bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3308: Chemoradiation sensitization effect of PARPi in non-small cell lung cancer
Authors: Ye Rui , Wang Kaile , Qiao Yawei , Xiao Zhenna , Yan Yun , He Jianzhong , Li Nan , Wang Yifan , Hu Min , Bai Shanshan , Sei Emi , Navin Nicholas , Lin Steven
Published: June 2022

Chemoradiation (CRT) is widely used to treat locally advanced non-small cell lung cancer (NSCLC) patients, but only around 30% of patients achieve pathological complete response. Here, we utilized an in vitro high-content clonogenic survival screening method to identify CRT sensitizers from the NCI Cancer Therapy Evaluation Program (CTEP) portfolio. Talazoparib (PARPi) was identified among the top candidates to show potent CRT sensitization effects in both KRAS mutant and TP53 mutant NCSLC cell lines. We validated the CRT sensitization effect of PARPi on lung tumors in vivo with cell line xenografts mouse models. To further investigate alterations in the tumor microenvironment (TME) induced by PARPi, we utilized syngeneic mouse models and showed that the combination of radiotherapy, PARPi, and PD-L1 blockade achieved superior tumor control effects. By applying single cell RNA sequencing technologies to the mouse tumors, we found that PARPi combined with CRT or immunotherapy significantly reprogrammed the tumor cells and TME, resulting in the increase of tumor-infiltrating T cells which elicit potent tumor control effects. Our data showed that PARPi sensitizes NSCLC tumors to CRT and immunotherapy through a combination of tumor-intrinsic and extrinsic phenomenon.

Citation Format: Rui Ye, Kaile Wang, Yawei Qiao, Zhenna Xiao, Yun Yan, Jianzhong He, Nan Li, Yifan Wang, Min Hu, Shanshan Bai, Emi Sei, Nicholas Navin, Steven Lin. Chemoradiation sensitization effect of PARPi in non-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 3308.
Abstract 3349: In-silico analysis identifies the unique role of the ADRB2-USP20 axis in T cell lymphoma
Authors: Tiwari Rajan Kumar , Kumar Ajay
Published: June 2022

T cell lymphoma represents an aggressive subgroup of lymphoma having a poor prognosis. Many factors, including psychological stress, define the onset/progression of the disease. Although psychological stress can cause several health problems, preclinical and clinical reports regarding its role in cancer have been mixed. Therefore, in this study, we sought to determine the role of psychological stress hormone in the progression of T cell lymphoma and provide a mechanistic framework of activity. Initially, we used the cBioportal and performed expression analysis of genes involved in stress pathways with large-scale cancer genomics TCGA datasets having nearly 10071 patient samples. Through a series of in-silico investigations, we identified Adrenoceptor Beta 2 (ADRB2), a key mediator of stress, highly expressed in T cell lymphoma compared to other tumors.Furthermore, the expression of ADRB2 was not gender-specific and equally represented in both males and females. String analysis further identified the interaction of ADRB2 with Ubiquitin carboxyl-terminal hydrolase 20 (USP20), which directly regulates Hypoxia-inducible factor 1-alpha (HIF1-A) and ADRB2. This regulation could lead to enhanced glucose metabolism to support T cell lymphoma growth and progression. Collectively, our in-silico findings suggest that psychological stress releases hormones that could modulate T cell lymphoma proliferation through the ADRB2-USP20 axis. Ongoing preclinical studies with stress hormones will be presented to provide undescribed mechanisms of their protumorigenic activity through the ADRB2-USP20 axis and their role in regulating cancer-specific metabolism. We sought to determine the role of psychological stress hormone These studies will provide an opportunity to learn the involvement of stress hormones in cancer progression and provide a framework for developing a novel approach for stress management during cancer.

Citation Format: Rajan Kumar Tiwari, Ajay Kumar. In-silico analysis identifies the unique role of the ADRB2-USP20 axis in T cell lymphoma [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 3349.
Abstract 335: c-KIT targeted ETBs for cancer therapy and HSC transplant conditioning
Authors: Howard Caleigh , Wiley Shu , Dong Wenzhao , Mendiola Andrea , Partridge Veronica , LeMar Sara , Amador Paul , Chaudhary Amit K. , Dekker Joseph D. , Zhao Jay , Durland Ross , Iberg Aimee
Published: June 2022

Engineered toxin bodies (ETBs) are next-generation immunotoxins that harbor an antibody-derived targeting domain and a cytotoxic payload derived from Shiga-like toxin-1 catalytic subunit A (SLTA). SLTA has been engineered to reduce innate immunogenicity and therefore increase the safety of ETBs whilst retaining potent cytotoxic properties. When targeted via a binding domain, SLTA is internalized and routes to the cytosol leading to irreversible ribosome inactivation and ultimately cell death.

ETBs have been developed to treat a wide variety of cancers, including breast, lymphoma, multiple myeloma and PD-L1 positive solid tumors. This technology holds promise for non-oncology indications as well, particularly as a targeted and non-genotoxic conditioning regimen for hematopoietic stem cell (HSC) ablation to prepare patients for autologous stem cell transplant.

c-KIT (CD117) is a well-known marker of hematopoietic stem and progenitor cells and is overexpressed in a high percentage of certain cancers including GIST, SCLC and AML. While tyrosine kinase inhibitors such as imatinib are effective therapies for c-KIT mutant GIST, resistance often occurs by the development of secondary mutations in the intracellular signaling domains. Thus, c-KIT represents a potential ETB target for both oncological and HSC transplant conditioning indications. Here we present data highlighting the in vitro potency and efficacy of CD117-targeting ETBs on cancer cell lines as well as on primary human CD34+ HSCs. CD117-targeted ETBs demonstrate exquisite specificity in vitro by killing only target positive CD34+ cells at picomolar potency while sparing the progenitors that lack CD117 expression. However, relatively low CD117 receptor levels on CD34+ HSCs prevent complete killing in vitro, limiting the observed efficacy. To overcome this challenge, an additional cytotoxic payload was conjugated to the ETB molecule to capitalize on ETBs’ unique internalization and routing properties to deliver a secondary mechanism of action. ETB-drug conjugates (ETB-DCs) exhibited improved cytotoxicity in vitro, especially in CD117-low target cells. Moving forward, we plan to explore both the ETB and the ETB-DC therapeutic index in vivo with a series of CD117+ tumor efficacy and HSC depletion models.

Citation Format: Caleigh Howard, Shu Wiley, Wenzhao Dong, Andrea Mendiola, Veronica Partridge, Sara LeMar, Paul Amador, Amit K. Chaudhary, Joseph D. Dekker, Jay Zhao, Ross Durland, Aimee Iberg. c-KIT targeted ETBs for cancer therapy and HSC transplant conditioning [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 335.
Abstract 341: Disruption of cellular crosstalk by blockage of ADAM17 inhibits tumor progression of pancreatic ductal adenocarcinoma
Authors: Wen Hui-Ju , Crawford Howard
Published: June 2022

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and will become the 2nd leading cause of cancer related death in the United States within the next 10 years. Lack of early symptoms and a poor response to current therapies make PDAC the deadliest of all major cancers. PDAC is characterized by a dense fibroinflammatory stroma which is composed of fibroblasts and immune cells and has been implicated to influence tumor progression and therapeutic outcome. In this study, we aim to disrupt cellular signaling pathways by targeting ADAM17 (a disintegrin and metalloprotease 17). ADAM17 is a membrane bound enzyme which cleaves cell surface proteins. Its function is closely linked with autocrine and paracrine signaling of immunomodulation as well as activation of EGFR, which is a central molecule for pancreatic tumorigenesis. To investigate whether EGFR is activated via a paracrine manner from macrophages, the most abundant immune-related stromal cells in pancreas cancers, we generated a pancreatic tumor mouse model with ADAM17 deletion in myeloid cells by using a dual recombinase strategy. We observed that lack of ADAM17 in the myeloid cells resulted in a delay of acinar cell transformation and an associated decrease in EGFR activation. To further examine the tumor supportive role of ADAM17, systemic inhibition of ADAM17 using anti-ADAM17 antibody, MEDI3622, was tested in orthotopic tumor bearing mice. Tumor regression was observed in the mice treated with MEDI3622 and was accompanied by high infiltration of cytotoxic T cells and low infiltration of G-MDSC (granulocytic myeloid-derived suppressor cells). In addition, activation of EGFR and STAT3, which are associated with two pro-tumoral signaling pathways, were reduced by MEDI3622. These results demonstrate a pronounced anti-tumor effect by ADAM17 blockage and indicate ADAM17 as a therapeutic target of pancreatic cancer.

Citation Format: Hui-Ju Wen, Howard Crawford. Disruption of cellular crosstalk by blockage of ADAM17 inhibits tumor progression of pancreatic ductal adenocarcinoma [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 341.
Abstract 3422: Combined treatment with interleukin-4 receptor-targeted cytotoxic peptide and PD-L1-blocking peptide efficiently induces immunogenic cell death of tumor cells and activates T-cell activity
Authors: Park Nawon , Lee Byungheon , Lee Hyunsu
Published: June 2022

Immune checkpoint blockade therapy has provided clinical benefit to some patients with advanced cancer including melanoma and non-small cell lung cancer. However, many patients still fail to respond to single immune checkpoint blockade therapy. The need for combination therapies to increase anti-tumor responses is becoming important. Interleukin-4 receptor (IL4R) is frequently overexpressed in various cancer types and promotes tumor cell survival. PD-L1, a well-known immune checkpoint, is up-regulated in malignant tumors and inhibits T-cell activity. In this study, we aimed at a combination therapy using an IL4R-targeted cytotoxic peptide and PD-L1-blocking peptide. To target IL4R-high tumor cells, we exploited IL4RPep-1-KLA composed of IL4RPep-1, an IL4R-binding peptide, and (KLAKLAK)2, a cytotoxic peptide. IL4RPep-1-KLA induced necrosis as well as apoptosis of IL4R-expressing tumor cells and increased the secretion of CRT, HMGB1, and ATP, well-known markers of immunogenic cell death (ICD). Flow cytometry analysis showed that the conditioned medium of tumor cells treated with IL4RPep-1-KLA enhanced the expression of CD86 and CD80 on dendritic cells, suggesting the activation and maturation of dendritic cells through ICD. Sequential treatment with IL4RPep-1-KLA followed by PD-L1Pep-2, a PD-L1-blocking peptide, during the co-culture of tumor cells and CD8+ T-cells activated T-cell activity including T-cell proliferation and cytokine secretion more efficiently than single treatment with IL4RPep-1-KLA or PD-L1Pep-2, or simultaneous treatment. These results suggest that sequential, combined treatment with the IL4R-targeted cytotoxic peptide and PD-L1-blocking peptide can induce ICD of tumor cells and maturation of dendritic cells and subsequently activate T-cells. This treatment is a promising strategy for cancer immunotherapy.

Citation Format: Nawon Park, Byungheon Lee, Hyunsu Lee. Combined treatment with interleukin-4 receptor-targeted cytotoxic peptide and PD-L1-blocking peptide efficiently induces immunogenic cell death of tumor cells and activates T-cell activity [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 3422.
Abstract 3450: Impact of model inaccuracy on dose estimation in TTFields therapy
Authors: Marciano Tal , Zeevi Oshrit , Bomzon Zeev
Published: June 2022

Introduction: Tumor Treating Fields (TTFields) is a modality for treating Glioblastoma (GBM). A recent study combining clinical data and simulations demonstrated that the simulation-based dose estimation at the tumor level is directly correlated with patient survival (Ballo M, et al. Int J Radiat Oncol Biol Phys. 2019;104(5):1106-1113). This study highlights the importance of computer-modelling based TTFields treatment planning in the clinic. Performing such planning in a meaningful manner requires an understanding about how inaccuracies in the patient model influence calculated TTFields distributions. In this study we show the effect of local perturbations in the model, errors in tumor segmentation, and inaccuracy in the patient head model on TTFields dose estimation.

Methods: Computational studies were performed with Sim4Life software. 1) Local model uncertainty outside of tumor region: To create defects in the models, conductive spheres with varying conductivities and radii were placed into the model’s brains at different distances from the tumor. Virtual transducer arrays were placed on the models, and delivery of TTFields numerically simulated. The error in the electric field induced by the defects as a function of defect conductivity, radius, and distance to tumor was investigated. 2) Tumor segmentation uncertainty: For illustrating segmentation errors in tumors and necrotic cores, layered spheres with various conductivities and radii were placed in different head locations. Tumor conductivity uncertainty was defined as (σ-σref)/σref where σref = 0.24 S/m is the standard tumor conductivity and σ is the varied conductivity over the tumor. The normalized tumor radius was calculated when each of the varied radii was normalized to the results obtained by all the other combinations.

Results: The results show that that when a defect of radius R is placed at a distance, d, from the tumor that is larger than seven times R, the error is below 1% regardless of the defect conductivity.

Conclusions: Our models and results show the impact of uncertainty in segmentation of the tumor or other tissue distant from it on the TTFields dose estimation. These results could serve as a guideline for model creation and tissue segmentation that would lead to optimal dose estimation in TTFields treatment planning.

Citation Format: Tal Marciano, Oshrit Zeevi, Zeev Bomzon. Impact of model inaccuracy on dose estimation in TTFields therapy [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 3450.
Abstract 3459: Patient derived gliomaspheres exhibit HA concentration dependent invasiveness in 3D hydrogels
Authors: Safarians Gevick , Solomon Itay , Sohrabi Alireza , Seidlits Stephanie
Published: June 2022

Hyaluronic acid (HA) is a highly abundant glycosaminoglycan within the central nervous system. In glioblastoma (GBM), interactions with HA mediate tumor cell invasion. An improved knowledge of the biological underpinnings of HA-dependent GBM cell migration can facilitate the development of efficacious therapeutics. To better study how HA in the tumor matrix affects invasion, we have developed a tunable, 3D culture system in which to study gliomaspheres (GSs) of patient-derived tumor cells. Photopolymerization (365 nm for 15 seconds) of GSs suspended in a solution 0.025 w/v% lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), thiolated 4-arm poly-ethylene glycol (20 kDa, Laysan Bio), 8-arm poly-ethylene glycol-norbornene (20 kDa, Laysan Bio), thiolated peptides containing an ‘RGD’ amino acid motif, and either 0.10, 0.25, 0.50, or 0.75 w/v% of thiolated HA (700 kDa average molecular weight, Lifecore Biomedical) yielded 3D hydrogels of varying HA concentrations and similar mechanical properties. Relative invasive capacity, quantified by shape factor (deviation from circularity) and migration length (maximum extension length of processes from the GS periphery), differed across patient lines and was independent of their Cancer Genome Atlas (TCGA) classification as either mesenchymal or proneural. Hydrogels with higher amounts of HA (>0.25% w/v) generally enhanced invasion as compared to low HA (0.10 w/v%) hydrogels. In certain cell lines, a biphasic relationship between HA concentration and migration was observed, in line with previous reports of CD44 expression and migration. Moreover, inhibition of the CD44-Ezrin-Actin axis, using NSC668394, reduced migratory activity in hydrogels with higher HA (>0.25% w/v), while slightly increasing invasion in hydrogels with low HA (0.10 w/v%). In sum, results demonstrate the use of a matrix-mimetic, 3D hydrogel system in which to study GBM invasion through the local extracellular matrix.

Citation Format: Gevick Safarians, Itay Solomon, Alireza Sohrabi, Stephanie Seidlits. Patient derived gliomaspheres exhibit HA concentration dependent invasiveness in 3D hydrogels [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 3459.
Abstract 3517: Pharmacologic inhibition of HPK1 kinase activity enhances immune cell activation and T cell mediated anti-tumor activity
Authors: Lee Jacob S. , Toy Pamela , Min-Oo Gundula , Lee Tony , Salvo Patrick , Belzile JeanPhilippe , Clancy Sheila , Nazareno Jonathan , Xu Mengshu , Xing Weimei , Giacomini Marilyn , Santos Rex , Stapleton Lance , Wang Adele , Juric Vladislava , Mitchell Scott A. , Kuhne Michelle
Published: June 2022

Hematopoietic progenitor kinase 1 (HPK1, mitogen-activated kinase kinase kinase kinase 1 [MAP4K1]), a cytosolic STE20 ser/thr kinase from the germinal center family of kinases, regulates the function of diverse immune populations including T cells, B cells, and dendritic cells. In T cells, activated HPK1 regulates T cell receptor (TCR) signaling by phosphorylating the adaptor protein SLP76 on Ser376, which induces the association of SLP76 with 14-3-3 proteins. This SLP76/14-3-3 complex leads to its disassociation from the TCR signalosome, resulting in reduced downstream TCR signaling. The kinase activity of HPK1 is necessary for its regulatory function as mice expressing a mutant kinase-inactive HPK1 demonstrate enhanced T cell activity and superior tumor growth control compared to their WT counterparts. Here we describe a highly potent, selective and orally bioavailable small molecule inhibitor of HPK1 which displays sub-nanomolar HPK1 inhibition, good selectivity against MAP4K family members and oral bioavailability in preclinical animal models. Pharmacological inhibition of HPK1 kinase activity with Gilead’s HPK1 inhibitor compound demonstrates robust inhibition of pSLP76 S376 with concomitant enhancement in T cell activation, proliferation and effector function in in vitro assays. These immune enhancing effects translate into in vivo preclinical tumor models, where treatment with Gilead’s HPK1 inhibitor compound results in heightened T cell activation and effector function and enhanced tumor growth control both as a single agent and in combination with PD-1 blockade. In summary, our data show that Gilead’s HPK1 inhibitor compound is expected to be a selective, orally bioavailable HPK1 inhibitor with potential to combine with checkpoint inhibitors and other immuno-oncology agents.

Citation Format: Jacob S. Lee, Pamela Toy, Gundula Min-Oo, Tony Lee, Patrick Salvo, JeanPhilippe Belzile, Sheila Clancy, Jonathan Nazareno, Mengshu Xu, Weimei Xing, Marilyn Giacomini, Rex Santos, Lance Stapleton, Adele Wang, Vladislava Juric, Scott A. Mitchell, Michelle Kuhne. Pharmacologic inhibition of HPK1 kinase activity enhances immune cell activation and T cell mediated anti-tumor activity [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 3517.
Abstract 3520: Designing a dendritic cell-targeted immunotherapy for the treatment of pancreatic ductal adenocarcinoma
Authors: Vaskovich-Koubi Daniella , kleiner Ron , Eldar-Boock Anat , Pozzi Sabina , Ben-Shushan Dikla Dikla , Florindo Helena F. , Satchi-Fainaro Ronit
Published: June 2022

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death. Low response rate, acquired resistance, severe side effects, highly desmoplastic, and immunosuppressive microenvironment have limited the clinical outcomes of immunotherapy in PDAC. To overcome these hurdles, we set to design novel immunotherapy that would be safe, efficacious, and selective to PDAC. The failure of immunotherapies to yield clinical response in PDAC is partially attributed to the inefficient antigen presentation by dendritic cells (DC) which results in insufficient T cells stimulation despite their expression of tumor-associated antigens (TAA). DC have an important role in the initiation and regulation of the innate and adaptive immune system. By efficient presentation of antigens, DC elicit an antigen-specific immune response. Trp53R172H is among the most common TP53 mutations in human PDAC, and is known as one of PDAC TAA. Despite the poor clinical outcomes, longer survival time was observed in PDAC patients with tumors that express high number of TAA combined with an abundant presentation of CD8+ T cell. To that end, we designed a DC-targeted nanoparticle (NP) containing PDAC Trp53R172H TAA and immune potentiators, with the DC targeting moiety, mannose, that was covalently conjugated to the NP, to enhance TAA presentation on DC. Thus, promote specific activation of T cells against PDAC’s TAA. The therapeutic activity of the NP was evaluated in vitro by our newly established 3D PDAC spheroids model, which composed of freshly isolated murine stromal cells, therefore, better imitates the complex microenvironment found in PDAC in vitro. Along with an in vivo PDAC model, we evaluated the safety profile and therapeutic effect of our NP. The NP proposed herein successfully activated splenocytes and induced a specific cytotoxic reaction against PDAC cells ex vivo, which may result in an improved survival rate.

Citation Format: Daniella Vaskovich-Koubi, Ron kleiner, Anat Eldar-Boock, Sabina Pozzi, Dikla Dikla Ben-Shushan, Helena F. Florindo, Ronit Satchi-Fainaro. Designing a dendritic cell-targeted immunotherapy for the treatment of pancreatic ductal adenocarcinoma [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 3520.
Abstract 3525: Lactobacillus plantarum IMB19 enhances anti-tumor immune response by modulating multi-layered innate and adaptive immunity
Authors: Sharma Garima , Sharma Amit , Kim Inhae , Lee SooWoong , Lee Hae-Na , Park ChangWook , Im Sin-Hyeog
Published: June 2022

Intestinal commensals are being increasingly appreciated for their role in modulating the therapeutic efficacy of cancer therapies. Human-associated bacterial strains with demonstrable modulation of anti-tumor immune responses have great potential to be developed as biotherapeutics.We developed the AVATIOME࣪ model, a screening prototype based on murine primary immune cells, rationally targeting the innate and adaptive immune system to identify immuno-stimulating commensals.Our lead Lactobacillus plantarum IMB19 (Lp IMB19), suppresses tumor progression in pre-clinical models of melanoma, renal cancer, and NSCLC. LpIMB19 efficiently potentiates the therapeutic effect of anti-PD-L1 in murine tumor models. A capsular component of LpIMB19, structurally defined as rhamnose-rich hetero-polysaccharide (RHP) recapitulates the anti-tumor efficacy of live bacteria.The TLR2 agonist specifically targets macrophages towards an inflammatory phenotype followed by an increase in the activity of CD8+ IFNy+ T-cells. LpIMB19 and RHP enhance iron sequestration by activated macrophages in the tumor microenvironment through a defined mechanism. Thus, depriving tumor cells of iron and suppressing tumor cell proliferation. Translational investigations revealed the efficacy of LpIMB19 in urinary bladder xenograft studies.LpIMB19 mediated iron sequestration by inflammatory tumor macrophages, a byproduct of innate immune activation along with systemic CD8+ T-cells activation leads to enhancement of anti-tumor immunity. Our data on human cancers suggests the applicability of LpIMB19 as a potential onco-microbiotic. Currently, LpIMB19 is being progressed for clinical investigation as a live bio-therapeutic product (LBP) in combination with immune check-point inhibitors.

Citation Format: Garima Sharma, Amit Sharma, Inhae Kim, SooWoong Lee, Hae-Na Lee, ChangWook Park, Sin-Hyeog Im. Lactobacillus plantarum IMB19 enhances anti-tumor immune response by modulating multi-layered innate and adaptive immunity [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 3525.
Abstract 3561: Pan-cancer-specific engineered oncolytic vaccinia virus
Authors: Yoo So Young
Published: June 2022

Here, we developed a novel oncolytic vaccinia virus (NOV) with the dual advantages of cancer selectivity and normal vessel reconstructive activity by replacing the viral thymidine kinase (vTk) and vaccinia growth factor (VGF) genes with genes encoding TNF-related apoptosis-inducing ligand (TRAIL) and angiopoietin 1 (Ang1), respectively. The pan-cancer-specific oncolytic potency of NOV was confirmed in various human and mouse cancer cell lines (colon, lung, liver, pancreas, cholangiocarcinoma, cervical cancer, osteosarcoma, and melanoma). Vaccinia virus (VV) treatment directly induced early apoptosis in tumors within 24 h, and this effect was enhanced with further engineering; VGF and Tk deletion with Ang1 and TRAIL insertion. Meanwhile, treatment with the conventional anti-cancer drug cisplatin did not induce apoptosis. A virus-treated mouse colon/lung cancer syngeneic model showed attenuated tumor growth, which was in accordance with the results of percent survival measurement, CD8 expression analysis, and TUNEL staining with advanced genetic engineering. Taken together, our results indicate that NOV induces cancer tissue apoptosis and anti-tumor immunity and may constitute a highly advantageous therapeutic agent for next-generation solid tumor virotherapy with pan-cancer-specific oncolytic activity and high biosafety.

Citation Format: So Young Yoo. Pan-cancer-specific engineered oncolytic vaccinia virus [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 3561.
Abstract 361: MicroRNA expression in murine spontaneous non-small cell lung cancer and human cell lines post-treatment of PRIMA-1
Authors: Perez Melanie , Grier Shaylyn , Gao Li , Duan Wenrui
Published: June 2022

A variety of cancers have been correlated with having a mutation on the TP53 gene, including lung cancer. Lung cancer has been one of the deadliest cancers in the United States. TP53-dependent reactivation and induction of massive apoptosis (PRIMA-1) changes mutant TP53’s conformation, resulting in the restoration of DNA binding and activation of p53 target genes. PRIMA-1 methylated analog, PRIMA-1Met (APR-246, Eprenetapopt) have been used in clinical trials to target cancers containing mutant TP53. It has been reported that PRIMA-1 induced apoptosis through the regulation of microRNAs. Our research group has previously developed a transgenic mice model with a mutant form of TP53 being expressed lung specifically, to closely model human lung cancer development. The aim of the current study is to investigate the effects of PRIMA-1 on miRNA expressions in a murine spontaneous lung cancer mice model, human lung cancer cell lines H211 and H1155. The transgenic FVB/N mice lung tumor model was developed using the lung specific human surfactant protein C (SPC) promoter to control the expression of mutant TP53(273H) following the standard injection method. Tumor bearing mice were identified with a micro-CT and were treated with the PRIMA-1 at a dose of 100mg/kg. Additionally, we treated two human cell lines H211 (containing mutant TP53 R248Q) and H1155 (containing mutant TP53 R273H) with the PRIMA-1. The miRNA expression profile was evaluated with the NanoString nCounter array analysis and qt-PCR array analysis. We found that three miRNAs were up-regulated (>1.5-fold change) in the human lung cancer cells H211, H1155, and murine spontaneous non-small cell lung cancers model post treatment of PRIMA-1. The result of the study showed that miR-200c, miR-181c, and miR-183 was up-regulated in the two human cell lines and the transgenic mice lung tumors after treatment of PRIMA-1. While there was no significant downregulation in miRNA expression in these human lung cancer cells and the murine spontaneous lung cancer model. However, the overall miRNA expression is lower in murine spontaneous lung tumors when compared to the overall miRNA expression of the cell lines post PRIMA-1 treatment. This difference is due to model specific expression. Further investigation is needed to better understand the effects of PRIMA-1 in regulation of micro-RNA expression in the treatment of lung cancers containing mutant p53.

Citation Format: Melanie Perez, Shaylyn Grier, Li Gao, Wenrui Duan. MicroRNA expression in murine spontaneous non-small cell lung cancer and human cell lines post-treatment of PRIMA-1 [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 361.
Abstract 3666: Dietary potassium and risk of colorectal cancer: Findings from the Singapore Chinese Cohort Study
Authors: Luu Hung N. , Paragomi Pedram , Yu Yi-Chuan , Jin Aizhen , Wang Renwei , Schoen Robert E. , Koh Woon-Puay , Yuan Jian-Min
Published: June 2022

Background: Colorectal cancer (CRC) is a commonly diagnosed subtype of cancer with a high mortality rate. Potassium is a necessary trace element in the human boy and is derived mainly from diet. Prior studies found high intakes of potassium was inversely associated with colorectal cancer occurrence in Western population. No such effort has been made in Asian population. Methods: We examined the associations for dietary potassium with the risk of CRC in the Singapore Chinese Health Study (SCHS), a population-based prospective cohort study that includes 61,321 Chinese men and women in Singapore who were 45-74 years of age at baseline. Daily intake of potassium was derived from the self-reported intake of pre-defined food items using a validated semi-quantitative food frequency questionnaire (FFQ) at baseline according to the Singapore Food Composition Table. Cox proportional hazard regression model was used to estimate the hazard ratios (HRs) and respective 95% confidence intervals (CIs) for CRC associated with higher quartile of potassium compared with the lowest quartile with adjustment for potential confounders. Results: After an average of 17.5 years of follow-up, 2,140 participants developed CRC. Dietary potassium was inversely associated with CRC risk. The multivariable-adjusted HR of CRC for the highest relative to the lowest quarter of daily potassium intake was 0.85 (95% CI 0.75-0.96, Ptrend=0.03). The inverse association between high intake of potassium and CRC risk was more apparent among participants with body mass index (BMI) ≥ 23 kg/m2 (HRQ4vsQ1=0.75, 95% CI: 0.63-0.89; Ptrend=0.003) and those with history of type 2 diabetes (HRQ4vsQ1=0.65, 95% CI: 0.42-1.00; Ptrend=0.36).

Conclusions: In a large population-based prospective cohort study of more than 61,000 Chinese Singaporeans, we found inverse associations between dietary potassium intake and CRC risk. Future studies are warranted to elucidate the biological mechanism for the protective effect of potassium on the development of CRC.

Citation Format: Hung N. Luu, Pedram Paragomi, Yi-Chuan Yu, Aizhen Jin, Renwei Wang, Robert E. Schoen, Woon-Puay Koh, Jian-Min Yuan. Dietary potassium and risk of colorectal cancer: Findings from the Singapore Chinese Cohort Study [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 3666.
Abstract 3687: Implementing geospatial technology to understand the prostate cancer health burdens and socioeconomic status in Alabama
Authors: Alagan Ram , Aladuwaka Seela , Singh Rajesh , Manne Upender , Mishra Manoj K.
Published: June 2022

Socioeconomic status and health disparities are a significant liability for the prevalence of many diseases, including cancer. Among many contributing factors, lack of socioeconomic advancement and inequality in resource distribution is closely associated with prostate cancer occurrence. The State of Alabama has one of the highest rates of prostate cancer in the nation and the third cancer epidemic at the state level. Due to widespread disparities in infrastructure development, political willpower, equal healthcare, and education opportunity, Alabama's Black Belt region has been further divided by socioeconomic statuses among the majority (Whites) and minority (African American) populations. The purpose of this research is to recognize Alabama's health burdens and socioeconomic status using geo-spatial technology (GIS) to examine prostate cancer health disparity. GIS has become a valuable decision-making tool in understanding the public health care sectors, including prostate cancer prevalence. GIS supports assembling spatial and non-spatial data, displays the spatial distribution of health disparities, and underlines further interconnectivity of policy-related questions. This research incorporates county-level prostate cancer data using GIS and outlining the correlation between prostate cancer prevalence and socioeconomic factors to understand Alabama's cancer health disparity and equity. A combination of socioeconomic factors and state and federal-level cancer epidemic data sources underline Alabama's black belt region (predominantly African American) prostate cancer prevalence is higher than the non-black belt. The GIS analysis demonstrated that effective cancer prevention programs are needed to eliminate health disparities and enhance health equity among underserved populations of Alabama.

Citation Format: Ram Alagan, Seela Aladuwaka, Rajesh Singh, Upender Manne, Manoj K. Mishra. Implementing geospatial technology to understand the prostate cancer health burdens and socioeconomic status in Alabama [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 3687.
Abstract 3714: The antitumor activity of cannabis sativa and CBD in prostate cancer PC3 cells
Authors: Motadi Lesetja Raymond , Moleya Nonhlanhla B.
Published: June 2022

Prostate cancer is the second most frequently occurring carcinoma in males worldwide and one of the leading causes of death in men around the world. Recent studies estimate that over 1.4 million males are diagnosed with prostate cancer on an annual basis, with approximately 375 000 succumbing to the disease annually. With current treatments continuing to show severe side effects, there is a need for new treatments. In this study we looked at the effect of cannabis sativa extract, cannabidiol and cisplatin on prostate cancer cells, PC3.

Methods: In addressing the above questions, we employed the MTT assay to measure the antiproliferative effect on PC3 cells following treatment with varying concentrations of Cannabis sativa extract, cisplatin and cannabidiol. xCELLigence was also used to confirm the IC50 activity in which cells were grown in a 16 well plate coated with gold and monitor cell. Caspase 3/7 activity was also measured using 96 well-plate following treatment. Western-blot and qRT-PCR was also used to measure the gene expression of tumor suppressor genes, p53, Bax and Bcl2. Animal studies were employed to measure the growth of PC3-mouse derived cancer to evaluate the effect of compounds in vivo.

Results: From the treatment with varying concentrations of Cannabis sativa extract, cannabidiol and cisplatin, we have observed that the three compounds induced antiproliferation of PC3 cancer cell lines through the activation of caspase 3/7 activity. We also observed induction of apoptosis in these cells following silencing of retinoblastoma binding protein 6 (RBBP6), with upregulation of p53 and bax mRNA expression, and a reduction in Bcl2 gene expression. The growth of tumors in the mouse models were reduced following treatment with cisplatin and cannabidiol.

Conclusion: We demonstrated that cannabidiol is a viable therapy to treat prostate cancer cells, in combination with silencing of RBBP6. This suggests that cannabidiol rather Cannabis sativa extract may play an important role in reducing cancer progression.

Citation Format: Lesetja Raymond Motadi, Nonhlanhla B. Moleya. The antitumor activity of cannabis sativa and CBD in prostate cancer PC3 cells [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 3714.
Abstract 3717: KMT2D loss cooperates with PTCH loss for medulloblastoma genesis
Authors: Dhar Shilpa S. , Brown Calena J. , Rizvi Ali S. , Abraham Janak R. , Sillitoe Roy V. , Chen Kaifu , Lee Min Gyu
Published: June 2022

We have previously reported that the histone H3 lysine 4 methyltransferase KMT2D (also called MLL4, MLL2, and ALR; a transcriptional coactivator) is required for neuronal differentiation of human neuron-committed NT2/D1 embryonal carcinoma stem cells. Notably, we have shown that brain-specific knockout of Kmt2d alone induces spontaneous medulloblastoma (MB) in mice and that Kmt2d loss in the brain highly upregulates several oncogenic signaling programs and downregulates tumor suppressor genes. Consistent with this, our analysis of several publicly available databases indicates that Kmt2d is the most frequently mutated epigenetic modifier (8%‒10%) in MB. In this study, we sought to assess whether Kmt2d loss cooperates with another oncogenic event in MB genesis. Particularly, PTCH (also known as PTCH1), a potent MB-signaling suppressor, is one of the most frequently mutated genes in MB, and KMT2D mutations co-occur with PTCH mutations more than with many other mutations in MB. Therefore, we determined the effect of Kmt2d loss on of Ptch+/--driven MB genesis by generating and analyzing Nestin-Cre Kmt2dfl/+ Ptch+/- mice. Our results showed that heterozygous loss of Kmt2d strongly increased the genesis and incidence of Ptch+/--driven MB. Supporting this, immunohistochemistry staining of Ki-67 (a proliferation marker) showed that heterozygous loss of Kmt2d in Ptch+/--driven MB highly increased the proliferation of MB cells. Our transcriptomic analysis showed that heterozygous Kmt2d loss upregulated tumor-promoting programs, including G-protein-coupled receptor signaling and oxidation-reduction process. In line with this, heterozygous Kmt2d loss upregulated oncogenic kinases (e.g., phospho-AKT1 and phospho-ERK) that may be downstream of G-protein-coupled receptor signaling. Mechanistically, our results indicate that these tumor-promoting programs are repressed, at least in part, by the transcription-repressive and tumor-suppressive factor (s) NCOR2, whose expression is activated by KMT2D. Our results would be the first to provide molecular insights into how co-losses of an epigenetic modifier and an MB-signaling suppressor cooperate for MB genesis. Our new mouse model would be helpful in future preclinical therapeutic experiments for MB treatment. Our findings suggest that targeting oncogenic effectors downstream of KMT2D loss can be considered a potential therapeutic strategy for MB treatment.

Citation Format: Shilpa S. Dhar, Calena J. Brown, Ali S. Rizvi, Janak R. Abraham, Roy V. Sillitoe, Kaifu Chen, Min Gyu Lee. KMT2D loss cooperates with PTCH loss for medulloblastoma genesis [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 3717.
Abstract 3731: Epigenetic control of tumor cell killing by natural killer cells
Authors: Pasion Joyce , Barisic Darko , Meydan Cem , Ng Kong Y. , Lafoz Maria Tello , Huse Morgan , Melnick Ari , Wendel Hans-Guido
Published: June 2022

Immunotherapies including the activation of endogenous immune cells have stimulated great interest for their anti-tumor functions. An initial focus has been on genetic lesions such as loss of MHC class I and class II molecules that facilitate tumor cell escape. More recently, epigenetic mechanisms such as the disruption of the SWI/SNF remodeling complex PBAF have been implicated in regulating tumor sensitivity to CD8 T cell-mediated killing. Here, I used an unbiased genetic screening approach to examine resistance and sensitivity of breast cancer cells to Natural Killer (NK) cells. Among expected hits including caspases, interferon receptors, and cell death executioners, the screen revealed a surprising role of alternate SWI/SNF complexes in controlling NK cell-mediated cytotoxicity that relate to interferon-γ and perforin/granzyme B, and may be pharmacologically reversible. Altogether, I will discuss a new epigenetic mechanism that affect NK cell-mediated cytotoxicity with a focus on SWI/SNF complexes.

Citation Format: Joyce Pasion, Darko Barisic, Cem Meydan, Kong Y. Ng, Maria Tello Lafoz, Morgan Huse, Ari Melnick, Hans-Guido Wendel. Epigenetic control of tumor cell killing by natural killer cells [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 3731.
Abstract 3778: Mitochondrial dynamics in cancer restored by a bioactive fraction of fermented wheat germ extract
Authors: Bencze Gyula
Published: June 2022

Bioactive fraction of Fermented Wheat Germ Extract (A250) was shown to be effective in increasing gene expression of mitochondrial proteins in a dose-dependent manner. According to the STRING protein network analysis these proteins are linked to the Krebs cycle and apoptosis. However, the in vivo therapy had no effect on the white blood cell count, and the increase in the immune cell profile was favorable, indicating that its effect was specific to tumor cells.

Citation Format: Gyula Bencze. Mitochondrial dynamics in cancer restored by a bioactive fraction of fermented wheat germ extract [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 3778.
Abstract 3816: Functional atlas of prostate mesenchyme
Authors: Pakula Hubert , Carelli Ryan , Fanelli Nicolo , Jere Madhavi , Unkenholz Caitlin , Omar Mohamed , Fidalgo Caroline Ribeiro- , Pederzoli Filippo , Abate-Shen Cory , Rickman David S. , Robinson Brian , Marchionni Luigi , Loda Massimo
Published: June 2022

Prostate cancer has a heterogeneous prognosis, and genetic alterations alone do not fully explain clinical behavior. We previously characterized the stroma of localized human prostates by Laser Capture Microdissection, and found that stroma was substantially different in prostates with and without tumor. Furthermore, a stromal gene signature reflecting bone remodeling was upregulated in high compared to low Gleason grade cases. To determine how stromal cells contribute to carcinogenesis and progression we study whether specific genetic alterations in the epithelium induce unique stromal changes. To do this, we utilized Genetically Engineered Mouse Models (GEMMs) representing common prostate cancer mutations and compared these to their wild-type conterparts: the Tmprss2-ERG fusion knock-in murine model induces histological alterations in the stroma in the absence of an epithelial phenotype; the Pten deletion mouse model (PtenKO) results in prostate intraepithelial neoplasia (PIN) but not invasive cancer; the Hi-Myc GEMM, leads to PIN and subsequently invasion; and the Pb4-Cre +/-;Pten f/f; LSL-MYCN +/+; Rb1 f/f (MNRPDKO) mouse model that leads to neuroendocrine prostate cancer (NEPC). We generated a comprehensive single-cell transcriptomic atlas of the mouse prostate cancer mesenchyme in these models. Using deep generative modeling followed by graph-based clustering and gene regulatory network inference, six (6) distinct subsets of fibroblasts and two (2) subsets of smooth muscle cells (myofibroblasts and pericytes) were identified. Notably, some subsets were common across all GEMMs and WT mice, while others aligned with specific genotypes. Moreover, we found a variable pattern of positive and negative Ar expressing cells between genotypes. Analysis by CellphoneDB of mesenchymal-epithelial communications revealed the complex cross-talk between mutated epithelial cells and the tumor microenvironment. Multiplex immunofluorescence phenotyping of mesenchymal cell confirmed the cluster subtypes by both expression and spatial location. Finally, stromal transcripts defining mesenchymal cluster subtypes associated with Tmprss2-ERG were conserved between mouse and human genotypes.This study lays the groundwork for understanding and ultimately targeting stromal-epithelial interactions in prostate cancer.

Citation Format: Hubert Pakula, Ryan Carelli, Nicolo Fanelli, Madhavi Jere, Caitlin Unkenholz, Mohamed Omar, Caroline Ribeiro- Fidalgo, Filippo Pederzoli, Cory Abate-Shen, David S. Rickman, Brian Robinson, Luigi Marchionni, Massimo Loda. Functional atlas of prostate mesenchyme [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 3816.