bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2551: Sexual dimorphic effects of tumour microenvironment dictate melanoma progression and therapy resistance
Authors: Chhabra Yash , Fane Mitchell , Huser Laura , Zabransky Daniel , Brezka Megan , Marino Gloria , Carey Alexis , Weeraratna Ashani 
Published: June 2022

Abstract
Melanoma is a disease of ageing with elderly patients showing poorer prognosis than younger patients. The role of the ageing microenvironment in melanoma progression is now recognized where aged stromal cells undergo cellular and molecular changes that are tumour permissive. However, sex-based differences in melanoma incidence and outcome have also been observed even when adjusted for several prognostic factors including age, with men having poorer outcomes compared to women. While the mechanisms underlying this disparity are not well understood but attributed to sex-specific behaviors as well as to the biologically intrinsic differences. In addition, most preclinical studies have ignored the contribution of the host sex and age to therapy response, with majority of the studies typically performed in 6-8 week old male mice. Dermal fibroblasts (dFs) are established to have profound impact on melanoma progression. We examined if both sex-dependent and age-related changes in dFs can alter the course of melanoma tumor growth, visceral metastasis, dormancy and variable responses to targeted therapy. We find that age-matched female dFs undergo early replicative senescence accompanied by reduced proliferation and morphology change. Despite being senescent, age-matched female dFs showed reduced SASP characteristics. This was assessed by testing dFs derived conditioned media on melanoma cells in spheroid invasion and resistance to BRAF/MEK inhibition which showed elevated expression of invasive drivers and oxidative stress from aged male dFs derived conditioned media. This was also apparent in vivo in syngeneic immunocompetent C57Bl/6 mice that showed reduced tumor growth and increased invasion specific to the aged male host. Our data provides an integrated view of how age and sex attributes of dFs within the microenvironment contribute to disease progression. Bridging this knowledge gap will improve patient stratification and assist in tailoring the therapy and achieve gender-equitable healthcare.
Citation Format: Yash Chhabra, Mitchell Fane, Laura Huser, Daniel Zabransky, Megan Brezka, Gloria Marino, Alexis Carey, Ashani Weeraratna. Sexual dimorphic effects of tumour microenvironment dictate melanoma progression and therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2551.
Abstract 2567: Targeting TBL1/β-catenin complex using peptides designed to competitively inhibit aberrant Wnt signaling in cancer
Authors: Rheinschmidt Shelby , Thode Trason , Sampson Samuel , Weston Alexis , Halder Tithi Ghosh , Ng Serina , Rodriguez del Villar Ryan , Kaadige Mohan , Zernov Anton , Machluf Marcelle , Soldi Raffaella , Sharma Sunil 
Published: June 2022

Abstract
Purpose: Canonical Wnt signaling is a key cascade in regulating development and stemness, however it can become dysregulated and tightly associated with oncogenesis. In human cancers, Wnt/β-catenin signaling is highly activated due to mutations of members associated with the pathway such as adenomatous polyposis coli (APC) and β-catenin. Transducin β-like protein 1 (TBL1) and highly related TBLR1, form a complex with β-catenin facilitating the translocation of β-catenin to the nucleus. The formation of this complex protects β-catenin from degradation by SIAH-1 ubiquitinase and aids β-catenin binding to TCF/LEF transcription factors to transcribe downstream Wnt target genes. We recently reported that the destruction of the TBL1/β-catenin complex using a small molecule results in ubiquitination of β-catenin and inhibition of downstream signaling. As an alternative approach, we designed a series of novel peptides to interfere with binding of β-catenin with TBL1.
Methods: Homologous competitive ELISA and thermal shift assays were performed to identify potential peptides that were able to displace β-catenin from TBL1. Additionally, we evaluated the ability of the peptides to disrupt the TBL1/β-catenin complex by performing pull-down assays and monitored the levels of β-catenin ubiquitination in response to peptide treatment in colon cell lines. To assess the levels of TCF/LEF transcriptional activation downstream the Wnt/β-catenin pathway, we performed TOPFlash assays in Wnt-activated cells transfected with plasmids for peptide expression.
Results: Our preliminary results identified a set of peptides that efficiently displaces β-catenin from TBL1. Homologous competitive ELISA showed that the peptides were able to displace β-catenin from TBL1 in a dose dependent manner. The top five peptide hits were then tested for their ability to inhibit Wnt signaling using the TOPFlash assay. Among these, one peptide in particular showed high efficiency in inhibiting TCF/LEF transcriptional activation downstream the Wnt/β-catenin pathway. Our study suggests that β-catenin therapeutic peptides may represent a new and exciting approach for Wnt driven cancer therapy.
Citation Format: Shelby Rheinschmidt, Trason Thode, Samuel Sampson, Alexis Weston, Tithi Ghosh Halder, Serina Ng, Ryan Rodriguez del Villar, Mohan Kaadige, Anton Zernov, Marcelle Machluf, Raffaella Soldi, Sunil Sharma. Targeting TBL1/β-catenin complex using peptides designed to competitively inhibit aberrant Wnt signaling in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2567.
Abstract 2583: Utilization of a novel double knock-in humanized mouse model to evaluate the efficacy of ipilimumab and pembrolizumab against EMT-6 mammary carcinoma tumors
Authors: Stackhouse Murray , Kuta Mariah , Kolb Joseph , Scatigno Sydney , Blackwell Amber , Hall Chassidy , Dowdy Christopher , Sil Payel , Gietl Diana , Festin Steve , De Marval Paula L. Miliani 
Published: June 2022

Abstract
The cancer immunotherapy field has seen an increasing demand for identifying and characterizing pre-clinical models to evaluate the efficacy of the checkpoint inhibitors such as, ipilimumab and pembrolizumab. PBMC- or CD34-humanized mouse models are invaluable tools to assess effector functions of human T-cells to immune check point inhibitors (ICI). However, these models offer limited understanding of the overall potential therapeutic activity as they lack a complete repertoire of human immune cells required to elicit a full immune response. Thus, the development of multigenic humanized knock-in models provide a unique approach to evaluate the efficacy of ICI specific for human cancer targets in a fully immunocompetent organism. Here we describe the response of the EMT-6 murine breast cancer tumor model to ipilimumab and pembrolizumab in a novel hPDCD1/hCTLA4-KI double knock-in humanized BALB/c mouse model. EMT-6 tumors were implanted subcutaneously in the flank of hPDCD1/hCTLA4-KI mice. Three days post-implant we initiated treatment with ipilimumab or pembrolizumab alone and in combination. We observed significant ipilimumab anti-tumor activity, whereas pembrolizumab did not show efficacy despite effective T-cell PD-1 blockade. Unexpectedly, sudden respiratory distress occurred in animals receiving the 4th dose of combination therapy and the treatment was discontinued. To assess the immune phenotypic profiles in response to ipilimumab and/or pembrolizumab therapies, we performed multi-parameter flow cytometry analysis of peripheral blood, spleens and tumors. Additionally, we performed histopathological evaluation of lung tissues to assess potential neutrophil infiltration-mediated anaphylaxis in the mice treated with the combination treatment. The preliminary results highlight the value of the hPDCD1/hCTLA4-KI double knock-in humanized Balb/c model as a tool to evaluate human-specific immune-checkpoint based modalities. These models represent some of the difficulties faced in treating refractory tumors as well as reproducing some of the adverse effects seen in the clinic.
Citation Format: Murray Stackhouse, Mariah Kuta, Joseph Kolb, Sydney Scatigno, Amber Blackwell, Chassidy Hall, Christopher Dowdy, Payel Sil, Diana Gietl, Steve Festin, Paula L. Miliani De Marval. Utilization of a novel double knock-in humanized mouse model to evaluate the efficacy of ipilimumab and pembrolizumab against EMT-6 mammary carcinoma tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2583.
Abstract 2602: Combined inhibition of AXL and ATR enhances cell death and immune response in small cell lung cancer
Authors: Ramkumar Kavya , Tanimoto Azusa , Stewart C. Allison , Wang Qi , Shen Li , Cardnell Robert J. , Rodriguez B. Leticia , Gibbons Don L. , Wang Jing , Gay Carl M. , Byers Lauren A. 
Published: June 2022

Abstract
Small cell lung cancer (SCLC) is an aggressive lung tumor of neuroendocrine origin with a dismal 5-year survival rate. Despite high response rates to initial therapy, rapid development of therapeutic resistance limits overall survival. There are also limited treatment options, particularly in the relapsed setting. Our group and others have shown that AXL, a TAM family receptor tyrosine kinase that is highly expressed in mesenchymal tumors, mediates resistance to chemotherapy, radiation and targeted therapies in SCLC, non-small cell lung cancer and other cancers, through its roles in driving epithelial to mesenchymal transition and DNA damage repair. AXL has also been implicated in immune escape. Based on these findings, we hypothesize that AXL targeting may be a potential therapeutic approach in SCLC. We screened BGB324 (bemcentinib), a selective small-molecule AXL inhibitor in clinical trials for various advanced solid tumors, in a panel of 60 human SCLC cell lines using cell viability assays. The SCLC cell lines showed a range of sensitivities, with IC50 values ranging from 41 nM to 10 µM (median IC50 3.1 µM) with NeuroD1-driven SCLC cell lines being highly sensitive to BGB324 (ANOVA p&lt;0.05). BGB324 also showed potent inhibition of tumor growth in an in vivo SCLC model. BGB324 further combined synergistically with an ATR inhibitor (AZD3738) and induces significant DNA damage. In a syngeneic model of SCLC, the combination of BGB324, AZD6738 and an anti-PDL1 antibody combination also induced significant tumor regression. Together, these promising findings show that AXL inhibition may be effective in SCLC and support further investigation of AXL and ATR inhibitor combinations with immune checkpoint blockade.
Citation Format: Kavya Ramkumar, Azusa Tanimoto, C. Allison Stewart, Qi Wang, Li Shen, Robert J. Cardnell, B. Leticia Rodriguez, Don L. Gibbons, Jing Wang, Carl M. Gay, Lauren A. Byers. Combined inhibition of AXL and ATR enhances cell death and immune response in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2602.
Abstract 2603: USP1 inhibitor synthetic lethality in BRCA1-mutant cancer is driven by PCNA ubiquitination
Authors: Engel Justin , Bandi Madhavi , Simoneau Antione , Lazarides Katherine , Gotur Deepali , Pham Truc , Liu Shangtao , Meier Samuel , Choi Ashley , Zhang Hongxiang , Shen Binzhang , Li Fang , Whittington Douglas , Gong Shanzhong , Pan Xuewen , Yu Yi , Gu Lina , Throner Scott , Maxwell John , Chen Yingnan , Huang Alan , Andersen Jannik , Feng Tianshu 
Published: June 2022

Abstract
CRISPR-based functional genomic screening is a powerful approach for identifying novel classes of synthetic lethal drug targets. Here, we define the deubiquitinase USP1 as a synthetic lethal target in cancers with underlying DNA repair vulnerabilities. A highly potent and selective small molecule USP1 inhibitor conferred a viability defect in BRCA1-mutant, but not WT cell lines by activating replication stress. Genome-wide CRISPR screening uncovered RAD18 and UBE2K, which promote PCNA mono- and poly-ubiquitination respectively, as key mediators of USP1-BRCA1 dependency. Increased cellular mono- and poly-ubiquitination reduced PCNA protein levels, and restoration of PCNA protein expression rescued USP1 inhibitor sensitivity. USP1 dependency is associated with upregulated RAD18 and UBE2K expression, suggesting that elevated PCNA ubiquitination in the context of BRCA1 deficiency mediates USP1 synthetic lethality. Interestingly, USP1, but not PARP1 inhibition, elicited a viability defect in a subset of BRCA1/2 WT lung cancer cell lines, indicative of novel synthetic lethal interactions unique to USP1. Moreover, dual inhibition of PARP1 and USP1 are strongly synergistic in PARP1 inhibitor-responsive cell line models. Strong in vivo anti-tumor activity across multiple tumor models was demonstrated with USP1 inhibition alone and in combination with the PARP1 inhibitor olaparib. Our studies suggest that USP1 and PARP1 inhibitors target BRCA1-mutant cancer though distinct yet synergistic mechanisms. As such, USP1 inhibitors may provide novel treatment strategies for PARP1 inhibitor-resistant and -naïve BRCA1-mutant cancer.
Citation Format: Justin Engel, Madhavi Bandi, Antione Simoneau, Katherine Lazarides, Deepali Gotur, Truc Pham, Shangtao Liu, Samuel Meier, Ashley Choi, Hongxiang Zhang, Binzhang Shen, Fang Li, Douglas Whittington, Shanzhong Gong, Xuewen Pan, Yi Yu, Lina Gu, Scott Throner, John Maxwell, Yingnan Chen, Alan Huang, Jannik Andersen, Tianshu Feng. USP1 inhibitor synthetic lethality in BRCA1-mutant cancer is driven by PCNA ubiquitination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2603.
Abstract 261: Released exosomes from colon cancer cells regulate formation and progression of perineural invasion
Authors: Knoblich Colewyn , Rezvani Khosrow 
Published: June 2022

Abstract
Colorectal cancer (CRC) is the third most diagnosed cancer and cause of cancer related mortality. CRC that metastasizes to distance sites results in poor prognosis, diminished survival, and reduced effectiveness of treatments. Perineural invasion (PNI) is an emerging field that aims to understand cancer-neuronal crosstalk that enables cancer to spread via nerves. Several studies have indicated that tumor derived exosomes (TDEs) play significant roles in the initiation and spread of cancer, along with driving chemoresistance. We hypothesize that CRC derived exosomes alter nerves within the surrounding environment and result in recruitment of nerves towards tumors for invasion along the nerve. Exosomes from both HCT116 and SW837 colon cancer cells were isolated and purified using a modified iodixanol ultracentrifugation gradient technique. A Proteomic analysis conducted on cancer derived exosomes revealed several potential proteins involved in neuronal growth and migration, including Vinculin (VCL), Periostin (POSTN or OSF-2), DCLK1, and USP9X. In another set of experiments, conditioned media (CM) from HCT116 and SW837 cells were added to both PC12 neuronal-like cells and dorsal root ganglion (DRG) from C57BL/6J mice to understand the effects of excreted cancer factors on neuronal outgrowth and differentiation. CM studies showed how signaling factors excreted from colon cancer cells induce increased nerite outgrowth in both PC12 cells and DRG. These results were not seen in CM from cancer cells that were grown in the presence of an exosome inhibitor. Altogether, these results indicate that CRC utilizes exosomes to alter the adjacent neuronal networks as a means to employ surrounding nerves for invasion.
Citation Format: Colewyn Knoblich, Khosrow Rezvani. Released exosomes from colon cancer cells regulate formation and progression of perineural invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 261.
Abstract 2623: Variants of CLIP-170 associated with taxane resistance in tumors
Authors: Thakkar Prashant V. , Kita Katsuhiro , del Castillo Urko , Stone William G. , Galletti Giuseppe , Madhukar Neel , Navarro Elena Vila , Barasoain Elena , Goodson Holly V. , Sackett Dan , Díaz José Fernando , Lu Yao , RoyChoudhury Arindam , Molina Henrik , Elemento Olivier , Shah Manish A. , Giannakakou Paraskevi 
Published: June 2022

Abstract
Despite its widespread use, the majority of patients with gastric cancer (GC) will not respond to taxane chemotherapy due to resistance mechanisms. Recently, we reported the discovery of a novel truncated variant of the microtubule plus-end binding protein CLIP-170, hereafter CLIP-170S, whose expression is enriched in taxane resistant cell lines and patients with GC. Mass-spec proteomics and 5’-RACE further showed that CLIP-170S lacked the first 155 amino acids, including the Cap-Gly motif required for microtubule plus-end localization. CLIP-170S knockdown reversed taxane resistance in cells and xenografts, whereas its re-expression led to resistance, suggesting causation. Unlike canonical CLIP-170, we showed that CLIP-170S was mislocalized from the MT plus-end to the MT lattice. Computational analysis of RNA-seq data in conjunction with the connectivity map from taxane-sensitive and resistant GC cell lines, predicted imatinib as the top candidate drug to overcome drug resistance. Imatinib treatment completely reversed taxane resistance, as predicted, and did so unexpectedly by selective depletion of CLIP-170S. Other RTK inhibitors also depleted CLIP-170S, suggesting a class effect. We are currently unraveling the molecular mechanisms by which a) CLIP-170S impairs taxane association to its microtubule binding site and b) Imatinib and other RTK inhibitors selectively deplete CLIP-170S. Our data show that CLIP-170S is a clinically prevalent variant that confers taxane resistance in tumors, whereas the discovery of Imatinib as a CLIP-170S inhibitor provides novel therapeutic opportunities for future trials.
Citation Format: Prashant V. Thakkar, Katsuhiro Kita, Urko del Castillo, William G. Stone, Giuseppe Galletti, Neel Madhukar, Elena Vila Navarro, Elena Barasoain, Holly V. Goodson, Dan Sackett, José Fernando Díaz, Yao Lu, Arindam RoyChoudhury, Henrik Molina, Olivier Elemento, Manish A. Shah, Paraskevi Giannakakou. Variants of CLIP-170 associated with taxane resistance in tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2623.
Abstract 263: PIM kinase regulates actin dynamics in hypoxia
Authors: Jensen Corbin C. , Warfel Noel A. 
Published: June 2022

Abstract
One of the leading factors in prostate cancer mortality is the onset of metastatic events. This is seen by the drastic decline in survival rates following tumor escape from the primary site. A key promoter of metastasis is tumor hypoxia, or low oxygen concentration. Our lab previously demonstrated that Proviral Integration site for Moloney murine leukemia virus (PIM)-1, a serine-threonine kinase, is upregulated in hypoxia and that inhibition of PIM1 reduced metastatic occurrence in orthotopic mouse models. Here, we identify a novel signaling pathway that links hypoxia and PIM kinase to the actin cytoskeleton and cell motility. An unbiased screen to discover new PIM substrates in hypoxia identified Abl-Interactor 2 (Abi2), an integral member of the actin regulating Wave Regulatory Complex (WRC), as a novel PIM kinase substrate. Biochemical analysis demonstrates that phosphorylation of Abi2 at our identified PIM sites increases Abi2 stability. Overexpression of PIM1 increases Abi2 and other WRC members at the protein level, resulting in increased actin protrusions and cell motility. CRISPR-generated Abi2 knockout cell lines showed diminished protrusive activity and negated both the necessity and sufficiency of PIM kinase to increases protrusive activity in cancer cells. Lastly, in vivo experiments show that overexpression of PIM1 increases tumor invasion into the surrounding tissue in an Abi2-dependent manner, and small molecule PIM inhibitors significantly reduce invasion. In summary, we uncovered a novel role for PIM1 in promoting cellular motility and protrusion, identified novel phosphorylation sites that control the stability of Abi2 in normoxic and hypoxic conditions, and highlight a novel PIM1/Abi2 signaling axis that regulates hypoxia-induced tumor invasion. This research provides important insight in the role of PIM signaling in prostate tumors and yields preclinical evidence for further use of PIM kinase inhibitors as a means to inhibit tumor invasion, a key driving step in the formation of lethal prostate cancer metastasis.
Citation Format: Corbin C. Jensen, Noel A. Warfel. PIM kinase regulates actin dynamics in hypoxia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 263.