daniel W. , Post Leonard
Published: February 2024

CD38 and ICAM-1 expression levels on the LD1-0029-370728 tumor
Figure S5 from CD38 x ICAM-1 Bispecific Antibody Is a Novel Approach for Treating Multiple Myeloma and Lymphoma
Authors: Chen Xiaocheng , Wong Oi Kwan , Reiman Lauren , Sherbenou Daniel W. , Post Leonard
Published: February 2024

CDC activity
Supplementary Fig. S9 from Amelioration of Tumor-promoting Microenvironment via Vascular Remodeling and CAF Suppression Using E7130: Biomarker Analysis by Multimodal Imaging Modalities
Authors: Ito Ken , Yamaguchi Masayuki , Semba Taro , Tabata Kimiyo , Tamura Moe , Aoyama Muneo , Abe Takanori , Asano Osamu , Terada Yasuhiko , Funahashi Yasuhiro , Fujii Hirofumi
Published: February 2024

In vitro cell growth inhibitory effect of E7130 on normal human fibroblast (BJ) and cancer cell lines (MCF-7 and HCT-116)
Supplementary Fig. S3 from Amelioration of Tumor-promoting Microenvironment via Vascular Remodeling and CAF Suppression Using E7130: Biomarker Analysis by Multimodal Imaging Modalities
Authors: Ito Ken , Yamaguchi Masayuki , Semba Taro , Tabata Kimiyo , Tamura Moe , Aoyama Muneo , Abe Takanori , Asano Osamu , Terada Yasuhiko , Funahashi Yasuhiro , Fujii Hirofumi
Published: February 2024

Representative IHC image for α-SMA expression levels in various xenografted tumors
Supplemental Table S5 from Amelioration of Tumor-promoting Microenvironment via Vascular Remodeling and CAF Suppression Using E7130: Biomarker Analysis by Multimodal Imaging Modalities
Authors: Ito Ken , Yamaguchi Masayuki , Semba Taro , Tabata Kimiyo , Tamura Moe , Aoyama Muneo , Abe Takanori , Asano Osamu , Terada Yasuhiko , Funahashi Yasuhiro , Fujii Hirofumi
Published: February 2024

Scan parameters for magnetic resonance imaging
Supplemental Table S4 from Amelioration of Tumor-promoting Microenvironment via Vascular Remodeling and CAF Suppression Using E7130: Biomarker Analysis by Multimodal Imaging Modalities
Authors: Ito Ken , Yamaguchi Masayuki , Semba Taro , Tabata Kimiyo , Tamura Moe , Aoyama Muneo , Abe Takanori , Asano Osamu , Terada Yasuhiko , Funahashi Yasuhiro , Fujii Hirofumi
Published: February 2024

The protein markers for multiplex imaging mass cytometer analysis
Supplemental Table S1 from Amelioration of Tumor-promoting Microenvironment via Vascular Remodeling and CAF Suppression Using E7130: Biomarker Analysis by Multimodal Imaging Modalities
Authors: Ito Ken , Yamaguchi Masayuki , Semba Taro , Tabata Kimiyo , Tamura Moe , Aoyama Muneo , Abe Takanori , Asano Osamu , Terada Yasuhiko , Funahashi Yasuhiro , Fujii Hirofumi
Published: February 2024

Inoculated cell number for mouse models
Figure S9 from SKP2 Knockout in Rb1/p53–Deficient Mouse Models of Osteosarcoma Induces Immune Infiltration and Drives a Transcriptional Program with a Favorable Prognosis
Authors: Ferrena Alexander , Wang Jichuan , Zhang Ranxin , Karadal-Ferrena Burcu , Al-Hardan Waleed , Singh Swapnil , Borjihan Hasibagan , Schwartz Edward L. , Zhao Hongling , Oktay Maja H. , Yang Rui , Geller David S. , Hoang Bang H. , Zheng Deyou
Published: February 2024

Pan-cancer TCGA analysis of macrophage infiltration correlation with SKP2 and survival via TIMER2.0
Figure S6 from SKP2 Knockout in Rb1/p53–Deficient Mouse Models of Osteosarcoma Induces Immune Infiltration and Drives a Transcriptional Program with a Favorable Prognosis
Authors: Ferrena Alexander , Wang Jichuan , Zhang Ranxin , Karadal-Ferrena Burcu , Al-Hardan Waleed , Singh Swapnil , Borjihan Hasibagan , Schwartz Edward L. , Zhao Hongling , Oktay Maja H. , Yang Rui , Geller David S. , Hoang Bang H. , Zheng Deyou
Published: February 2024

Immunohistochemistry of endothelial marker Cd31
Figure S4 from SKP2 Knockout in Rb1/p53–Deficient Mouse Models of Osteosarcoma Induces Immune Infiltration and Drives a Transcriptional Program with a Favorable Prognosis
Authors: Ferrena Alexander , Wang Jichuan , Zhang Ranxin , Karadal-Ferrena Burcu , Al-Hardan Waleed , Singh Swapnil , Borjihan Hasibagan , Schwartz Edward L. , Zhao Hongling , Oktay Maja H. , Yang Rui , Geller David S. , Hoang Bang H. , Zheng Deyou
Published: February 2024

Macrophage polarization marker derivation from reanalysis of MacSpectrum single-cell RNA-seq data.
Table S1 from Targeting Dysregulated Ion Channels in Liver Tumors with Venom Peptides
Authors: Achimba Favour , Faezov Bulat , Cohen Brandon , Dunbrack Roland , Holford Mandë
Published: February 2024

HCC cell lines available for research.
Figure S1 from Targeting Dysregulated Ion Channels in Liver Tumors with Venom Peptides
Authors: Achimba Favour , Faezov Bulat , Cohen Brandon , Dunbrack Roland , Holford Mandë
Published: February 2024

Differential expression of TRP channels in various HCC cell lines. Transcriptome data from EMBL-EBI's expression atlas shows that TRP C1 and TRPV2 have high transcript expression levels in many cancer cell lines. TRPC6, TRPC3 and TRPV6 are moderately to highly expressed in some cell lines.
Data from Design and Evaluation of Phosphonamidate-Linked Exatecan Constructs for Highly Loaded, Stable, and Efficacious Antibody–Drug Conjugates
Authors: Schmitt Saskia , Machui Paul , Mai Isabelle , Herterich Sarah , Wunder Swetlana , Cyprys Philipp , Gerlach Marcus , Ochtrop Philipp , Hackenberger Christian P.R. , Schumacher Dominik , Helma Jonas , Vogl Annette M. , Kasper Marc-André
Published: February 2024

Abstract
Topoisomerase I (TOP1) Inhibitors constitute an emerging payload class to engineer antibody–drug conjugates (ADC) as next-generation biopharmaceutical for cancer treatment. Existing ADCs are using camptothecin payloads with lower potency and suffer from limited stability in circulation. With this study, we introduce a novel camptothecin-based linker–payload platform based on the highly potent camptothecin derivative exatecan. First, we describe general challenges that arise from the hydrophobic combination of exatecan and established dipeptidyl p-aminobenzyl-carbamate (PAB) cleavage sites such as reduced antibody conjugation yields and ADC aggregation. After evaluating several linker–payload structures, we identified ethynyl-phosphonamidates in combination with a discrete PEG24 chain to compensate for the hydrophobic PAB–exatecan moiety. Furthermore, we demonstrate that the identified linker–payload structure enables the construction of highly loaded DAR8 ADCs with excellent solubility properties. Head-to-head comparison with Enhertu, an approved camptothecin-based ADC, revealed improved target-mediated killing of tumor cells, excellent bystander killing, drastically improved linker stability in vitro and in vivo and superior in vivo efficacy over four tested dose levels in a xenograft model. Moreover, we show that ADCs based on the novel exatecan linker–payload platform exhibit antibody-like pharmacokinetic properties, even when the ADCs are highly loaded with eight drug molecules per antibody. This ADC platform constitutes a new and general solution to deliver TOP1 inhibitors with highest efficiency to the site of the tumor, independent of the antibody and its target, and is thereby broadly applicable to various cancer indications.
Data from SKP2 Knockout in Rb1/p53–Deficient Mouse Models of Osteosarcoma Induces Immune Infiltration and Drives a Transcriptional Program with a Favorable Prognosis
Authors: Ferrena Alexander , Wang Jichuan , Zhang Ranxin , Karadal-Ferrena Burcu , Al-Hardan Waleed , Singh Swapnil , Borjihan Hasibagan , Schwartz Edward L. , Zhao Hongling , Oktay Maja H. , Yang Rui , Geller David S. , Hoang Bang H. , Zheng Deyou
Published: February 2024

Abstract
Osteosarcoma is an aggressive bone malignancy with a poor prognosis. One putative proto-oncogene in osteosarcoma is SKP2, encoding a substrate recognition factor of the SCF E3 ubiquitin ligase. We previously demonstrated that Skp2 knockout in murine osteosarcoma improved survival and delayed tumorigenesis. Here, we performed RNA sequencing (RNA-seq) on tumors from a transgenic osteosarcoma mouse model with conditional Trp53 and Rb1 knockouts in the osteoblast lineage (“DKO”: Osx1-Cre;Rb1lox/lox;p53lox/lox) and a triple-knockout model with additional Skp2 germline knockout (“TKO”: Osx1-Cre;Rb1lox/lox;p53lox/lox;Skp2−/−), followed by qPCR and immunohistochemistry validation. To investigate the clinical implications of our results, we analyzed a human osteosarcoma patient cohort (“NCI-TARGET OS”) with RNA-seq and clinical data. We found large differences in gene expression after SKP2 knockout. Surprisingly, we observed increased expression of genes related to immune microenvironment infiltration in TKO tumors, especially the signature genes for macrophages and to a lesser extent, T cells, B cells, and vascular cells. We also uncovered a set of relevant transcription factors that may mediate these changes. In osteosarcoma patient cohorts, high expression of genes upregulated in TKO was correlated with favorable overall survival, which was largely explained by the macrophage gene signatures. This relationship was further supported by our finding that SKP2 expression was negatively correlated with macrophage infiltration in the NCI-TARGET osteosarcoma and the TCGA Sarcoma cohorts. Overall, our findings indicate that SKP2 may mediate immune exclusion from the osteosarcoma tumor microenvironment, suggesting that SKP2 modulation in osteosarcoma may induce antitumor immune activation.
Abstract A016: The breast cancer genome and its association with the breast tissue bacteriome
Authors: McCaw Ariana , Jiang Rachel , Marian Lindsey , Stiemsma Leah
Published: February 2024

BC is the most prevalent and leading fatal cancer type in women, yet the causes of most cases are unknown, indicating the necessity of deciphering contributing factors to quicken detection and inform therapeutic options. This research explores the relationship between the breast cancer (BC) genome and breast tissue bacteriome. BC forms in microenvironments in which genes and bacteria are in close proximity and research evidences gene-bacteria communication, but the relationship between the BC genome and the changing breast tissue bacteriome is not well understood. We hypothesized that genetic variation in the top ten genes commonly linked to BC: BRCA1, BRCA2, PTEN, TP53, PALB2, CHEK2, ATM, BRIP1, BARD1 , and STK11 would be associated with variations in the breast tissue bacteriome. We conducted 30X whole genome sequencing on 60 breast tissue samples (healthy, H (n=15), pre-diagnostic, PD (n=15), tumor, T (n=15), and adjacent normal, AN (n=15)) donated to the Susan G. Komen and Indiana University Simon Cancer Center Tissue Banks. These same samples were previously analyzed for microbiome composition and function using 16S rRNA sequencing (published in mSystems, 2022). Following sequence pre-processing, variant calling, and alternate allele frequency calculation by the UC Davis Bioinformatics Core, we selected only high and moderate variants for these genes with a quality score ≥ 55 for further analysis. Of the ten we intended to analyze, only 8 met these criteria within our data set: BRCA1, BRCA2, PTEN, TP53, PALB2, CHEK2, ATM , and BRIP1 . We ran generalized linear models to select variants with differences in alternate allele frequency among the tissue types (H, PD, AN, T, p ≤ 0.2). Alternate allele frequencies and genotypes of these variants that passed this filter were then associated with bacterial ASVs deemed differentially abundant relative to the H tissue type (mSystems, 2022) using MaAsLin2. Three BC-linked genes BRCA1, TP53 , and ATM show significant associations with the taxa, Muribaculaceae, Alcaligenes faecalis, Oceanobacillus, Romboutsia, Pseudomonas , and Pseudomonas fragi , at a p-value ≤ 0.01 and q-value ≤ 0.25. These genera belong to phyla (Bacteroides, Firmicutes, and Actinobacteria) which have been shown to either interact directly with the genome to produce cancer-causing DNA damage, or to be associated with other types of cancer, suggesting their likely role in tumorigenesis. The discovered associations further our understanding of the genetic and microbial determinants of breast cancer and may highlight the breast tissue bacteriome as a biomarker of BC.

Citation Format: Ariana McCaw, Rachel Jiang, Lindsey Marian, Leah Stiemsma. The breast cancer genome and its association with the breast tissue bacteriome [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A016.
Abstract A018: Dihydroceramide desaturase 1 (DES1) promotes anchorage-independent survival and metastasis of HER2-positive and basal breast cancer through regulation of caspase 14
Authors: Peperno Deanna M , Lambadis Danielle , Alvarado Victoria , Resnick Andrew E , Clarke Christopher J
Published: February 2024

Despite improvements in therapies, metastasis still leads to high mortality rates in breast cancer (BC). Consequently, discovering new therapies that are effective at targeting metastatic disease remains a critical need, particularly for the aggressive HER2+ and basal BC subtypes. The ability of cancer cells to survive in the absence of an extracellular matrix – termed anchorage-independent survival (AIS) – is central to the metastatic cascade and has emerged as a target biology of interest for reducing metastatic burden. Previously, we identified the SL enzyme dihydroceramide desaturase 1 (DES1) as a critical node for AIS of HER2+ BC cells. Here, we have extended these data to show that targeting DES1 through pharmacological inhibitors (4HPR), siRNA, or CRISPR-cas9 knockout was able to overcome AIS in basal BC cells as well as HER2+ BC cells that, functionally, led to a reduction of in vitro colony formation in soft agar. Extending these findings in vivo, we found that DES1 knockout led to a significant reduction in lung metastasis of both HER2+ and basal BC cells in murine models of experimental metastasis. Moreover, treatment of PyMT mice with the DES1 inhibitor 4HPR was able to reduce metastatic burden. To define downstream effectors of DES1 required for AIS, we performed a microarray analysis of control and DES1 knockout cells in suspension, leading us to identify caspase 14 as a downstream effector of DES1 in HER2+ and basal BC. Consistent with these findings, siRNA knockdown of caspase 14 led to a striking decrease in cell viability in colony formation assays. Finally, analysis of publicly available data found that high levels of DES1 and Caspase 14 were associated with poor clinical outcomes in both HER2+ and basal BC. Taken together, these data establish DES1 as a mediator of BC metastasis, likely through promoting AIS, and define caspase 14 as a target of DES1-driven signaling. Furthermore, results suggest that both DES1 and caspase 14 expression may be useful as biomarkers of metastasis-prone tumors.

Citation Format: Deanna M Peperno, Danielle Lambadis, Victoria Alvarado, Andrew E Resnick, Christopher J Clarke. Dihydroceramide desaturase 1 (DES1) promotes anchorage-independent survival and metastasis of HER2-positive and basal breast cancer through regulation of caspase 14 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A018.
Abstract A019: IGF-1R protein pathway activation is associated with pathologic complete response to an anti-IGF-1R regimen (paclitaxel, ganitumab, and metformin) in the I-SPY2 neoadjuvant breast cancer trial
Authors: Petricoin Emanuel F. , Wolf Denise M. , Yau Christina , Wulfkuhle Julia , van ‘t Veer Laura , Gallagher Rosa I. , Hirst Gillian L. , Brown-Swigart Lamorna , Esserman Laura J. , Yee Douglas
Published: February 2024

BACKGROUND: The addition of PGM followed by doxorubicin/cyclophosphamide versus control was evaluated as neoadjuvant therapy. Here IGF-1R pathway based protein and phosphoprotein (p) biomarkers were examined for their predictive utility. METHODS: Reverse phase protein array evaluated 102 pretreatment PGM and 169 control HER2- specimens. 32 pre-specified biomarker candidates were examined. A logistic regression model adjusted for hormone receptor (HR) status. The Benjamini-Hochberg (BH) method adjusted for multiple hypothesis testing. ROC analysis identified dichotomizing thresholds for select biomarkers. RESULTS: In the entire PGM population in a model adjusting for HR status, higher levels of pIGF-1R (Y1135/Y1136)/IR (Y1150/Y1151) (OR=2.13 p<0.002; BH p<0.05) and lower levels of p27 T187 (OR= 0.41 p<0.002; BH p<0.05) were significantly associated with pCR. Downstream IGF-1R signaling proteins were nominally associated with pCR (IRS-1 S612, p90 RSK S380, FOXO1 T24/FOXO3a T32). In HR+ tumors (n=58), pIGF-1R retained its significant positive association with pCR (OR=4.08 P<0.002; LR p<0.05), with an AUC of 0.79 [95% CI: 0.56-1]. Using an optimal dichotomizing threshold, 16% (9/58) of HR+HER2- were classified pIGF-1R.IR-High; and 56% (5/9) of these patients achieved pCR vs. 6% (3/49) in the pIGF1R.IR-Low subset. In TN patients (n=44), pIGF-1R did not associate with response. However, lower pp27 remained nominally associated with higher pCR rates for PGM treatment (OR=0.42 p<0.009; BH p>0.05) with an AUC of 0.74 [95% CI: 0.58-0.89]; and when optimally dichotomized, 52% (13/25) of pp27 Low TN patients achieved pCR vs. 12% (2/17) in the pp27 High group. None of these PGM-response-predictive biomarkers associated with response in the control arm. Total receptor levels did not associate with response. CONCLUSION: We are the first to show that pre-treatment levels of IGF-1R protein pathway activation-based signaling phosphoproteins, including levels of pIGF-1R, the drug target for ganitumab, may be predictive biomarkers for drugs targeting this receptor especially in the HR+ subset.

Citation Format: Emanuel F. Petricoin, Denise M. Wolf, Christina Yau, Julia Wulfkuhle, Laura van ‘t Veer, Rosa I. Gallagher, Gillian L. Hirst, Lamorna Brown-Swigart, Laura J. Esserman, Douglas Yee. IGF-1R protein pathway activation is associated with pathologic complete response to an anti-IGF-1R regimen (paclitaxel, ganitumab, and metformin) in the I-SPY2 neoadjuvant breast cancer trial [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A019.
Abstract A044: P2Y2 signaling disruption reduces ATP-dependent calcium elevation and actin localization to promote breast tumor cell dissemination
Authors: Mull Makenzy , Pratt Stephen , Thompson Keyata , Annis David , Ju Julia , Stemberger Megan , Boyman Liron , Vitolo Michele , Lederer W. Jonathan , Martin Stuart
Published: February 2024

The tumor microenvironment and wound healing after injury both contain extremely high concentrations of the extracellular signaling molecule, adenosine triphosphate (ATP) compared to normal tissue. P2Y2 receptor, an ATP-activated purinergic receptor, is typically associated with pulmonary, endothelial, and neural cell signaling. Here we report the importance of ATP-dependent P2Y2 signaling in breast epithelial cells and how it is altered in metastatic breast cancer. In response to ATP activation, P2Y2 receptor signaling causes an increase of intracellular calcium (Ca2+) in non-tumorigenic breast epithelial cells, while their tumorigenic and metastatic counterparts have significantly reduced Ca2+ responses. The non-tumorigenic cells respond to increased Ca2+ with actin polymerization and localization to cell edges, while the metastatic cells remained unaffected. The increase in intracellular Ca2+ after ATP stimulation was blunted using a P2Y2 antagonist, which also prevented actin mobilization and caused cell dissemination from spheroids in non-tumorigenic breast epithelial cells. Furthermore, the lack of Ca2+ concentration changes and actin mobilization in the metastatic breast cancer cells could be due to reduced P2Y2 expression, which correlates with poorer overall survival in breast cancer patients. This study elucidates rapid changes that occur after elevated intracellular Ca2+ in breast epithelial cells and how metastatic cancer cells have adapted to evade this cellular response.

Citation Format: Makenzy Mull, Stephen Pratt, Keyata Thompson, David Annis, Julia Ju, Megan Stemberger, Liron Boyman, Michele Vitolo, W. Jonathan Lederer, Stuart Martin. P2Y2 signaling disruption reduces ATP-dependent calcium elevation and actin localization to promote breast tumor cell dissemination [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A044.
Abstract A079: Loss of BPTF restores estrogen-regulated programs and suppress metastatic development of mammary tumors
Authors: Chen Chen , Ciccone Michael F. , Trousdell Marygrace c. , Chatterjee Deeptiman , Zhao Yixin , Lewis Steven M. , Anandan Dhivya , Wilkinson John E. , Pomerantz William C. K. , Siepel Adam , dos Santos Camila O.
Published: February 2024

Chromatin remodeling controls transcriptional programs that drive mammary epithelial lineage commitment and cellular differentiation. This process is also important for the regulation of highly dynamic cellular states during mammary tumorigenesis, and perturbing the chromatin landscape of cancer cells can halt cellular and molecular mechanisms of mammary cancer development and progression. However, this paradigm assumes that all cancer cells that develop in the mammary tissue bear the same chromatin dependencies, and rely on similar programs throughout cancer progression. Here, we show that molecular dependencies regulated by the epigenetic factor BPTF control tumor development and progression across distinct mammary cancer cell states. With the utilization of classical models of mammary tumorigenesis, single cell transcriptional profiling, and organoid cultures, we demonstrate that BPTF loss results in the development of mammary tumors with a longer latency of ER•+ expression and tamoxifen sensitivity and the inhibition of lung metastasis development. While gain of ER• expression was associated with gain of luminal markers in Krt5+ BPTF KO mammary epithelial cells (MECs), metastasis-like signatures were significantly perturbed in cells with defined luminal fate. In addition, we detected a partial rescue of metastatic features via the activation of transcriptional programs controlled by TGF-•, thus indicating that BPTF sits atop a canonical metastatic pathway. Collectively, our studies illustrate how BPTF-specific chromatin remodeling inhibition induces phenotypes that differentially affect tumor development and progression, while allowing for the development of a murine model of ER•+ mammary tumorigenesis.

Citation Format: Chen Chen, Michael F. Ciccone, Marygrace c. Trousdell, Deeptiman Chatterjee, Yixin Zhao, Steven M. Lewis, Dhivya Anandan, John E. Wilkinson, William C. K. Pomerantz, Adam Siepel, Camila O. dos Santos. Loss of BPTF restores estrogen-regulated programs and suppress metastatic development of mammary tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A079.
Abstract A081: Real-world treatment patterns and clinical outcomes in patients with HER2+ metastatic breast cancer receiving systemic therapy in Ontario, Canada
Authors: Jerzak Katarzyna J , Moulson Ruth , Hsu Ling-I , Lenhu Chris , Krishnathasan Dhivo , Weiss Jessica , Brezden-Masley Christine
Published: February 2024

Background: Real-world data on treatment patterns and prevalence of brain metastases in patients with HER2+ metastatic breast cancer (mBC) are limited. This study described treatment patterns and clinical outcomes among patients with HER2+ mBC in Canada. Methods: This was a retrospective chart review of adult patients diagnosed with de-novo or recurrent HER2+ mBC between Jan 1, 2014 and Mar 1, 2021 (prior to wide availability of new treatments) at Sunnybrook Research Institute and Sinai Health, two large BC treatment centres in Canada. Data on patient characteristics and treatment regimens were extracted. Treatment patterns, time to next treatment (TTNT; as a proxy for progression-free survival), and presence of brain metastases were assessed in the first-line (1L), second-line (2L), and third-line (3L) settings. TTNT analyses used Kaplan-Meier methodology to account for censoring. Results: Of 121 patients with HER2+ mBC, the median (IQR) age was 54.0 (17.0) years. 38.0% of patients had de-novo disease and 62.0% had recurrent mBC; 12 (9.9%) had brain metastases at the time of mBC diagnosis. Systemic therapies generally aligned with Canadian funded regimens for 1L (101 of 121 patients [83.5%] received trastuzumab + pertuzumab ± chemotherapy ± subsequent endocrine therapy; 8/121 [6.6%] received endocrine therapy only) and 2L (50/68 [73.5%] received T-DM1 ± endocrine therapy; 9/68 [13.2%] received endocrine therapy only). However, treatment patterns were heterogeneous in the 3L setting (14/46 [30.4%] received anti-HER2 TKI + chemotherapy ± trastuzumab; 10/46 [21.7%] received endocrine therapy only; 10/46 [21.7%] received chemotherapy). Median (95% CI) TTNT in months was 21.4 (16.1, 27.2) in 1L, 11.0 (8.5, 16.5) in 2L, and 8.7 (5.4, 15.6) in 3L. Median (IQR) follow-up was 29.9 (25.2) months. In total, 57 patients (47.1%) were diagnosed with brain metastases during the study period (17 pre-1L, 24 post-1L/pre-2L, 6 post-2L/pre-3L) and of these, 73.7% received radiation therapy. Conclusions: In patients with HER2+ mBC in Canada, 3L treatment patterns are heterogeneous, median TTNT is <1 year, and almost half develop brain metastases. These data from two large treating centres in Ontario suggest a high unmet need for more effective treatment regimens in later lines of therapy, particularly 3L, for patients with HER2+ mBC.

Citation Format: Katarzyna J Jerzak, Ruth Moulson, Ling-I Hsu, Chris Lenhu, Dhivo Krishnathasan, Jessica Weiss, Christine Brezden-Masley. Real-world treatment patterns and clinical outcomes in patients with HER2+ metastatic breast cancer receiving systemic therapy in Ontario, Canada [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A081.
Abstract B009: TWEAK/Fn14 signalling driven super-enhancer reprogramming promotes pro-metastatic metabolic rewiring in Triple-Negative Breast Cancer
Authors: Li Yinghui , Sim Nicholas , Carter Jean-Michel , Deka Kamalakshi , Tan Benita Kiat Tee , Sim Yirong , Tan Suet-Mien
Published: February 2024

Triple Negative Breast Cancer (TNBC) is the most aggressive breast cancer subtype suffering from a lack of targeted treatment options. There is a high priority to identify effective molecular markers or driver factors specific to TNBC patients for targeted therapies. The Tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK)/Fibroblast growth factor-inducible 14 (Fn14) pathway is one such signalling cascade implicated in the pathogenesis of TNBC and other solid tumours. However, the clinical significance and biological roles of deregulated TWEAK/Fn14 signalling in regulating the epigenetic plasticity and transcriptome of TNBCs remain elusive. In this study, we performed integrative transcriptomic and epigenomic analyses of TNBC cell lines and patient samples to characterise the gene regulatory roles of TWEAK/Fn14 pathway in remodelling the super-enhancer (SE) landscape of TNBC tumours. Here, we show that Fn14 is specifically overexpressed in TNBC patients and associated with poor survival. We demonstrate that constitutive Fn14 signalling rewires the transcriptomic and epigenomic landscape of TNBC, leading to enhanced tumour growth and metastasis. We further illustrate that such mechanisms activate TNBC-specific super enhancers (SE) to drive the transcriptional activation of cancer dependency genes via chromatin looping. In particular, we uncover the SE-driven upregulation of NAMPT, which promotes NAD+ and ATP metabolic reprogramming critical for filopodia formation and metastasis. Collectively, our study details the complex mechanistic link between TWEAK/Fn14 signalling and TNBC metastasis, which reveals several vulnerabilities which could be pursued for the targeted treatment of TNBC patients.

Citation Format: Yinghui Li, Nicholas Sim, Jean-Michel Carter, Kamalakshi Deka, Benita Kiat Tee Tan, Yirong Sim, Suet-Mien Tan. TWEAK/Fn14 signalling driven super-enhancer reprogramming promotes pro-metastatic metabolic rewiring in Triple-Negative Breast Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B009.
Abstract B014: Bioinformatic and in-vitro analyses identify cAMP/PKA/CREB signaling as a major molecular alteration in invasive lobular breast cancer
Authors: Wedn Abdalla , Puthanmadhom-Narayanan Susrutha , Lee Adrian , Oesterreich Steffi
Published: February 2024

Invasive lobular cancer (ILC) is the second most common subtype of breast cancers after invasive carcinoma of no special type (NST) but associated with worse outcomes. Despite the known molecular differences between ILC and NST, ILC treatment is the same as stage matched NST making the development of ILC targeted therapies an urgent need. Therefore, this study was conducted to identify novel molecular alterations in ILC that could be exploited for therapeutic purposes. Differential gene expression and Geneset Enrichment and Variation analyses were performed on RNA-seq data from three large public breast cancer databases – the Sweden Cancerome Analysis Network-Breast (SCAN-B), The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). Pathways enriched in overlapping differentially expressed genes from these datasets were clustered using Jaccard index to identify novel pathways related to ILC. The cAMP/PKA/CREB signaling was studied in ILC, ILC-like and NST cell lines and patient-derived organoids (POD) using Forskolin, an activator of the pathway. Clinicopathological features of patients with ILC and NST in SCAN-B were similar to prior population-based studies. There was a consistent pattern of up-regulation of cAMP/PKA/CREB related signaling in ILC compared to NST tumors in SCAN-B, TCGA and METABRIC. Treatment with forskolin resulted in a greater increase in phospho-CREB in ILC cell lines and organoids compared to NST. CRISPR deletion of CDH1 in NST cell lines did not alter response of cells to forskolin as measured by phospho-CREB. Co-immunofluorescence supported the enhanced nuclear localization and subsequent phosphorylation of CREB at Serine 133 in ILC cell lines. Forskolin treatment caused growth inhibition in ILC and NST cells, with ILC cell lines being more sensitive to forskolin-mediated growth inhibition. Collectively the data indicate that the cAMP/PKA/CREB signaling is higher in ILC than NST tumors. This was consistent across three separate cancer datasets and was validated in cell lines and organoids. Loss of CDH1 is not sufficient to mediate this phenotype in lobular tumors. Future studies should investigate the mechanisms for differential cAMP/PKA/CREB signaling in ILC and NST and investigate the potential for therapeutic targeting especially in patients with ILC.

Citation Format: Abdalla Wedn, Susrutha Puthanmadhom-Narayanan, Adrian Lee, Steffi Oesterreich. Bioinformatic and in-vitro analyses identify cAMP/PKA/CREB signaling as a major molecular alteration in invasive lobular breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B014.
Abstract B028: Investigating immune activity caused by a novel anti-cancer cell penetrating peptide
Authors: Hecksel Ryan , Escoto Angelica , Schroeder Joyce
Published: February 2024

Activating the immune system against cancerous cells represents a promising therapy against multiple cancer types, particularly breast cancer. The epidermal growth factor receptor (EGFR) represents an emerging target in immunotherapy. A novel anti-cancer cell penetrating peptide was recently discovered to affect immune recruitment and potentially function in a murine model of breast cancer. This peptide, termed cSNX1.3, is a targeted therapy to block the nuclear localization of the epidermal growth factor receptor (EGFR), a phenomenon thought to occur primarily in cancerous cells. This suggests that nuclear localized EGFR may play a role in suppressing an anti-cancer immune response. To gain a better understanding of this in vivo data, we used in vitro immune cell co-culture techniques, migration assays, and other techniques to investigate immune recruitment and function after cancer cells are treated with this novel peptide therapy. In addition, we are investigating the mechanism of cSNX1.3 mediated cell death to determine if it can induce immunogenic cell death. To determine if nuclear EGFR plays a role in immune cell suppression, we are using a CRISPR/Cas9 strategy to mutate the nuclear localization sequence. This will provide a valuable tool to better understand the seemingly cancer-specific trafficking phenomenon. Together, this work will expand our understanding of therapy induced immune cell recruitment and trafficking.

Citation Format: Ryan Hecksel, Angelica Escoto, Joyce Schroeder. Investigating immune activity caused by a novel anti-cancer cell penetrating peptide [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B028.