bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 863: Transfer learning for gene expression prediction with deep neural networks
Authors: Arslan Emre , Rai Kunal
Published: September 2020

Conventional machine learning approaches try to solve problems in an isolated manner whereas humans utilize previous experiences between similar tasks. Transfer learning (TL) imitates this efficient approach and transfer knowledge that was learned in a source/domain task and employ that knowledge to improve learning in a related target task. We propose a deep convolutional neural networks (CNNs) structure to predict gene expression via epigenomic signals around the TSS. This structure allows to transfer knowledge that we learn in a cancer type to another one. We use H3K4me1, H3K4me3, H3K27Ac, H3K4me3, H3K27me3 histone modification marks for breast, lung, colon, glioma, ovarian, melanoma, and pancreas cancers as input and predict gene expression for each sample. Our model with transfer learning has improved prediction rates for various cancer types compared to the other established methods like Support Vector Machine (SVM), Random Forest (RF), and eXtreme Gradient Boosting (XGBoost). We also compared performances for different percentages of data with previously proposed DeepChrome algorithm. We checked normal datasets contribution for cancer samples as well. For this purpose, we train our model with normal samples from Roadmap Epigenome Project (REMC) repository first and passed the learned parameters to cancer datasets. It seems normal samples do not have common epigenomic patterns with cancer ones as we do not see any prediction of gene expression improvement. To our knowledge, there is no proposed transfer learning method in epigenetic data analysis. The proposed transfer learning mechanism will lead to avoid generating a significant amount of epigenomic data for different cancer types and will accelerate epigenomic studies in different cancer types.

Citation Format: Emre Arslan, Kunal Rai. Transfer learning for gene expression prediction with deep neural networks [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 863.
Abstract 865: Using machine learning to detect heterogeneity in single cell multi-omics datasets
Authors: Gulati Saurabh , Wang Shu , Parikh Saurabh , Liu Ben , Gokhale Kaustubh , Manivannan Manimozhi , Sahu Sombeet , Kim Dong , Parikh Anup
Published: September 2020

Background: While scRNA-seq helps in obtaining high-resolution views of single-cell heterogeneity through characterization of the functional state of cells, our understanding of the cellular properties and population architectures of heterogeneous tissues will be greatly advanced by the multi-omics investigation of single cells. Recently, several computational methods have been developed to integrate data from multiple different single cell experiments measuring individual analytes. But unambiguous inference that a cellular phenotype is caused by a genotype can only be achieved by their measurement from the same single cell. To address this gap, we have developed the Tapestri multi-omics workflow to analyze the RNA and DNA information from the same cell.

Methods: After pre-processing of the reads, cell calling is done by identifying the good barcodes using both DNA and RNA reads. DNA reads are processed to identify genetic variants in each cell. The variant cell matrix is then filtered for data completeness to ensure only high-quality data is used in downstream processing. Ploidy is estimated using by normalizing DNA reads, genetic variants and ploidy information together is used to identify subclones. The RNA reads are log normalized and scaled within each cell. Next we set the mean expression of each transcript to 0 and scale the variance to 1. This avoids downstream analysis being skewed by high expressors. We then trained a random forest classifier to identify significantly differentially expressed transcripts across subclones which were identified using genetic variants and ploidy information.

Results: Using the top differentially expressed transcripts we performed dimensionality reduction followed by clustering of cell types. The resulting visualization showed how well the genotypic and transcriptomic datasets integrated with one another. We tested this method on a model system with Raji and KG1 cell lines titrated at 50:50 ratio and were clearly able to associate the transcriptional variation with the genotypic variation of the 2 different cell lines. The method was also validated on a PBMC sample to ensure robustness of methods. We were able to identify the different cell types present the sample and were able to overlay that information with genetic variants to identify sub-clones in the identified cell types.

Citation Format: Saurabh Gulati, Shu Wang, Saurabh Parikh, Ben Liu, Kaustubh Gokhale, Manimozhi Manivannan, Sombeet Sahu, Dong Kim, Anup Parikh. Using machine learning to detect heterogeneity in single cell multi-omics datasets [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 865.
Abstract 891: CRISPR-Cas9-gRNA RNP mediated gene knockout of TGFBR2 and CISH enhances CD19-CAR NK cell function and provides resistance to TGFβ
Authors: Guo Chao , Chan Ivan H. , Buren Luxuan , Fan Yanying , Aronov Alexander , Trager James B.
Published: September 2020

Natural killer (NK) cells, known for their ability to kill tumor cells, represent a promising ‘off the shelf' therapeutic for cell-based cancer immunotherapy. One of the major challenges with NK cell-based therapies includes their lack of persistence and expansion after adoptive transfer. In addition, the presence of inhibitory signals within the tumor microenvironment and mediated by tumor cells also contributes to the poor infiltration and activation of NK cells at the tumor site. To improve NK cell function, we developed an optimized CRISPR-Cas9 system utilizing electroporation of CRISPR-gRNA ribonucleoproteins (RNPs) to disrupt important regulatory genes to enhance and/or protect primary human NK cell function. This method allowed efficient knockout of the TGFBR2 and CISH genes in NK cells, genes that have a functional impact on NK cells. FACS and Amplicon NGS Sequencing data confirmed both genes were successfully disrupted. Furthermore, we were able to transduce and expand CRISPR/Cas9 edited NK cells to express a CD19-CAR construct and membrane bound IL-15. Cytotoxicity assays demonstrated that TGFBR2 knockout CD19-CAR NK cells were resistant to TGFβ inhibition of cytotoxicity. We also showed that CISH gene-edited CD19-CAR NK cells have significantly improved proliferation, survival, cytokine production, and cancer cell cytotoxicity. In summary, this data demonstrates that this platform enables effective primary human NK cell gene knockout to enhance NK function and provide resistance to tumor microenvironment inhibition.

Citation Format: Chao Guo, Ivan H. Chan, Luxuan Buren, Yanying Fan, Alexander Aronov, James B. Trager. CRISPR-Cas9-gRNA RNP mediated gene knockout of TGFBR2 and CISH enhances CD19-CAR NK cell function and provides resistance to TGFβ [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 891.
Abstract 955: Long-term gemcitabine treatment reshapes the pancreatic tumor microenvironment and sensitizes murine carcinoma to combination immunotherapy
Authors: Principe Daniel R. , Narbutis Matthew , Kumar Sandeep , Park Alex , Viswakarma Navin , Dorman Matthew J. , Kamath Suneel D. , Grippo Paul , Fishel Melissa L. , Hwang Rosa F. , Thummuri Dinesh , Underwood Patrick W. , Munshi Hidayatullah G. , Trevino Jose G. , Rana Ajay
Published: September 2020

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death with a median survival time of 6-12 months. As most patients present with disseminated disease, the majority are offered palliative chemotherapy. With no approved treatment modalities for patients who progress on chemotherapy, we explored the effects of long-term Gemcitabine on the tumor microenvironment in order to identify potential therapeutic options in chemo-refractory PDAC. Using a combination of mouse models, patient-derived xenografts, primary and established cell lines, we first evaluated chemotherapy-induced alterations in the tumor secretome and immune surface proteins by high throughput proteomic arrays. In addition to enhancing antigen presentation and immune checkpoint expression, Gemcitabine consistently increased the synthesis of CCL/CXCL chemokines and TGFβ-associated signals. These secreted factors altered the composition of the tumor stroma, conferring Gemcitabine-resistance to cancer-associated fibroblasts in vitroand further enhancingTGFβ1 biosynthesis. We therefore combined Gemcitabine with anti-PD-1 in transgenic models of murine PDAC, which failed to alter disease course unless mice also underwent genetic or pharmacologic ablation of TGFβ signaling. In the setting of TGFβ signal deficiency, Gemcitabine and anti-PD-1 led to a robust CD8+ T-cell response and decrease in tumor burden, markedly enhancing overall survival. These results suggest that Gemcitabine may prime PDAC tumors for immune checkpoint inhibition by enhancing antigen presentation, but requires the inhibition of an immunosuppressive cytokine barrier. Given the current lack of third line treatment options, this approach warrants consideration in the clinical management of Gemcitabine-refractory PDAC.

Citation Format: Daniel R. Principe, Matthew Narbutis, Sandeep Kumar, Alex Park, Navin Viswakarma, Matthew J. Dorman, Suneel D. Kamath, Paul Grippo, Melissa L. Fishel, Rosa F. Hwang, Dinesh Thummuri, Patrick W. Underwood, Hidayatullah G. Munshi, Jose G. Trevino, Ajay Rana. Long-term gemcitabine treatment reshapes the pancreatic tumor microenvironment and sensitizes murine carcinoma to combination immunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 955.
Abstract 958: PARP-inhibition induces cancer immunogenic cell death in response to high levels of interferon-gamma in the tumor microenvironment
Authors: Kinjyo Ichiko , Adams Sarah F.
Published: September 2020

Background: We recently demonstrated that treatment with poly(ADP-ribose) polymerase (PARP) inhibitors sensitize BRCA1-deficient ovarian cancers to immune checkpoint blockade in preclinical models. The extended survival in response to this combination was associated with a significant increase in IFNg producing effector T cells in the tumor environment. In vitro experiments identified a significant interaction between PARP-inhibition and IFNg that promoted tumor cytotoxicity in a caspase-independent manner. We hypothesized that IFNg engages immunogenic cell death mechanisms in response to PARP-inhibition to promote immune-mediated tumor clearance.

Methods: To distinguish cell death mechanisms in vitro, we exposed ovarian cancer cells to a PARP-inhibitor (10 microg/ml) and IFNg (2 ng/ml). Calreticulin translocation to the cell membrane and the release of high-mobility group protein 1 (HMGB-1) were assessed as characteristic features of immunogenic cell death. Innate cell activation was evaluated by analysis of dendritic cells in draining lymph nodes after vaccination. Evidence of immunogenicity was confirmed in vivo with vaccination studies.

Results: Tumor cells treated with a PARP-inhibitor in combination with IFNg, but not the cells exposed to the PARP-inhibitor alone, demonstrated calreticulin translocation and HMGB-1 release. In vivo, vaccination using cells treated with both the PARP-inhibitor and IFNg protected animals from intraperitoneal tumor challenge. Vaccinated mice also rejected secondary and tertiary tumor challenges demonstrating durable protective memory. Vaccinated tumor cells were phagocytosed by DCs in draining lymph nodes and induced co-stimulatory ligand and MHC expression. Adoptive transfer of splenocytes from vaccinated animals confirmed that this protective effect was T cell-mediated.

Conclusions: These results identify a novel mechanism by which PARP-inhibition drives immunogenic cell death in response to IFNg in the ovarian tumor environment. These effects can be leveraged to enhance tumor clearance in combination with immune therapy, and may present a strategy to circumvent adaptive treatment resistance associated with high levels of IFNg in the tumor microenvironment.

Citation Format: Ichiko Kinjyo, Sarah F. Adams. PARP-inhibition induces cancer immunogenic cell death in response to high levels of interferon-gamma in the tumor microenvironment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 958.
Abstract 978: Monocyte-derived macrophages contribute to the inflammation-induced survival of experimental micrometastases in the lung
Authors: Arif Arif A. , Freeman Spencer A. , Atif Jawairia , Dean Pamela , Gilmour Megan , Blanchet Marie-Renee , Wiegand Kimberly , McNagny Kelly M. , Underhill Michael , Gold Michael , Johnson Pauline , Roskelley Calvin D.
Published: September 2020

Circulating tumor cells become fully metastatic if they are able to extravasate from the microvasculature and move into microenvironmental niches that facilitate their survival within distant site organs. To determine if inflammation promotes this process in the lungs, inflammatory asthma, hypersensitivity pneumonitis, or bleomycin-induced injury were initiated prior to the intravenous introduction of low malignant potential B16F0 melanoma cells. All three conditions increased end-stage metastatic burden without increasing the initial tumor cell extravasation from the lung microvasculature. There was, however, an increase in the number and size of early micrometastatic lesions within the lung interstitia that were visible 96 hr after melanoma cell introduction. There was also an increase in tumor cell survival within these early lesions located in the inflamed lungs that was associated with the presence of nearby newly recruited CD11c+CD11b+ monocyte-derived macrophages (MoDM). Adoptive transfer experiments indicated that these MoDM cells facilitated B16F0 cell metastasis in the absence of inflammation. Additionally, a factor, or factors, secreted by MoDM promoted B16F0 cell survival under stress-inducing condition. Taken together, these findings demonstrate that inflammation-induced monocyte-derived macrophages act as a modifier of the post-extravasation microenvironment that appears to facilitate the early emergence of distant site metastasis.

Citation Format: Arif A. Arif, Spencer A. Freeman, Jawairia Atif, Pamela Dean, Megan Gilmour, Marie-Renee Blanchet, Kimberly Wiegand, Kelly M. McNagny, Michael Underhill, Michael Gold, Pauline Johnson, Calvin D. Roskelley. Monocyte-derived macrophages contribute to the inflammation-induced survival of experimental micrometastases in the lung [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 978.
Abstract 996: Reversing tumor induced immune suppression: Role of the secretory autophagy pathway
Authors: Howard Marissa Ashton
Published: September 2020

The goal is to reverse cancer immune evasion at the level of the sentinel lymph node. Reduced expansion of CD8+Tcells and other innate immune effector cells in the cancer draining SLN is associated with progression and resistance to checkpoint inhibitors. Cancer derived extracellular vesicles (EVs) that are PD-L1 positive suppress immune recognition at the level of the SNL. Experimental goal: To remodel the SNL to overcome cancer EV-associated immune suppression and induce immune rejection of the tumor. We developed three methodologies for this project a) Collection of draining lymph fluid to characterize extracellular vesicles (EVs) shed by 4T1 syngeneic breast tumors growing in the mammary fat pad. b) Chromatographic separation and characterization of the repertoire of EVs shed by tumors into the tumor microenvironment interstitial space using western blotting, mass spectrometry, and electron microscopy. c) Nanoparticle delivery of purified classes of EVs to the tumor draining SNL in combination with cytokine chemoattractants for innate immune cells. Results: Murine and human breast cancer cell lines shed classic exosomes and autophagosomes. The latter are shed extracellularly by the activation of the secretory autophagy pathway. The classic exosomes(exosome marker positive) contained PD-L1. In contrast the LC3 I/II P62 positive double membrane extracellular autophagosomes contained mitochondrial components (mitophagy). SLN immune cell populations could be massively remodeled by introducing hydrogel nanoparticles that affinity release chemoattractants locally in the subcapsular sinus. Nanoparticles could also be used to deliver concentrated packages of EVs of different classes to the SLN. Introduction of the autophagosome containing EV population to the SLN augmented tumor growth, angiogenesis, and metastasis, even when cytokine induction was used to remodel the SLN. In marked contrast, introduction of the PD-L1 positive exosomes to the SLN in combination with nanoparticle release of T-cell and dendritic cell chemoattractants, induced immune rejection of the syngeneic breast cancer, reducing tumor growth and blocking metastasis. The findings demonstrate that different classes of EVs have opposite effects on cancer immune evasion at the level of the SLN and that immune suppression can be reversed by SLN remodeling to augment dendritic and CD8 T cells.

Citation Format: Marissa Ashton Howard. Reversing tumor induced immune suppression: Role of the secretory autophagy pathway [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 996.
Abstract CT123: Phase I study of a B cell-based and monocyte-based immunotherapeutic vaccine, BVAC-C, in human papillomavirus type 16- or 18-positive recurrent cervical cancer
Authors: Choi Chel Hun , Choi Hyun Jin , Lee Jeong-Won , Kang Eun-Suk , Cho Duck , Park Byung Kwan , Kim Yong-Man , Kim Dae-Yeon , Seo Hyungseok , Park Myunghwan , Kim Wuhyun , Choi Ki-Young , Oh Taegwon , Kang Chang-Yuil , Kim Byoung-Gie
Published: September 2020

BVAC-C is a B cell-based and monocyte-based immuno-therapeutic vaccine transfected with a recombinant human papillomavirus (HPV) 16/18 E6/E7 gene and loaded with alpha-galactosyl ceramide, which is a natural killer T cell ligand. This phase I study sought to determine the tolerability and immunogenicity of BVAC-C in platinum-resistant recurrent cervical cancer patients. Patients with HPV 16-positive or 18-positive recurrent or persistent cervical cancer who had received at least one prior platinum-based combination chemotherapy were enrolled. BVAC-C was injected intravenously three times every four weeks, and dose escalation was planned in a three-patient cohort design at doses of 1×107, 4×107, or 1×108 cells/dose. Eleven patients were enrolled, and six (55%) patients had received two or more lines of platinum-based chemotherapy prior to enrollment. Treatment-related adverse events (TRAEs) were observed in 21 cycles. Most TRAEs were mild fever (n = 6.55%) or myalgia (n = 4.36%). No dose-limiting toxicities occurred. The overall response rate was 11% among nine patients evaluable, and the duration of response was 10 months. Five patients (56%) achieved a stable disease for 4.2-11 months as their best overall response. The median progression-free survival in all patients was 6.8 months (95% CI, 3.2 to infinite months), and the overall survival rate at 6 and 12 months was 89% (95% CI, 71 to 100%) and 65% (95% CI, 39 to 100%), respectively. BVAC-C induced the activation of natural killer T cells, natural killer cells, and HPV 16/18 E6/E7-specific T cells upon vaccination in all patients evaluated. BVAC-C was well tolerated and demonstrated a durable anti-tumor activity with an immune response in HPV 16-positive or 18-positive recurrent cervical carcinoma patients. A Phase 2 efficacy trial is currently underway.

Citation Format: Chel Hun Choi, Hyun Jin Choi, Jeong-Won Lee, Eun-Suk Kang, Duck Cho, Byung Kwan Park, Yong-Man Kim, Dae-Yeon Kim, Hyungseok Seo, Myunghwan Park, Wuhyun Kim, Ki-Young Choi, Taegwon Oh, Chang-Yuil Kang, Byoung-Gie Kim. Phase I study of a B cell-based and monocyte-based immunotherapeutic vaccine, BVAC-C, in human papillomavirus type 16- or 18-positive recurrent cervical cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT123.
Abstract CT137: A pilot pharmacokinetic study of VAL413 in patients with recurrent pediatric solid tumors
Authors: Geller James I. , Brown Dennis , Bacha Jeffrey , Sankar Neil , Kanekal Sarath , Leggas Mark , Wagner Lars
Published: September 2020

Background: Ewing's sarcoma (EWS) is the second most common malignant bone tumor affecting children, adolescents and young adults. Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also widely used off-label as salvage therapy for patients with recurrent EWS, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, and medulloblastoma. Prior adult and pediatric trials demonstrate that the combination of intravenous irinotecan and temozolomide has significant antitumor activity in advanced EWS. Recently, commercially available intravenous irinotecan has been administered orally (IRN-IVPO) in pediatric patients to reduce intravenous administration-related side effects, improve convenience and reduce clinic time and costs. Unfortunately, the taste of the iv preparation can be limiting, leading to poor compliance especially in pediatric patients. Development of an advanced formulation to improve tolerability and patient compliance is an important unmet need. Methods: VAL-413 is novel formulation developed to improve tolerability of oral irinotecan for the treatment of cancer. This study (USIND#135675) aims to establish the recommended phase II dose of VAL-413 when given in combination with temozolomide. Secondary objectives include characterization of the pharmacokinetics of VAL-413 vs. conventional irinotecan given orally (IRN-IVPO), evaluating palatability of VAL-413, assessing the toxicity profile of VAL-413 in combination with temozolomide, and assessment of tumor response. Up to 20 patients >= 1 to <= 30 years of age with recurrent pediatric solid tumors will be enrolled at two different dose levels of VAL-413 in combination with fixed-dose temozolomide using a standard 3 + 3 design. During the first cycle of treatment, each patient will receive 4 daily doses of VAL-413 and one daily dose of IRN-IVPO, together with 5 days of concurrent temozolomide. During all subsequent cycles, only VAL-413 will be given with temozolomide in 5-day courses administered every 21 days. Up to 17 cycles of treatment may be administered on this study. This study design will test the hypothesis that VAL-413 will not have significant pharmacokinetic differences from IRN-IVPO using intra-patient comparison of pharmacokinetic profiles. The evaluation of two dose levels will help to formally define a recommended Phase II dose for further studies. Toxicity will be evaluated based on CTCAEv5 and tumor response based on RECISTv1.1.

Citation Format: James I. Geller, Dennis Brown, Jeffrey Bacha, Neil Sankar, Sarath Kanekal, Mark Leggas, Lars Wagner. A pilot pharmacokinetic study of VAL413 in patients with recurrent pediatric solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT137.
Abstract CT144: PD-1-CD28-enhanced receptor and anti-CD19 CAR-modified tumor-infiltrating T lymphocytes produce potential anti-tumor ability in solid tumors
Authors: Chen Xinfeng , Zhao Xuan , Wang Liping , Gu Weiyue , Zhang Yi
Published: September 2020

Purpose: Limited expansion ability and cytotoxic function are major problems of using tumor-infiltrating lymphocytes (TILs) in vivo. We sought to determine whether adoptive transfer of autologous modified TILs mediates regression of advanced tumors.

Experimental Design: First, anti-tumor effects of switching PD-1 to CD28 signaling and anti-CD19 CAR-modified NY-ESO-1-TCR T cells (hereafter “PD-1-CD28 TCR-T” and “Anti-CD19 CAR-TCR-T” cells, respectively) were tested in vitro and in vivo. Furthermore, the safety and anti-tumor ability of S-TILs (TILs modified by transducing with anti-CD19 CAR and PD-1-CD28 vectors) were evaluated in vivo. PD-1-CD28 TCR-T cells produced formidable anti-tumor ability overcoming PD-1/PD-L1 signaling in vivo.

Results: Anti-CD19 CAR-TCR-T cells stimulated with CD19+ B cells exhibited powerful expansion and anti-tumor ability in vitro and in vivo. Three patients with refractory solid tumors received S-TIL infusion. There was no treatment-related mortality, and none of the patients experienced severe side effects. One patient with melanoma achieved a partial response and two patients with colon or kidney cancer achieved long-term stable disease following S-TIL therapy.

Conclusions: To our knowledge, this is the first report describing the safety and efficacy of adoptive transfer of autologous S-TILs to control disease in patients with advanced cancers, suggesting that S-TILs may be a promising alternative therapy for cancer treatment.

Citation Format: Xinfeng Chen, Xuan Zhao, Liping Wang, Weiyue Gu, Yi Zhang. PD-1-CD28-enhanced receptor and anti-CD19 CAR-modified tumor-infiltrating T lymphocytes produce potential anti-tumor ability in solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT144.
Abstract CT205: Phase 2 study to evaluate the safety, pharmacokinetics, and clinical activity of the PI3K / mTOR inhibitor paxalisib (GDC-0084) in glioblastoma (GBM) with unmethylated O6-methylguanine-methyltransferase (MGMT) promotor status
Authors: Wen Patrick Y. , de Groot John , Battiste James D. , Goldlust Samuel A. , Garner James S. , Simpson Jeremy A. , Kijlstra Jelle , Olivero Alan , Cloughesy Timothy
Published: September 2020

Introduction: Paxalisib (previously GDC-0084) is a potent, oral, selective, brain-penetrant, small molecule inhibitor of class I phosphoinositide 3-kinase and mammalian target of rapamycin. The PI3K pathway is upregulated in ~85% of GBM cases and paxalisib has shown efficacy in preclinical models. A phase I study (NCT01547546) investigated paxalisib dosed once daily in 47 patients with recurrent high-grade gliomas and established a maximum tolerated dose (MTD) of 45mg once daily. The current phase II study (NCT03522298) aims to explore the safety, tolerability, and clinical activity of paxalisib in newly diagnosed GBM and an unmethylated MGMT promotor following surgery and temozolomide chemoradiation per Stupp regimen. Methods: This study has a 2-part design: an open-label, dose-escalation phase to assess the safety, tolerability and MTD (Part 1), followed by an expansion cohort (Part 2) at the MTD. Dose-escalation started at 60mg and progressed in 15mg increments using a 3+3 design. Part 2 recruits 20 patients who are randomised to administration in fed or fasted states. Results: Part 1 is complete. Nine patients were recruited and an MTD of 60mg was determined. DLTs were hyperglycemia and oral mucositis, with toxicity and patterns of AEs consistent with prior experience and other PI3K-targeting agents. For eight response-evaluable patients in Part 1, the median progression-free survival (PFS) was 8.4 months, and 25% of patients remained progression free after 15 months of follow-up. Part 2 is ongoing.

Citation Format: Patrick Y. Wen, John de Groot, James D. Battiste, Samuel A. Goldlust, James S. Garner, Jeremy A. Simpson, Jelle Kijlstra, Alan Olivero, Timothy Cloughesy. Phase 2 study to evaluate the safety, pharmacokinetics, and clinical activity of the PI3K / mTOR inhibitor paxalisib (GDC-0084) in glioblastoma (GBM) with unmethylated O6-methylguanine-methyltransferase (MGMT) promotor status [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT205.
Abstract CT217: POLO: Homologous recombination repair gene mutations (HRRm) in metastatic pancreatic cancer (mPaC) tumors
Authors: Lai Zhongwu , Golan Talia , Kindler Hedy L. , Dougherty Brian , Matakidou Athena , Dong Liqin , Locker Gershon , Harrington Elizabeth A.
Published: September 2020

mPaC patients (pts) with HRRm, including BRCA1 and/or BRCA2 mutations (BRCAm), derive benefit from platinum-based treatment (Pishvaian. J Clin Oncol 2019). In the Phase III POLO trial (NCT02184195) maintenance olaparib conferred a progression-free survival benefit over placebo in pts with a germline (g) BRCAm and mPaC. A prespecified exploratory analysis was conducted to determine the prevalence of tumor tissue biomarkers in pts screened for inclusion in POLO.

Archival tumor samples were provided if available and, irrespective of subsequent pt randomization, DNA was analyzed using a gene panel from Foundation Medicine Inc. (FMI) or exome sequencing by Human Longevity Inc. (HLI). Results were compared with cohorts from FMI (mPaC; FoundationOne CDx panel) and The Cancer Genome Atlas (TCGA; primary and mPaC; exome sequencing).

Tumor samples from 187/3315 (5.6%) pts screened for entry into POLO were available and sequenced. Prevalence of tumor HRRm in the POLO, FMI and TCGA cohorts are presented in the Table. The higher BRCAm prevalence observed in the POLO and FMI cohorts compared with TCGA may be due to sample size or differences in ethnicity or tumor sample location (primary vs metastatic). Mutations in BRCA2, BRCA1 and ATM were most common and were generally mutually exclusive. The prevalence of somatic (s) BRCAm in POLO was consistent with the FMI dataset (~2%); g and s BRCAm were mutually exclusive. Of the HRRm observed in non-BRCA genes, mutations in ATM were most prevalent. Prevalence of mutations in non-HRR genes (CDKN2A, SMAD4, KRAS, TP53) in POLO was consistent with that seen in other pancreatic cancer cohorts.

TablePrevalence, %*POLO (N=187)FMI (N=1046)TCGA (N=146)BRCA24.84.32.1BRCA13.22.10ATM5.32.55.5PALB21.10.90.7CDK1200.50RAD51C00.10RAD51B00.20RAD54L00.20RAD51D00.20BRIP10.50.30.7FANCI00.30FANCL0.50.10BARD10.50.20.7CHEK100.20CHEK200.62.1Any HRR15.512.011.0Non-BRCA HRR7.55.68.9*Some tumors had a mutation in >1 gene

In summary, based on the subgroup of pts with analyzed tumor tissue, the genetic profile of the screened POLO population is reflective of that seen in the overall pancreatic cancer population. ~8% of pts had tumors harboring a BRCAm, with mutations in BRCA2 more prevalent than BRCA1; ~7% of pts had tumors harboring a non-BRCA HRRm, most commonly in ATM (~5%).

Citation Format: Zhongwu Lai, Talia Golan, Hedy L. Kindler, Brian Dougherty, Athena Matakidou, Liqin Dong, Gershon Locker, Elizabeth A. Harrington. POLO: Homologous recombination repair gene mutations (HRRm) in metastatic pancreatic cancer (mPaC) tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT217.
Abstract CT274: Diagnosis based on signal : The first time break the routinely used circle of signal-to-image-to-diagnose
Authors: Dong Di , He Bingxi , Kong Boyu , Zhang Lei , Tong Lixia , Huang Feng , Han Dong , Huang Zhipei , Zhang Huimao , Tian Jie
Published: September 2020

Purpose: The routinely used diagnostic scheme of cancers follows the process of signal-to-image-to-diagnosis. It is essential to reconstruct the visible images from the signal of medical device so that the human doctor can perform diagnosis. However, the huge amount of information inside the signal is not optimally mined, which causes the current unsatisfactory performance of image based diagnosis. In this study, for the first time, we developed an AI based diagnostic scheme for lung nodules directly from the signal (rawdata) to diagnosis, skipping the reconstruction step. Experimental Design: In this study, we focused on the discrimination of malignant from benign lung nodules using CT rawdata. We collected a simulation dataset (n=606, from LUNA public dataset; rawdata was generated from CT images) and a prospective dataset (n=268, from the First Hospital of Ji Lin University, China; Clinical trials: NCT04241614). In the prospective dataset, all patients underwent preoperative CT scan (both rawdata and CT images were available) and had pathologically confirmed result of the nodules. We used 3D-CNN (Convolutional Neural Networks) to generate a model from rawdata (Model_rawdata) and another model from CT image (Model_image). The performances of the two models were compared with area under curve (AUC). In addition, we explored the additional value of rawdata to image-based diagnostic scheme. Results: The simulation study showed that rawdata could distinguish malignant lung nodules (AUCs for training and validation cohorts were 0.88 and 0.80, respectively). In the prospective study using only the lung area, both Model_rawdata and Model_image had good classification performance (both AUCs were greater than 0.65). In the prospective study using only the nodule area, the Model_rawdata performed similar with Model_image (both AUCs were greater than 0.7). The stratification analysis showed that the Model_rawdata was not affected by CT scanning parameters. Furthermore, the addition of rawdata to image (Model_combination) could improve the diagnostic performance. Conclusions: Without reconstruction, the rawdata from CT system had comparative performance to image-based diagnosis. The rawdata could provide additional diagnostic value to images. This research breaks the routinely used circle of imaged based diagnosis, which may open up a new field for AI based diagnosis.

Citation Format: Di Dong, Bingxi He, Boyu Kong, Lei Zhang, Lixia Tong, Feng Huang, Dong Han, Zhipei Huang, Huimao Zhang, Jie Tian. Diagnosis based on signal : The first time break the routinely used circle of signal-to-image-to-diagnose [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT274.
Abstract LB-015: Yap reprograms de novo lipogenesis to fuel liver cancer
Authors: Salmi Talhah M. , Vaidyanathan Srimayee , McConville Malcolm J. , Brown Kristin K. , Cox Andrew G.
Published: September 2020

Hepatocellular carcinoma (HCC) is the most common form of liver cancer, originating from liver cells known as hepatocytes. At the molecular level, HCC is driven by transcription factors which are able to reprogram metabolism to support tumorigenesis that are still poorly understood. The Yes-associated protein (Yap) is the nuclear effector of the Hippo pathway, responsible in regulating organ size control and metabolism. Metabolic reprogramming has recently emerged as a fundamental hallmark of cancer. In our previous studies, we found that Yap integrates the anabolic demands of tumour growth by reprogramming glutamine and glucose metabolism to support nucleotide biosynthesis. The central aim of this study was to determine the role that Yap plays in regulating lipid metabolism in the context of liver cancer. We took advantage of a larval zebrafish model in which a hyperactivated form of Yap is specifically expressed in hepatocytes (lf:YapS87A;lf:NLS-mcherry). We found that the expression of Yap was sufficient to stimulate de novo lipogenesis (DNL) and induce lipid droplet formation in hepatocytes (steatosis). To determine whether the stimulation of DNL was required for oncogenic growth, we exposed larvae to pharmacological inhibitors of DNL and examined the impact on growth at the cellular level by multiphoton microscopy. Strikingly, we identified that fatty acid synthase (FAS) and stearoyl-CoA desaturase (SCD) inhibitors suppressed Yap-driven growth. To complement these studies, we took a genetic approach using CRISPR to generate FAS and SCD KO zebrafish larvae and we found that Yap-driven growth required both FAS and SCD. Importantly both chemical and genetic suppression of FAS and SCD activity had no effect on normal liver growth. Together, these findings suggest that oncogenic Yap-driven growth is conditionally dependent upon the stimulation of DNL. Consequently, these studies provide a rationale for examining the clinical efficacy of DNL inhibitors to combat liver cancer.

Citation Format: Talhah M. Salmi, Srimayee Vaidyanathan, Malcolm J. McConville, Kristin K. Brown, Andrew G. Cox. Yap reprograms de novo lipogenesis to fuel liver cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-015.
Abstract LB-052: Photochemistry mediated tumor priming potentiates cytoreduction of distant metastases to enable potential surgical cure in a late stage model of pancreas cancer
Authors: Anbil Sriram , Mai Zhiming , Pigula Michael , Hasan Tayyaba
Published: September 2020

Pancreatic cancer is a devastating disease for which the 5 year survival rate remains < 10% despite years of concerted research efforts. Potentially curative surgical resection cannot even be offered to most patients due to the presence of distant metastases at the time of diagnosis. Here, we present a neoadjuvant strategy comprised of photochemistry mediated tumor modulation combined with systemic therapy to significantly cytoreduce, and in 50% of cases completely eliminate, distant metastases to create a window of potential resectability. In a late stage model of pancreas cancer in which distant metastases are present at the time of treatment, combined photodynamic therapy (PDT) and gemcitabine/abraxane led to a 10,000 fold decrease in the number of distant metastases compared to untreated controls. In comparison, gemcitabine + abraxane, the current standard of care for pancreas cancer, only led to a 100 fold cytoreduction. 50% of animals treated with PDT + gem/abraxane harbored no detectable metastases 51 days after treatment compared to 0% of gem/abraxane treated animals, suggesting that PDT plus cytoreduction could enable potentially curative surgery in a sizeable percentage of animals. The strategy presented here is rapidly translatable and holds significant promise to dramatically increase the percentage of patients that are currently eligible for curative therapy for this devastating disease.

Citation Format: Sriram Anbil, Zhiming Mai, Michael Pigula, Tayyaba Hasan. Photochemistry mediated tumor priming potentiates cytoreduction of distant metastases to enable potential surgical cure in a late stage model of pancreas cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-052.
Abstract LB-056: A novel cyclic peptide inhibitor targeting the YAP-TEAD protein-protein interaction shows potent anti-tumor effect in a variety of human malignancies including mesothelioma
Authors: HU YI P. , Wang Yinghua M. , Lee Daniel , Ren Yi
Published: September 2020

The Hippo signaling pathway plays an important role in organ size control. Dysregulations of this pathway have been implicated in human cancer. Oncoprotein YAP is a major downstream effector molecule for Hippo pathway and has no intrinsic DNA binding domain. The functionality of YAP depends on the interaction of YAP with transcription factor TEAD in cell nucleus. Inhibitors targeting YAP-TEAD PPI could rectify abnormal Hippo pathway, leading to tumor remission. Screening through a carefully designed peptide library derived from the YAP protein, we have successfully identified potent YAP inhibiting peptides (YIP). Surface plasmon resonance (SPR) showed that the YIP bind to TEAD with high affinity in the nM-pM (KD) range. Subsequently, the binding interaction was confirmed by Pull-down experiments. In cell-based assays, YIP inhibited cell proliferation in various cancer cell lines at low µM (IC50) range. Furthermore, cellular nuclear tests indicated that YIP could penetrate into the nucleus and inhibited YAP-TEAD interaction by TEAD-luciferase assay in a dose dependent manner. In several s.c. xenograft animal models, a lead YIP strongly suppressed the tumour growth including NF-2 mutant mesothelioma cells. The lead YIP has good drug-like pharmacological properties and represents a promising candidate targeting the Hippo pathway as an effective treatment for cancers.

Citation Format: YI P. HU, Yinghua M. Wang, Daniel Lee, Yi Ren. A novel cyclic peptide inhibitor targeting the YAP-TEAD protein-protein interaction shows potent anti-tumor effect in a variety of human malignancies including mesothelioma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-056.
Abstract LB-062: A live-cell, protein-protein interaction assay identified inhibitors of KRAS4b-G12D interaction with full-length RAF1
Authors: Columbus John , Turbyville Thomas J. , Wall Vanessa , Esposito Dominic , Barda David A. , Peng Sheng-Bin
Published: September 2020

KRAS4b is a major driver of cancers of the pancreas, lung, and colon, and until recently was considered undruggable. However, recent discoveries have revealed that molecules can target KRAS directly, and that our understanding of KRAS is incomplete. To exploit this new appreciation of KRAS druggability and biology, we have developed several protein-protein interaction (PPI) assays to target KRAS activity in live cells. Here we report on a campaign where we screened a 20,000-compound library against full length KRAS4b-G12D and RAF1 interactions in live HEK293 cells using the NanoBRET platform. From the list of screening hits, we identified several structurally related active compounds with dose-dependent, albeit weak, inhibition of the PPI signal. We expanded these active compounds to a more complete list of structural analogs which we tested in a full dose response. From this expanded group of compounds, we identified several with low µM IC50s. Follow up with these compounds in secondary assays revealed promising biological readouts, including inhibition of downstream pERK levels in G12D mutant PANC1 cells. In summary, by using well-designed live cell assays, we have identified promising leads, which we are pursuing with mechanism of action studies.

Citation Format: John Columbus, Thomas J. Turbyville, Vanessa Wall, Dominic Esposito, David A. Barda, Sheng-Bin Peng. A live-cell, protein-protein interaction assay identified inhibitors of KRAS4b-G12D interaction with full-length RAF1 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-062.
Abstract LB-087: Blockade of β-catenin-induced CCL28 suppresses gastric cancer progression via inhibition of Treg cell infiltration
Authors: Ji Lu , Zhu Helen He , Ma Bin , Gao Wei-Qiang
Published: September 2020

Dysregulation of Wnt/β-catenin signaling is frequently observed in human gastric cancer. Elucidation of tumor immune microenvironment is essential for the understanding of tumorigenesis and the development of immunotherapeutic strategies. However, it remains unclear how β-catenin signaling regulates stomach tumor immune microenvironment. Our in vitro study unraveled CCL28 as a direct transcriptional target gene of β-catenin/T cell factor (TCF). Protein levels of β-catenin and CCL28 were positively correlated in human gastric adenocarcinoma. β-Catenin-activated CCL28 was able to recruit Regulatory T (Treg) cells in transwell migration assay. In a clinically relevant mouse gastric cancer model established by Helicobacter (H.) felis infection and MNU treatment, inhibition of β-catenin/TCF activity by a pharmacological inhibitor iCRT14 suppressed CCL28 expression and Treg cell infiltration in the stomach. Moreover, anti-CCL28 antibody attenuated Treg cell infiltration and tumor progression in H. felis/MNU mouse models. Diphtheria toxin (DT)-induced Treg cell ablation restrained gastric cancer progression in H. felis/MNU-treated DEREG (Foxp3-DTR) mice, clarifying the tumor-promoting role of Treg cells. Thus, the β-catenin-CCL28-Treg cell axis may serve as an important mechanism for immunosuppression of the stomach tumor microenvironment. Our findings highlighted an immunoregulatory role of β-catenin signaling in stomach tumors and the therapeutic potentials of CCL28 blockade for the treatment of gastric cancer.

Citation Format: Lu Ji, Helen He Zhu, Bin Ma, Wei-Qiang Gao. Blockade of β-catenin-induced CCL28 suppresses gastric cancer progression via inhibition of Treg cell infiltration [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-087.