bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase I Study of Autologous Dendritic Cell Vaccine Pulsed with Allogeneic Stem-like Cell Line Lysate in Patients with Newly Diagnosed or Recurrent Glioblastoma
Authors: Hu Jethro L. , Omofoye Oluwaseun A. , Rudnick Jeremy D. , Kim Sungjin , Tighiouart Mourad , Phuphanich Surasak , Wang Hongqiang , Mazer Mia , Ganaway Toni , Chu Ray M. , Patil Chirag G. , Black Keith L. , Shiao Stephen L. , Wang Rongfu , Yu John S. 
Published: December 2021

AbstractPurpose:Glioblastoma (GBM) is a heterogeneous malignancy with multiple subpopulations of cancer cells present within any tumor. We present the results of a phase I clinical trial using an autologous dendritic cell (DC) vaccine pulsed with lysate derived from a GBM stem-like cell line.Patients and Methods:Patients with newly diagnosed and recurrent GBM were enrolled as separate cohorts. Eligibility criteria included a qualifying surgical resection or minimal tumor size, ≤ 4-mg dexamethasone daily dose, and Karnofsky score ≥70. Vaccine treatment consisted of two phases: an induction phase with vaccine given weekly for 4 weeks, and a maintenance phase with vaccines administered every 8 weeks until depletion of supply or disease progression. Patients with newly diagnosed GBM also received standard-of-care radiation and temozolomide. The primary objective for this open-label, single-institution trial was to assess the safety and tolerability of the autologous DC vaccine.Results:For the 11 patients with newly diagnosed GBM, median progression-free survival (PFS) was 8.75 months, and median overall survival was 20.36 months. For the 25 patients with recurrent GBM, median PFS was 3.23 months, 6-month PFS was 24%, and median survival was 11.97 months. A subset of patients developed a cytotoxic T-cell response as determined by an IFNγ ELISpot assay.Conclusions:In this trial, treatment of newly diagnosed and recurrent GBM with autologous DC vaccine pulsed with lysate derived from an allogeneic stem-like cell line was safe and well tolerated. Clinical outcomes add to the body of evidence suggesting that immunotherapy plays a role in the treatment of GBM.
Abstract CC01-01: The landscape of precision cancer combination therapy: A single-cell perspective
Authors: Ahmadi Saba , Sukprasert Pattara , Vegesna Rahulsimham , Sinha Sanju , Schischlik Fiorella , Artzi Natalie , Khuller Samir , Schäffer Alejandro A. , Ruppin Eytan 
Published: December 2021

Abstract
The availability of single-cell transcriptomics data opens new opportunities for rational design of combination cancer treatments in a systematic manner. Mining such data, we employed combinatorial optimization techniques to explore the landscape of optimal combination therapies in solid tumors, including brain, head and neck, melanoma, lung, breast and colon cancers. We assume that each individual therapy can target any one of 1269 genes encoding cell surface receptors, which may be targets of CAR-T, conjugated antibodies or coated nanoparticle therapies. In most cancer types, personalized combinations composed of at most four targets are sufficient to kill at least 80% of the tumor cells while killing at most 10% of the non-tumor cells in each patient. The number of distinct targets needed to do that for all patients in 8 of the 9 cohorts we studied is at most 11, while one larger melanoma cohort requires over 30 distinct targets. Further requiring that the target genes be lowly expressed across many different healthy tissues uncovers qualitatively similar trends. However, as one requires either more stringent killing thresholds or more stringent sparing of non-cancerous tissues beyond these baseline values, the number of targets needed rises rapidly. Emerging promising targets include the gene PTPRZ1, which is frequently found in the optimal combinations for brain and head and neck cancers, and EGFR, a recurring target in multiple tumor types. In sum, this is the first systematic single-cell based characterization of the landscape of combinatorial receptor-mediated cancer treatments, identifying promising targets for future development.
Citation Format: Saba Ahmadi, Pattara Sukprasert, Rahulsimham Vegesna, Sanju Sinha, Fiorella Schischlik, Natalie Artzi, Samir Khuller, Alejandro A. Schäffer, Eytan Ruppin. The landscape of precision cancer combination therapy: A single-cell perspective [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr CC01-01.
Abstract IACC0103: Predicting outcomes of Phase III oncology trials with Bayesian mediation modeling
Authors: Hobbs Brian P. 
Published: December 2021

Abstract
Pivotal cancer trials often fail to yield evidence in support of new therapies thought to offer promising alternatives to standards-of-care. Conducting RCTs in oncology tends to be more expensive than studies of other diseases with comparable sample size. Moreover, phase III trial design often takes place with a paucity of survival data for experimental therapies. Experts have explained the failures on the basis of design flaws which produce studies with unrealistic expectations. This article presents a framework for predicting outcomes of phase III oncology trials using Bayesian mediation models. Predictions, which arise from interim analyses, derive from multivariate modeling of the relationships among treatment, tumor response, and their conjoint effects on survival. Acting as a safeguard against inaccurate pre-trial design assumptions, the methodology may better facilitate rapid closure of negative studies.
Additionally the models can be used to inform re-estimations of sample size for under-powered trials that demonstrate survival benefit via tumor response mediation. The methods are applied to predict the outcomes of three colorectal cancer RCTs.
Citation Format: Brian P. Hobbs. Predicting outcomes of Phase III oncology trials with Bayesian mediation modeling [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr IACC0103.
Abstract IACC0601: Radiopharmaceuticals and their future in cancer care
Authors: Kunos Charles A. 
Published: December 2021

Abstract
Radiopharmaceutical agents have been an appealing treatment approach since the use of 131I to treat thyroid malignancies. Advances in cancer radiobiology and radiochemistry have brought radiopharmaceuticals forward to the cutting edge of oncology clinical research. The National Cancer Institute (NCI) and its partnering academic and clinical research networks monitor radiopharmaceutical discoveries that might be incorporated into cancer treatment strategies for patients with unmet therapeutic needs. Such endeavors happen through leveraged partnerships between NCI's Cancer Therapy Evaluation Program (CTEP), its Radiation Research Program (RRP), and academic institutions in the Experimental Therapeutics Clinical Trials Network (ETCTN). If innovative discoveries are made, NCI supports clinician scientists to plan new and original radiopharmaceutical phase I and II monotherapy or combination trials. The clinical trial infrastructure needs, such as radiopharmaceutical dosimetry and treatment planning, are now available in government workflow and regulatory oversight. This presentation introduces a modern approach to the clinical development of radiopharmaceutical agents in an era of molecular targets and personalized cancer therapeutics.
Citation Format: Charles A. Kunos. Radiopharmaceuticals and their future in cancer care [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr IACC0601.
Abstract LBA012: Engineered mini-livers for high-throughput tumor organoid screening of prodrugs
Authors: Tebon Peyton J , Soragni Alice 
Published: December 2021

Abstract
Several anti-cancer compounds, including chemotherapy and targeted agents such as ifosfamide, cyclophosphamide, and imatinib, are administered as prodrugs which are metabolized to become pharmacologically active. Prodrugs are particularly difficult to study in vitro or ex vivo as many are activated in the liver by Cytochrome P450 enzymes. Preclinical studies of these compounds are restricted to in vivo models, as cancer cells typically do not express the enzymes required to transform prodrugs into their active form. While animal models effectively recapitulate the complexity of systemic drug metabolism and distribution, in vivo studies are time-consuming, expensive, and unsuitable for high-throughput drug screening studies. In previous work, we have developed a platform for screening patient-derived tumor organoids that yields results within a week of surgery (Phan et al, Commun Biol 2, 78, 2019; Nguyen and Soragni, STAR Protoc 1, 2, 2020; Al Shihabi et al, bioRxiv, 2021). Tumor organoids are promising pre-clinical models as they closely recapitulate features of the parent tumor, including drug responses. Here, we expand the physiological relevance of tumor organoid screenings by including mini-livers to metabolize prodrugs of interest. To retain the ability to perform automated, high-throughput screenings, we engineered a miniature liver insert (MLI). The MLI is a removable system that facilitates the addition of liver organoids to specific wells of 96-well plates in which prodrugs are tested. The MLI is designed to integrate with our existing tumor organoid screening platform (Phan et al, Commun Biol 2, 78, 2019; Nguyen and Soragni, STAR Protoc 1, 2, 2020; Al Shihabi et al, bioRxiv, 2021), and allows for simultaneous monitoring of tumor organoids and hepatocytes with brightfield and fluorescent imaging. Hepatocytes seeded in the MLI are viable and maintain their expression of the key Cytochrome P450 enzymes responsible for the metabolism of many clinically used prodrugs. Finally, we demonstrate that incorporating the MLI into prodrug screening experiments sensitizes tumor organoids to treatment with chemotherapeutic and targeted agents. Due to the facile integration with existing screening protocols, the MLI is a simple and effective system for studying anti-cancer prodrugs ex vivo. The MLI is a novel tool that facilitates the co-culture of functional liver organoids with clinically relevant tumor organoid models for drug discovery studies and precision medicine applications.
Citation Format: Peyton J Tebon, Alice Soragni. Engineered mini-livers for high-throughput tumor organoid screening of prodrugs [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA012.
Abstract LBA024: IL-36γ induces immune infiltration and suppresses tumor growth in a syngeneic mouse model for pancreatic cancer
Authors: Halder Kuntal , Von Hoff Daniel D , Han Haiyong 
Published: December 2021

Abstract
Pancreatic cancer (PC) is one of the most aggressive and lethal types of cancer. It is the third leading cause of cancer-related mortality in U.S., accounting for 6% of annual death. Immunotherapeutic strategies such as immune checkpoint inhibitors have shown great success in a number of tumor types, but only with limited activity in patients with PC. Pancreatic tumor is characterized by the presence of dense stromal tissue which primarily consists of immune-suppressive fibroblasts. The immune microenvironment remains dysfunctional due to the lack of tumor infiltrating lymphocytes (TILs) and immune stimulatory molecules. Proinflammatory cytokines play a pivotal role in regulating tumor immunogenicity and antitumor immunity. Elucidating the role of proinflammatory host mediators can contribute to the development of new therapies for PC. IL-36γ, a proinflammatory mediator is important for the IL-23/IL-17-dominated inflammation and induces Th1 immune responses. The role of IL-36γ in pancreatic tumor immunity has not been well studied. In this study, we examined the expression and functional regulation of IL-36γ in PC cells and found that IL-36γ cytokine treatment induces immune infiltration and suppresses tumor growth in a murine PC model. Immunohistochemical (IHC) analysis of pancreatic ductal adenocarcinoma (PDAC) specimens showed minimal IL-36γ positive staining, thus indicating very low expression of IL-36γ in PDAC. Intratumoral treatment with recombinant IL-36γ in a syngeneic mouse model of PDAC significantly inhibited tumor growth (57.8% inhibition after two weeks of treatment) without any significant animal weight loss compared to the vehicle control. Flow cytometry analysis showed increased infiltration of lymphocyte subsets (CD45+ and CD3+ cells) in tumors derived from the IL-36γ treated mice. Further studies are ongoing to investigate the effect of IL-36γ treatment on dendritic cells and macrophages in PDAC tumors. Our study establishes the potential role of IL-36γ in promoting antitumor immune responses and lay the foundation for clinical application in PC (This work was supported by TGen’s Women Philanthropy Council).
Citation Format: Kuntal Halder, Daniel D Von Hoff, Haiyong Han. IL-36γ induces immune infiltration and suppresses tumor growth in a syngeneic mouse model for pancreatic cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA024.
Abstract LBA027: Mechanistic insights on the effects of the lead next generation galeterone analog, VNPP433-3β in castration resistant prostate cancer
Authors: Thomas Elizabeth , Thankan Retheesh S , Purushottamachar Puranik , Njar Vincent C.O. 
Published: December 2021

Abstract
Introduction Metastatic castration-resistant prostate cancer (mCRPC) remains the second leading cause of cancer-related death in men in the United States and the second most frequently diagnosed cancer among males worldwide. Dysregulated androgen receptor (AR) is associated with nearly all known cases of prostate cancer (PCa) and its expression level has been correlated with poor survival. This study describes the mechanism of action of VNPP433-3β, a next generation galeterone analog (NGGA) in inhibiting PCa. Methods PCa cell lines CWR22Rv1 and LNCaP were treated with VNPP433-3β and followed up using cellular thermal shift assay (CETSA), RNA seq, mRNA 5’ cap-binding assay, translation and proteasome inhibition assays. Co-immunoprecipitation, molecular docking and fluorescence spectroscopy were used to study the interactions. Results VNPP433-3β, the lead next generation galeterone analog (NGGA) directly interacts with AR and inhibits metastatic castration resistant PCa (mCRPC) by enhancing degradation of full-length AR (fAR) and its splice variant AR-V7 in a dose-dependent manner. Moreover, VNPP433-3β drives the proteasomal degradation of fAR and AR-V7 by augmenting the interaction between AR and E3 ligases MDM2 & CHIP but disrupting HSP90 binding to AR. VNPP433-3β also impedes eIF4E phosphorylation by depleting MNK1/2 besides disrupting binding of eIF4E and eIF4G to mRNA 5’ cap thereby impeding translational activity of the cancer cells. Finally, the transcriptome analyses by RNA-seq reveal that VNPP433-3β modulates transcription of several genes and activates more than 20 cellular pathways, each of which synergistically contribute to PCa inhibition. Hence, VNPP433-3β obstructs PCa by invoking 1) transcriptional regulation of AR-responsive oncogenes via degrading AR, 2) translational regulation by depleting MNK1/2 thereby impeding phosphorylation of eIF4E and subsequent mRNA 5’cap-dependent translation initiation and 3) affecting AR half-life through enhanced proteasomal degradation. Conclusion As VNPP433-3β promotes degradation of fAR and AR-V7, concurrently depletes Mnk1/2, prevents eIF4E phosphorylation and modulates several cellular pathways to halt PCa, it could potentially be developed for clinical trials in mCRPC patients.
Citation Format: Elizabeth Thomas, Retheesh S Thankan, Puranik Purushottamachar, Vincent C.O. Njar. Mechanistic insights on the effects of the lead next generation galeterone analog, VNPP433-3β in castration resistant prostate cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA027.
Abstract LBA042: Male Sex is an Independent Predictor of Recurrence-Free Survival in Middle Eastern Papillary Thyroid Carcinoma
Authors: AL-KURAYA KHAWLA S. , Parvathareddy Sandeep Kumar , Siraj Abdul K , De Vera Felisa , Annaiyappanaidu Padmanaban , Ahmed Saeeda O. , Al-Sobhi Saif S. , Al-Dayel Fouad 
Published: December 2021

Abstract
Background: Disparity between sexes with regards to incidence, disease aggressiveness, and prognosis has been documented in several cancers. Although various reports have documented the association between male sex and aggressive papillary thyroid carcinoma (PTC), the prognostic impact of sex on PTC has been inconsistent. The role of sex in PTC aggressiveness and outcome in Middle Eastern PTC remains unknown. Therefore, our study retrospectively analyzed the data of a large cohort of Middle Eastern PTC patients to address this issue. Methods: We compared men and women with respect to clinico-pathological characteristics, disease persistence, structural recurrence, risk stratification and prognosis. We included 1430 patient - 1085 (75.9%) women and 345 (24.1%) men. Results: The median follow up was 9.5 years. At diagnosis, 27% (93/345) of men were ≥ 55 years, compared with 17.8% (193/1085) of women (p = 0.0003). Men had significantly more advanced disease at presentation: higher stage (p = 0.0074), larger tumor size (p = 0.0069), higher rates of lymphovascular invasion (p = 0.0129), extrathyroidal extension (p = 0.0086), regional lymph node metastasis (p = 0.0279), and distant metastasis (p = 0.0101). There was a higher rate of recurrence (p &lt; 0.0001) and TERT mutations (p = 0.0003) in male PTC patients than in female patients. Additionally, radioiodine refractoriness was higher in male PTC patients (p = 0.0014). In multivariate analysis, male sex was an independent prognostic factor for poor recurrence-free survival (RFS) (Hazard ratio = 1.59; 95% Confidence interval = 1.21 – 2.07; p = 0.0010). Conclusions: Men with PTC are more likely to present with more advanced and aggressive diseases. Importantly, male sex was an independent prognostic factor for RFS. Thus, men may benefit from more aggressive management and therapeutic interventions.
Citation Format: KHAWLA S. AL-KURAYA, Sandeep Kumar Parvathareddy, Abdul K Siraj, Felisa De Vera, Padmanaban Annaiyappanaidu, Saeeda O. Ahmed, Saif S. Al-Sobhi, Fouad Al-Dayel. Male Sex is an Independent Predictor of Recurrence-Free Survival in Middle Eastern Papillary Thyroid Carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA042.
Abstract LBA043: mRNA expression of mTOR signaling components as potential predictive biomarker in pancreatic neuroendocrine neoplasms
Authors: Wolfshöfer Sebastian , Lock Adrian C , Kaemmerer Daniel , Wirtz Ralph M , Briest Franziska , Haugvik Sven P , Buchholz Malte , Rinke Anja , Arsenic Ruza , Pavel Marianne , Hörsch Dieter , Koch Arend , Grabowski Patricia 
Published: December 2021

Abstract
Medical therapeutic options for the treatment of well-differentiated pancreatic neuroendocrine neoplasms (pNENs) include the mTOR pathway inhibitor everolimus (in combination with 5-Fluorouracil). Criteria to assess prognosis in pNEN patients are still limited, as biomarkers to predict the therapeutic response are still unknown. Several studies could show aberrant mTOR signaling pathway activity at different levels of the signaling cascade in pNENs. In this study, we analyzed the mRNA expression of different mTOR pathway components in well-differentiated pNENs, in order to identify potential prognostic and predictive biomarkers. In this retrospective multicenter study, real-time quantitative TaqMan reverse transcriptase-polymerase chain reaction was used to analyze mRNA expression of eleven different mTOR pathway genes (IGF-1, IGFBP-3, PIK3CA, AKT-1, MTOR, MLST8, DEPTOR, RAPTOR, RICTOR, 4EBP1 und VEGF-A), in tumor tissue of 75 patients with well-differentiated pNENs in comparison to normal pancreatic tissue. Relative gene expression was determined according to the 40-ΔCT method using CALM2 as housekeeping gene. The analysis of mRNA expression levels of the aforementioned eleven genes indicated an increased mTOR signaling activity in pNENs. A distinct linear correlation only occurred between MTOR and AKT-1. Clear association between mRNA expression and a clinical feature was only found for RAPTOR: High RAPTOR mRNA expression was significantly correlated with better overall survival in unselected patients. No prediction to everolimus treatment response could be deduced by mRNA expression analysis in a small subgroup of 21 patients. Even though mRNA expression of different mTOR pathway components indicated an enhanced activity of this signaling cascade in tumor tissue of pNEN patients, we could not identify a statistical significant parameter useful for prediction of everolimus treatment response. The predictive value of this study is limited due to the low number of patients who received treatment with everolimus. Further prospective studies analyzing the predictive value of the expression of mTOR pathway genes are desirable.
Citation Format: Sebastian Wolfshöfer, Adrian C Lock, Daniel Kaemmerer, Ralph M Wirtz, Franziska Briest, Sven P Haugvik, Malte Buchholz, Anja Rinke, Ruza Arsenic, Marianne Pavel, Dieter Hörsch, Arend Koch, Patricia Grabowski. mRNA expression of mTOR signaling components as potential predictive biomarker in pancreatic neuroendocrine neoplasms [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA043.