bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2630: Meta-analysis of pazopanib and trabectedin in 2L+ metastatic synovial sarcoma (2L+ mSS)
Authors: Carroll Charlotte , Patel Nashita , Gunsoy Necdet B. , Parks Dan , Stirnadel-Farrant Heide A. , Pokras Shibani
Published: July 2021

Background: Pazopanib (P) and trabectedin (T) are approved targeted treatments for metastatic soft tissue sarcoma (mSTS). Our objective was to evaluate the efficacy (from clinical trials [CT]) and effectiveness (from real-world studies [RW]) of P and T in second line (2L+) mSS.

Methods: This meta-analysis included all English language studies assessing P or T efficacy/effectiveness in patients with 2L+ mSS, 1999 onwards, identified by a systematic literature review. Outcomes were overall response rate (ORR) representing the proportion of patients who have achieved CR or PR during the study and median overall survival (mOS) in months (mos) from start of study medication. Proportions from studies were pooled using generalized linear mixed models to account for small sample sizes, zero events and random site effects. Medians were combined using the weighted median of the medians method with 95% confidence intervals from an inverted sign test.

Results: 16 studies with 405 patients with 2L+ mSS met the inclusion criteria. Response was measured variably across studies (CT: RECIST v1.0, v1.1; RW: modified RECIST or clinician assessment). ORR estimates were higher in RW than CTs (Table). OS results were consistent across CTs and RW (Table).

Conclusions: This is the first study to provide estimates for patients with mSS in the 2L+ setting, distinct from mSTS and pool outcomes of targeted therapies. RW estimates of ORR for both treatments were higher than those observed in trials likely due to variable definition of response and in underlying prognostic factors. mOS was consistent across both types of studies and was similar to mOS seen on placebo (10.7 mos in PALETTE study) suggesting a high unmet need in this population.

Funding: GSK (213368).

Outcomes with pazopanib (P) and trabectedin (T) in clinical trials (CT) and real-world (RW) studiesPTP & T pooledORR-ALL (%)N=6, n=96, 18.9 (8.5, 41.8)N=7, n=162, 12.3 (8.0, 18.9)N=13, n=258, 14.7 (9.2, 23.4)ORR-CT (%)N=1, n=38, 13.2 (2.4, 23.9)†N=3, n=57, 7.0 (2.7, 18.1)N=4, n=95, 9.5 (5.1, 17.6)ORR-RW (%)N=5, n=58, 20.2 (7.4, 54.8)N=4, n=105, 15.2 (9.7, 23.9)N=9, n=163, 17.7 (9.9, 31.5)mOS-ALL (mos)N=4, n=96, 10.3 (8.7, 13.8)N=4, n=165, 9.9 (1.5, 13.9)N=8, n=261, 9.9 (9.2, 13.9)mOS-CT (mos)ND*ND*N=3, n=113, 10.3 (8.7, 13.9)mOS-RW (mos)ND*ND*N=5, n=148, 9.9 (9.2, 13.9)*Not done due to small sample size; †results of study since N=1. N=number of studies; n=number of patients. Estimates presented with 95% confidence intervals.

Citation Format: Charlotte Carroll, Nashita Patel, Necdet B. Gunsoy, Dan Parks, Heide A. Stirnadel-Farrant, Shibani Pokras. Meta-analysis of pazopanib and trabectedin in 2L+ metastatic synovial sarcoma (2L+ mSS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2630.
Abstract 2660: The gene mutation profile in HCC patients with different AFP levels at diagnosis
Authors: Kui Xiang , Wu Liqun , Ke Yang , Wang Yan , Li Hai , Zhao Juan , He Tingting , Wang Lin
Published: July 2021

Background: Alpha-fetoprotein (AFP) blood level in Hepatocellular carcinoma (HCC)is an important marker widely used in clinical practice. Although different AFP levels indicate the different prognosis of HCC patients, the gene mutation profile is still unclear. The research was to conduct a comprehensive study of the gene mutation profile in HCC patients with different AFP levels at diagnosis.

Methods: Retrospective analysis was carried out on medical records of HCC patients who had received a hepatectomy between January 2016 and December 2018. Formalin-fixed, paraffin-embedded (FFPE) HCC tissues and matched blood samples were collected for targeted next-generation sequencing (NGS) assay at OrigiMed (Shanghai, China), a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Genomic variants including single nucleotide variations (SNV), short/long insertion/deletions (Indel), copy number alterations and gene rearrangements were analyzed.

Results: A total of 180 HCC cases were enrolled in the study. The patients were categorized into AFP<10ng/ml (n=63) group, 10ng/ml≤AFP<1000ng/ml (n=71) group, and AFP≥1000ng/ml (n=46) group. The higher AFP level at diagnosis was positively correlated with younger incidence age (P=0.012), lower blood glucose (P=0.008), larger diameter of tumor nodules (P=0.006), more microvascular invasion (P=0.01), higher grade of tumor differentiation (P<0.001), poorer overall survival (P=0.023), and recurrence free survival (P=0.007). AXIN1 mutation frequency significantly increased with the rise of the APF level: AFP<10ng/ml (7.9%), 10ng/ml≤AFP<1000ng/ml (25.4%), and AFP≥1000ng/ml (42.2%, P<0.001), while TP53 mutation frequency decreased with the rise of the AFP level: AFP<10ng/ml (65.1%), 10ng/ml≤AFP<1000ng/ml (57.7%), and AFP≥1000ng/ml (48.9%) with only near significance (P=0.095) among three groups. Furthermore, we identified 11q13 (FGF3, FGF4, FGF19, CCND1) amplification frequency increased with AFP level: AFP<10ng/ml 4.8%, 10ng/ml≤AFP<1000ng/ml 12.7%, and AFP≥1000ng/ml 20.9%, P=0.015.

Conclusion: We demonstrated AXIN1 mutation frequency increased with the rise of the AFP level. Because these AXIN1 mutations can result in inactivating the AXIN1 protein and the AXIN1 is a known negative regulator of the Wnt/β-catenin signaling pathway, we reason that the Wnt/β-catenin signaling pathway has a deleterious effect on the poor prognosis in the higher AFP groups, and/or directly on the rise of the AFP level.

Citation Format: Xiang Kui, Liqun Wu, Yang Ke, Yan Wang, Hai Li, Juan Zhao, Tingting He, Lin Wang. The gene mutation profile in HCC patients with different AFP levels at diagnosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2660.
Abstract 2840: HK1 induces epithelial-mesenchymal transition and promotes metastasis of colorectal cancer
Authors: Zheng Xiaobin , Liu Huashan , Zhong Xiaoli , Liu Xuanhui , Cai Zerong , Chen Yufeng , He Xiaosheng , Lan Ping , Wu Xiaojian
Published: July 2021

Hexokinase 1 (HK1) has been implicated in tumorigenesis. However, its role in tumor metastasis and progression has not been evaluated. The aim of this study is to evaluate the role of HK1 in the metastasis in CRC.

Methods: The expression level of HK1 was detected using quantitative RT-PCR and western blot in 9 CRC cell lines and 1 human colon epithelial cell line NCM460 (Figure 1A). HK1 was overexpressed via lentiviral vector system and silenced using specific small interference RNA (si-HK1) in DLD1 and HCT8. Then wound-healing, migration assay and invasion assay were carried out to investigate the function of HK1 in CRC cells. RT-PCR and Western blot was performed to detect the change of Snail2 following the up-regulated expression of HK1.

Results: HK1 expression was overexpressed by HK1-cDNA and was inhibited by si-HK1 in DLD1 and HCT8 (Figure 1B and 1C). Ectopic expression of HK1 promoted cell migration and invasion in CRC cells and promoted lung metastasis in mouse models (Figure 1D). Furthermore, HK1 induced migration and invasion in CRC cells was found to activate expression of Snail2 and in turn, induce epithelial-mesenchymal transition (EMT) and cancer progression (Figure 1E).

Conclusions: High expression of HK1 could activate expression of Snail2 and in turn, induce EMT. Our findings suggest that HK1 may be a potential prognostic biomarker and therapeutic target for CRC invasion and metastasis.

Keywords: Colorectal Cancer, HK1, Migration, Invasion

Figure 1. A. The expression level of HK1 in 10 cell lines. B, C. HK1 expression was overexpressed by HK1-cDNA and was inhibited by si-HK1 in DLD1 and HCT8. *P< 0.05. D. Overexpression of HK1 in HCT8 increased the capacity of cell migration and invasion in vitro and in vivo. E. Expression levels of Snail2 and EMT were induced after HK1 overexpression.

Citation Format: Xiaobin Zheng, Huashan Liu, Xiaoli Zhong, Xuanhui Liu, Zerong Cai, Yufeng Chen, Xiaosheng He, Ping Lan, Xiaojian Wu. HK1 induces epithelial-mesenchymal transition and promotes metastasis of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2840.
Abstract 2869: Blockade of oxidative phosphorylation by metformin promotes anoikis
Authors: Adeshakin Funmilayo Oladunni , Zhang Guizhong , Adeshakin Adeleye O. , Wan Xiaochun
Published: July 2021

Metastasis remains the foremost cause of death in cancer patients. Cells with metastasizing potentials are equipped to evade anoikis, a form of cell death resulting from cell detachment from extracellular matrix. Evasion of anoikis signals avails cells the ability to detach, migrate, and invade secondary sites, colonizing these sites thereby promote cancer metastasis. Cellular reprogramming has been identified as a crucial factor for tumor metastasis and yet to be fully explored. Our data showed upregulation in oxidative phosphorylation (OXPHOS) related genes in detached cells compared to adherent cells, suggesting that OXPHOS activity may enhance resistance to anoikis. Accordingly, treatment with metformin, a mitochondrial complex 1 inhibitor promoted anoikis in different cancer cells (cervical cancer - Hela, breast - MCF7, melanoma -B16F10 and Lewis Lungs carcinoma - LLC). Furthermore, metformin decreased spheroid formation, repressed ATP production, accumulated misfolded protein, and sensitized cells to anoikis via activation of caspase 3 and ROS production. More importantly, targeting OXPHOS with metformin inhibited pulmonary tumor metastasis, impaired lung nodules formation, and reduced lung weight in the B16F10 tumor model of balb/c nude mice. Collectively, our findings suggest therapeutic targeting of energy metabolism using metformin as a promising approach to enhance anoikis and attenuate tumor metastasis.

Citation Format: Funmilayo Oladunni Adeshakin, Guizhong Zhang, Adeleye O. Adeshakin, Xiaochun Wan. Blockade of oxidative phosphorylation by metformin promotes anoikis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2869.
Abstract 3053: Armed oncolytic virus for treatment of pediatric diffuse intrinsic pontine glioma
Authors: Gupta Sumit , Laspidea Virginia , Fueyo Juan , Becher Oren , Nguyen Teresa , Shin Dong Ho , Jiang Hong , Sohoni Sagar , Fan Xuejun , Yi Yanhua , Gumin Joy , Lang Frederick , Gomez-Manzano Candelaria , Alonso Marta M.
Published: July 2021

Diffuse Intrinsic Pontine Glioma (DIPG) is the leading cause of pediatric death by brain tumors with a median survival of only 9 months, in spite of the current standard of therapy which includes radiation. The purpose of our study is to explore the use of oncolytic adenoviruses as a new therapeutic modality. Our group is leading a phase I clinical trial in naive DIPGs treated with the oncolytic adenovirus Delta-24-RGD, also named DNX-2401 (NCT03178032), which results are still pending. Of interest, clinical trials using Delta-24-RGD in adult gliomas resulted in encouraging results with long-term survivors and the presence of a strong anti-tumor immunity. In this study, we aim to test the effect of armed Delta-24-RGD with immune costimulatory ligands such as GITRL (Delta-24-GREAT) and OX-40L (Delta-24-RGDOX or DNX-2440) for the treatment of DIPGs. We used a panel of murine DIPG cell lines (NP53 and XFMA) to test the effect of these armed-oncolytic adenoviruses. Infectivity assay using an Ad-RGD-GFP vector and flow cytometry showed the expression of the ectopic GFP in more than 80% of the NP53 cells (50 MOIs) and XFMA cells (30 MOIs). Consistent results were obtained using flow cytometry and western blot to detect the expression of the ectopic ligands GITRL and OX-40L in these cultures. These cells were semipermissive for viral replication as assessed by the detection of the viral structural protein hexon in western blot analysis. Preliminary in vivo data using immunocompetent mice models where DIPG cells have been implanted into the pons showed a dose-dependent effect and the generation of immune memory. Our results suggest that oncolytic adenoviruses expressing positive immunocheckpoints might prove be a new effective modality for treating DIPG and hence, increase survival in children suffering this dismal disease.

Citation Format: Sumit Gupta, Virginia Laspidea, Juan Fueyo, Oren Becher, Teresa Nguyen, Dong Ho Shin, Hong Jiang, Sagar Sohoni, Xuejun Fan, Yanhua Yi, Joy Gumin, Frederick Lang, Candelaria Gomez-Manzano, Marta M. Alonso. Armed oncolytic virus for treatment of pediatric diffuse intrinsic pontine glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3053.
Abstract 3067: Exploring strategies to modulate mitochondrial metabolism to alleviate tumor hypoxia
Authors: Benej Martin , Wu Jinghai , Kreamer McKenzie , Vibhute Sandip , Papandreou Ioanna , Denko Nicholas C.
Published: July 2021

Radiation therapy is a standard type of treatment modality used as a part of curative or palliative treatment in more than 50% of all cancer patients. However, tumor hypoxia reduces the effectiveness of radiation therapy by limiting the biologically effective dose. Here, we explore and compare strategies to alleviate hypoxia by modifying the oxygen supply or demand within mouse tumor models. We used pODD-Luc, a dynamic in vivo luciferase reporter system that monitors relative levels of tumor hypoxia in real time. We show that in mouse tumor models, contrary to the reported results of human clinical trials, acute manipulation of systemic oxygen delivery significantly reduces the level of hypoxia. We then examined pharmacological manipulation of oxygen demand, which is an emerging trend in therapeutic efforts to sensitize tumors to anti-cancer therapy. Mitochondrial oxygen consumption (OCR) constitutes more than 90% of cellular oxygen demand by coupling carbon source oxidation with ATP generation in a series of redox reactions transferring electrons from reduced cofactors to molecular oxygen. Mechanistically, a decrease in mitochondrial OCR would lead to increased oxygen availability within the tumor, allowing initially hypoxic areas to become re-oxygenated. We found that strategies that directly stimulate mitochondrial OCR exacerbate levels of hypoxia while OCR suppression in turn promotes tumor re-oxygenation. We have previously shown that papaverine, an FDA-approved phosphodiesterase 10A (PDE10A) inhibitor effectively reduces hypoxic tumor fractions in vivo by an off-target effect that inhibits mitochondrial complex I. Here we show that its novel derivative SMV-32 that acts as complex I inhibitor with reduced PDE10A effect mediates superior OCR inhibition in both orthotopic and heterotopic mouse tumor models. These findings further establish the direct impact of OCR manipulation on tumor hypoxia and support the role of mitochondrial metabolism as an attractive target to alleviate tumor hypoxia and overcome treatment resistance.

Citation Format: Martin Benej, Jinghai Wu, McKenzie Kreamer, Sandip Vibhute, Ioanna Papandreou, Nicholas C. Denko. Exploring strategies to modulate mitochondrial metabolism to alleviate tumor hypoxia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3067.
Abstract 483: TIGIT/PVR/NECTIN immune checkpoint axis expression across breast cancer subtypes
Authors: DuPree Kelly J. , Molinero Luciana
Published: July 2021

Background: Targeting the PD1:PD-L1 pathway revolutionized treatment options for patients with metastatic triple negative breast cancer (TNBC). Other immune checkpoint inhibitors are being investigated in clinical settings, such as anti-TIGIT antibodies. The goal of this analysis was to evaluate the expression of the TIGIT/PVR/NECTIN molecule family in breast cancer subtypes.

Methods: We used the publicly available METABRIC dataset (Curtis C, Nature 2012; Pereira B, Nature Comm 2016) to evaluate microarray RNA expression levels for TIGIT, CD226, PVR, PVRIG, NECTIN2, NECTIN3, NECTIN4, PDCD1 and CD274 from primary breast tumors annotated with ER, PR and HER2 IHC status (Hormone receptor positive [HR+]: n=1369; HER2 amplified [HER2+]: n=236; TNBC: n=299). Biomarker association with overall survival (OS) was evaluated using Cox proportional hazard analysis adjusted for clinical covariates.

Results: Expression of the TIGIT/PVR/NECTIN members revealed three expression patterns across breast cancer subtypes: 1) highest in TNBC, followed by HER2+ and then by HR+ BC (PVR); 2) similar levels in TNBC and HER2+, and higher than HR+ BC (TIGIT, CD226, PVRIG, NECTIN4); 3) highest in HR+, followed by HER2+ and then by TNBC (NECTIN2). NECTIN3 showed the lowest expression differences across subtypes. Correlation of these genes with each other varied: 1) Receptors TIGIT, CD226 and PVRIG were moderately correlated with each other and with PDCD1 (Pearson correlation index [r]: 0.45 - 0.78) and strongly correlated with the T cell markers CD3E, CD8A, and GZMB (r: 0.53 - 0.90); 2) PVR family ligands PVR, NECTIN2, NECTIN3 and NECTIN4 were not correlated with each other, nor to the receptors or biomarkers for T-cell, macrophage or stromal biology (r: -0.36 - 0.30). CD274, the PD1 ligand, was weakly associated with TIGIT, CD226, PVRIG, PDCD1 and with immune cell markers (0.25 - 0.38). This pattern was similar across breast cancer subtypes. No OS prognostic value was observed for the TIGIT/PVR family members in HR+ or HER2+ BC. Only CD226 was associated with an improved OS in TNBC (HR: 0.69 [0.48-0.99]). As expected, PDCD1, CD274, and T-cell biomarkers were linked to improved OS prognosis (HR: 0.61-0.69), observed only in TNBC.

Conclusions: Overall, RNA expression levels of TIGIT/PVR/NECTIN family members are higher in HER2+ and TNBC compared to HR+ in the large breast cancer METABRIC dataset. While TIGIT, CD226 and PVRIG are clearly associated with T cells, the cell subsets expressing the PVR/NECTIN ligands remain to be defined in breast cancer. Our analysis suggests that TNBC and HER2+ are the breast cancer subtypes more likely to benefit from anti-TIGIT therapeutic targeting.

Citation Format: Kelly J. DuPree, Luciana Molinero. TIGIT/PVR/NECTIN immune checkpoint axis expression across breast cancer subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 483.
Abstract 498: ZL-1201, a differentiated CD47 therapeutic antibody with improved hematological safety profile
Authors: Wan Bing , Fang Xu , Li Shou , Shi Wenhua , Li Holly , Bellovin David , Wang Lei , Zhu Yusong , Lin Yuan , Qi Shali , Yin Sophia , Tao Frank , Kang Lishan , Kabbarah Omar , Zhou Haiying , Veiby Petter , Yan James , Hsu Karl
Published: July 2021

The interaction between CD47 that is overexpressed on tumor cells and SIRPα on macrophages facilitates a “don't-eat-me” signal that inhibits macrophage-mediated phagocytosis of tumor cells. Blockade of the CD47/SIRPα interaction using antibodies against CD47 or SIRPα-Fc fusion proteins promotes phagocytosis and tumor cell destruction, which represents a promising strategy for tumor immunotherapy. However, CD47 is ubiquitously expressed on all cells including erythrocytes and platelets, which form a large antibody sink and lead to potential hematological toxicities. In fact, anemia and thrombocytopenia have been observed in non-human primates and tumor patients that are subjected to anti-CD47 treatment in preclinical and clinical studies. We have developed ZL-1201, a recombinant, humanized monoclonal antibody that specifically targets CD47. ZL-1201 was engineered to reduce Fc-mediated antibody effector function. Preclinical in vitro studies show that ZL-1201 displays potent binding to CD47 thereby blocking interaction with SIRPα and effectively facilitates macrophage-mediated phagocytosis of hematological and solid tumor cells. Importantly, ZL-1201 induces minimal red blood cell (RBC) phagocytosis and does not induce hemagglutination, though it does bind to human RBCs and platelets. In vivo studies demonstrate that ZL-1201 possesses potent antitumor efficacy in rodent xenograft tumor models, while displaying remarkably improved hematological safety profile as compared with the benchmark antibody in a toxicology study in cynomolgus monkeys. Thus, ZL-1201 treatment represents an effective CD47-targeting therapy with improved hematological safety consequences. A Ph1 dose escalation study to assess the safety of ZL-1201 is currently ongoing in patients with solid tumors, and future combination studies are planned for both hematologic and solid tumor indications.

Citation Format: Bing Wan, Xu Fang, Shou Li, Wenhua Shi, Holly Li, David Bellovin, Lei Wang, Yusong Zhu, Yuan Lin, Shali Qi, Sophia Yin, Frank Tao, Lishan Kang, Omar Kabbarah, Haiying Zhou, Petter Veiby, James Yan, Karl Hsu. ZL-1201, a differentiated CD47 therapeutic antibody with improved hematological safety profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 498.
Abstract 704: Sex and age differences in telomere length and susceptibility to COVID-19
Authors: Kamal Manar Ahmed , Alamiry Kareem Reda , Zaki Mahmoud
Published: July 2021

Background: Telomeres are the ends of a chromosome and play a fundamental role as vanguards contra the chromosomal decay. Due to the inability of DNA polymerase to replicate chromosomal ends, a reduction in telomeres length happens after each cell division. The existence of shorter telomeres in older people is related to diminished immune functions. Viral infections able to stimulate remodeling of cells, stress responses, and telomere shortening. Moreover, telomere shortening can be caused by extrinsic environmental variables which induce oxidative stress under conditions of inflammation.

Aim: To identify the correlation between telomere shortening and susceptibility to Novel Coronavirus Disease 2019 (COVID-19). In addition to clarifying changes in telomere length according to the viral infection, the effect of sex and age differences in telomere length in confirmed positive COVID-19 cases are also reviewed.

Conclusion: There is a correlation between telomere length and COVID-19 infection with higher susceptibly of elderly patients and males due to shortening in their telomere length. Approximately 53% of (111,428) infected cases (≥50) years old are males, and 47% of (111,428) infected cases (≥50) years old are females.

Citation Format: Manar Ahmed Kamal, Kareem Reda Alamiry, Mahmoud Zaki. Sex and age differences in telomere length and susceptibility to COVID-19 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 704.
Abstract 714: From cancer to COVID-19- development of a dendritic cell-targeted nano-vaccine for prevention and therapy of COVID-19
Authors: Vaskovich-Koubi Daniella , Kleiner Ron , Liubomirski Yulia , Yeini Eilam , Tiram Galia , Pozzi Sabina , Eldar-Boock Anat , Florindo Helena F. , Satchi-Fainaro Ronit
Published: July 2021

Dendritic cells (DC) are antigen-presenting cells with an important role in the initiation and regulation of the innate and adaptive arms of the immune system. By efficient presentation of antigens, DC elicit an antigen-specific immune response. Therefore, we previously established in our laboratory a melanoma-DC-targeted NP that was evaluated and validated against aggressive melanoma. Although DC-therapy is mainly exploited in the treatment of cancer, DC are becoming a key therapeutic target in other pathologies such as infectious diseases. Viral pathogens, similarly, to cancer, modulate the host defense mechanisms to their benefit. COVID-19, an ongoing pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally and is already infecting tens of millions of people worldwide. Historically, vaccines are among therapies with the greatest impact in health and constitute an unmet medical need against coronavirus disease-19 (COVID-19) pandemic. To that end, we repurposed our recently published melanoma-targeted NP to co-deliver modulators of host immune response and SARS-CoV-2 specific antigen epitopes discovered by a computational approach integrating 3D information with large-scale statistical analysis. The immune response kinetics in patients infected with SARS-CoV-2 is poorly understood, but recent reports show that germinal B cells and active follicular T-helper cells, IgM/IgG SARS-CoV-2 antibodies, in addition to an enhanced cellular immunity, are found in patients with mild-to-moderate SARS-CoV-2 infection. Our preliminary data demonstrated that our nano-vaccine was able to activate specific immune cell response of effector T cells and B cells and decrease the regulatory activity of T cells, compared to controls. Moreover, we found that our DC-targeted SARS-CoV-2 NP successfully induced antigen-specific secretion of IgM and IgG antibodies with high binding affinity to the antigens. Importantly, our nano-vaccine elicited specific neutralization of Spike virus like particles (VLPs) by sera of immunized mice. We hypothesize that implementing our novel nano-vaccine platform for COVID-19 will lead to a safe and efficacious COVID-19 vaccine ready for first-in-human clinical trials.

Citation Format: Daniella Vaskovich-Koubi, Ron Kleiner, Yulia Liubomirski, Eilam Yeini, Galia Tiram, Sabina Pozzi, Anat Eldar-Boock, Helena F. Florindo, Ronit Satchi-Fainaro. From cancer to COVID-19- development of a dendritic cell-targeted nano-vaccine for prevention and therapy of COVID-19 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 714.
Abstract 786: Geography and adolescent and young adult cancer stage and survival
Authors: Johnson Kimberly J. , Wang Xiaoyan , Barnes Justin , Delavar Arash
Published: July 2021

Background. Survival improvement in adolescents and young adults (AYA) diagnosed with cancer has lagged behind other age groups. Few studies have focused on geographic factors and outcomes in AYA. Our objective was to evaluate evidence for geographic disparities in cancer diagnosis stage and overall survival in AYAs. We also examined whether stage mediated survival associations.

Methods. National Cancer Database data on AYA 15-39 years diagnosed from 2010-2014 were obtained. Rural/metro residence at diagnosis was defined using Rural Urban Continuum Codes. Distance between the case's residence and the reporting hospital was classified as short (<12.5 miles), intermediate (>12.5 and <50 miles), and long (>50 miles). Logistic and Cox proportional hazards regression models were used for analyses.

Results. The stage and survival analyses included 146,418 and 178,688 AYA. The odds of a late vs. early stage diagnosis (stages 3 and 4 vs. 1 and 2) were 1.22 (95% CI 1.10 to1.35) times higher for AYA living in rural vs. metro counties and 1.23 (1.19 to1.28) times higher for AYA living at long vs. short distances. The hazard of death was 1.18 (1.04 to 1.34) and 1.37 (1.31 to 1.43) times higher for those living in rural vs. metro counties and for long vs. short distances. Stage mediated 41% and 27% of the associations between survival and rural/metro residence and residential distance.

Conclusions. Rural residence and living long distances from the reporting hospital were associated with later-stage diagnoses and lower survival in AYA cancer patients. Further research is needed to understand mechanisms.

Citation Format: Kimberly J. Johnson, Xiaoyan Wang, Justin Barnes, Arash Delavar. Geography and adolescent and young adult cancer stage and survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 786.
Abstract 852: Index-based dietary patterns and risk of pancreatic ductal adenocarcinoma: Results from the NIH-AARP Diet and Health Study
Authors: Julián-Serrano Sachelly , Reedy Jill , Robien Kim , Stolzenberg-Solomon Rachael
Published: July 2021

Background: There is limited-suggestive evidence for individual dietary components, and few studies have examined whether dietary patterns are associated with pancreatic cancer risk.

Objective: We examined the associations between five established index-based dietary quality patterns and pancreatic ductal adenocarcinoma (PDAC) risk in middle aged and older US adults.

Methods: The Healthy Eating Index (HEI)-2015, Alternative HEI-2010 (AHEI-2010), alternate Mediterranean diet (aMED), and two Dietary Approaches to Stop Hypertension (DASH) scores (Fung et al. and Mellen et al.) were calculated using responses from a food frequency questionnaire data from 535,398 (315,780 men and 224,044 women) NIH-AARP Diet and Health Study participants aged 51-70 years at baseline (1995-1996). Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for PDAC risk according to each dietary pattern quintile. Covariates included in multivariable models were age, sex, smoking, body mass index, diabetes, and energy intake.

Results: During follow-up though 2011 (15.5 years median), 3,137 incident PDAC cases were identified. Participants with the highest adherence scores compared to those with the lowest adherence scores for each dietary pattern (Q5 versus Q1), had a significantly lower risk of PDAC, except for AHEI-2010: HRs (95% CIs) for HEI-2015 [0.84 (0.75, 0.94)], aMED [0.82 (0.73, 0.93)], DASH-Fung [0.86 (0.77, 0.96)], DASH-Mellen [0.86 (0.77, 0.99)] and AHEI-2010 [0.93 (0.83, 1.04)]. Sex-stratified analyses showed stronger results in men for the HEI-2015 [0.78 (0.68, 0.90)], DASH-Fung [0.78 (0.67, 0.91)], and DASH-Mellen [0.82 (0.71, 0.95)] indices. Only the aMED score remained statistically significantly associated with PDAC risk in women [0.76 (0.63, 0.92)]. Tests for interaction by sex were not significant (P-values > 0.07).

Conclusions: In this analysis of dietary patterns and PDAC, we observed a 14-24% lower cancer risk with greater adherence to index-based dietary quality patterns. Our findings support the hypothesis that adherence to dietary recommendations such as the Dietary Guidelines for Americans, Harvard's Healthy Eating Plate, the Mediterranean Diet and the DASH diet may reduce the risk of developing PDAC

Citation Format: Sachelly Julián-Serrano, Jill Reedy, Kim Robien, Rachael Stolzenberg-Solomon. Index-based dietary patterns and risk of pancreatic ductal adenocarcinoma: Results from the NIH-AARP Diet and Health Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 852.
Abstract 925: Introduction to the preclinical profile of SYD1875, a novel site-specifically conjugated duocarmycin-based 5T4-targeting antibody-drug conjugate
Authors: Groothuis Patrick , Jacobs Danielle , Berentsen Kim , van der Vleuten Monique , Coumans Ruud , Elgersma Ronald , Blomenrohr Marion , van den Dobbelsteen Diels , Beusker Patrick , Ubink Ruud , van der Lee Miranda , Dokter Wim H.A.
Published: July 2021

5T4 is an oncofetal antigen with low expression in healthy tissues which is frequently overexpressed in different tumor types. Despite its overexpression in various malignancies and its association with poor prognosis, there are currently no marketed drugs that target this tumor antigen. We developed a novel antibody-drug conjugate (ADC), named SYD1875, comprising a humanized, HC41-cysteine-engineered IgG1 monoclonal antibody directed against 5T4, site-specifically conjugated to a proprietary cleavable synthetic duocarmycin-based linker-drug (vc-seco-DUBA). SYD1875 showed sub-nanomolar binding affinity to human and cynomolgus 5T4, rapid internalization, and induction of both target- and bystander-mediated cell killing. SYD1875 showed superior in vitro cytotoxicity and in vivo activity compared to A1-mcMMAF -also known as PF-6263507-, a 5T4-targeting ADC that is no longer in clinical development. A single dose of SYD1875 induced strong anti-tumor activity in patient-derived xenograft models of multiple tumor types with low, moderate and high 5T4 expression. The GLP toxicity study in cynomolgus monkey showed an acceptable toxicity and PK profile. A first-in-human dose-finding trial was initiated to evaluate safety and explore efficacy (NCT04202705).

Citation Format: Patrick Groothuis, Danielle Jacobs, Kim Berentsen, Monique van der Vleuten, Ruud Coumans, Ronald Elgersma, Marion Blomenrohr, Diels van den Dobbelsteen, Patrick Beusker, Ruud Ubink, Miranda van der Lee, Wim H.A. Dokter. Introduction to the preclinical profile of SYD1875, a novel site-specifically conjugated duocarmycin-based 5T4-targeting antibody-drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 925.
Abstract 948: Preclinical evaluation of VEGF Ang2 bispecific nanobody BI836880 in patient-derived xenograft models of nasopharyngeal carcinoma
Authors: Wong Eric Chi , Lam Gigi , Wong Connie , Lam Rachel C. , Lo Kwok Wai , Hui Edwin Pun , Chan Anthony Tak , Ma Brigette B.
Published: July 2021

BI836880 is a humanized bispecific nanobody directed against angiopoietin-2 (Ang2) and vascular endothelial growth factor (VEGF)-derived peptides, with selective and potent antiangiogenic and antineoplastic activities. It comprises of blocking domains that bind to Ang2 and VEGF and prevents Ang2- and VEGF-mediated signalling; thus, inhibits both angiogenesis and tumour cell proliferation. Tumor angiogenesis contributes to progression of nasopharyngeal cancer (NPC) and VEGF/receptor inhibitors agents have activity in NPC patients. In this study, the preclinical activity of a novel VEGF/Ang-2 bi-specific nanobody, BI836880, was evaluated in two NPC-PDX models - Xeno-2117 and Xeno-666. The effect of BI836880 on tumor growth was compared with the control, bevacizumab - an anti-VEGF antibody which has been evaluated in NPC patients. Tumor-bearing mice were randomized into three groups: vehicle control, 15mg/kg bevacizumab (b.i.w) and 15mg/kg BI836880 (b.i.w.). Drug was administered by intraperitoneal injection and the treatment duration was four weeks. Tumor sizes and body weights were monitored by caliper and balance, respectively.

The results showed that BI836880 was very well tolerated in mice, with no signs of stress and loss of weight observed during the treatment. At day 14, the mean tumor volumes of BI836880, bevacizumab vs vehicle control was 264.5±36.0, 290.0±32.4 vs 697.38±88.4 mm3 in Xeno-666 (p<0.001, BI836880 vs control), and 293.5±39.3, 319.6±37.6 vs 1016.8±107.6 mm3 in Xeno-2117 (p<0.0001, BI836880 vs control), respectively. Angiogenesis marker CD34 was analyzed by IHC staining and the microvessel densities were calculated by Image J. The results showed that BI836880 could significantly reduce the numbers of microvessels to a comparable extent as bevacizumab in NPC model. In addition, BI836880 had increased the tumor internal necrotic area by 118.7% compared to vehicle control in Xeno-2117 (p=0.0148), but the effect was insignificant in Xeno-666 (p=0.5467).

In conclusion, BI836880 can inhibit NPC growth to an extent that is comparable to bevacizumab, further investigation in combination with cytotoxic or immunotherapeutic agents are warranted.

Citation Format: Eric Chi Wong, Gigi Lam, Connie Wong, Rachel C. Lam, Kwok Wai Lo, Edwin Pun Hui, Anthony Tak Chan, Brigette B. Ma. Preclinical evaluation of VEGF Ang2 bispecific nanobody BI836880 in patient-derived xenograft models of nasopharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 948.
Abstract 971: Chaperone-mediated protein degradation (CHAMP): A novel technology for tumor-targeted protein degradation
Authors: Foley Kevin P. , Ye Long , Wang Mingkai , Ying Chenghao , Yin Wei , Zhang Lingjie , Ying Weiwen
Published: July 2021

The HSP90 chaperone mediates folding of many important client proteins and mutated oncoproteins, but can also direct its substrates towards degradation by the ubiquitin-proteasome system. Further, in tumor tissues, HSP90 complexes are in a highly activated state relative to normal tissues, which results in HSP90-binding small molecule compounds displaying unique tumor-selective pharmacokinetics. In order to take advantage of these attributes of HSP90 to degrade the transcription factor BRD4 in a tumor-selective fashion, hetero-bifunctional small molecule compounds were synthesized, termed chaperone-mediated protein degraders (CHAMPs), that chemically induced proximity between BRD4 and HSP90. In vitro, treatment of MV-4-11 leukemia cells with a BRD4-CHAMP compound resulted in formation of a BRD4:CHAMP:HSP90 ternary complex and subsequent proteasome-dependent BRD4 degradation and inhibition of cell proliferation. CHAMPs were identified that induced selective degradation of BRD4 and displayed only minimal effects on other HSP90-regulated client proteins. While BRD4 is a known HSP90 client protein, non-HSP90 clients such as mutated KRAS could also be degraded using this approach. In vivo, in the MV-4-11 mouse xenograft model, a selective BRD4-CHAMP compound displayed prolonged pharmacokinetics in tumors relative to plasma and normal tissues, with its tumor concentration remaining above the in vitro cytotoxicity EC50 value for at least 7 days following a single dose. This resulted in greater than 90% and prolonged degradation of BRD4 in tumors, as well as decreased expression of the BRD4-regulated MYC gene. Treatment with BRD4-CHAMP at its MTD resulted in dramatic tumor regressions after a single dose and the majority of tumors were undetectable following 3 weekly doses. In contrast, daily dosing of a clinical stage pan-BET inhibitor at its MTD resulted in stable to progressive disease, indicating that BRD4-CHAMP has a greatly improved therapeutic index in this model. CHAMP technology has a number of advantages relative to other targeted protein degradation approaches, such as PROTAC, including an improved safety margin due to selective accumulation in tumor tissues.

Citation Format: Kevin P. Foley, Long Ye, Mingkai Wang, Chenghao Ying, Wei Yin, Lingjie Zhang, Weiwen Ying. Chaperone-mediated protein degradation (CHAMP): A novel technology for tumor-targeted protein degradation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 971.
Abstract CT134: A phase I study of avelumab, palbociclib, and cetuximab (APC) in recurrent or metastatic head and neck squamous cell carcinoma (RM HNSCC)
Authors: Gold Kathryn A. , Sacco Assuntina , Bykowski Julie , Daniels Gregory , Pittman Emily , Messer Karen , Chen Ruifeng , Cohen Ezra
Published: July 2021

Background: Checkpoint inhibitors have activity in RM HNSCC, but response rates to single agent therapy are low. Combination therapy may improve outcomes. We aimed to study a novel combination of palbociclib (P) and cetuximab (C) with the PD-L1 inhibitor avelumab (A) in RM HNSCC. Methods: Eligible patients (pts) with RM HNSCC received P in combination with A 10 mg/kg IV every 2 wks and C 400 mg/m2 IV x 1, then 250 mg/m2 weekly. The starting dose of P was 75 mg PO daily on days 1 to 21 of a 28 day cycle. The 3+3 dose escalation design included planned doses of P 100 mg and P 125 mg, with no intra-patient escalation. The primary objective was to identify the recommended phase II dose (RP2D); secondary objectives included response rate and progression free survival (PFS). Results: As of 10/15/20, 12 pts have been treated in 3 cohorts: P 75 mg PO daily (3 pts), 100 mg PO daily (3 pts), and 125 mg PO daily (6 pts). Median age was 56 yo, 92% were male, with 58% p16+, 25% p16-, 17% p16 unknown. One DLT was observed in cohort 3: a grade 3 infusion reaction related to C. The RP2D was P 125 mg, with A and C at standard doses. Other grade 3 AEs were leukopenia (4 pts), neutropenia (4 pts), acneiform rash (2 pts), cellulitis (1pt), increased WBC (1pt). One pt had grade 4 leukopenia. There were no grade 5 AEs. Tx related AEs occurring in > 30% of pts were: acneiform rash (11pts), fatigue (10pts), mucositis (7pts), dry skin (6 pts), decreased WBCs (5 pts), paronychia (5 pts), nausea (5pts), hypomagnesemia (4pts). Response rate by RECIST 1.1 was 42% (3 CRs, 2PRs); median duration of response has not been reached. Median PFS was 6.5 m. Reasons for discontinuation were disease progression (8 pts), pt choice (1 pt). 3 patients remain on therapy (after 20, 15, and 9 months). Conclusions: The combination of APC was well tolerated in patients with RM HNSCC; no unexpected toxicities were seen. The RP2D is A 10 mg/kg every 2 wks, C 400 mg/m2 x 1 then 250 mg/m2 wkly, and P 125 mg daily, 3 wks on, one wk off. Promising response rates were seen, and several pts have had durable responses. These data support further development of this combination. Biomarker analyses on tissue and blood are ongoing. NCT03498378.

Citation Format: Kathryn A. Gold, Assuntina Sacco, Julie Bykowski, Gregory Daniels, Emily Pittman, Karen Messer, Ruifeng Chen, Ezra Cohen. A phase I study of avelumab, palbociclib, and cetuximab (APC) in recurrent or metastatic head and neck squamous cell carcinoma (RM HNSCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT134.
Abstract LB074: Chymostatin, a cathepsin L inhibitor, inhibits lung cancer cell proliferation and COVID-19 Mpro in vitro
Authors: Yarla Nagendra Sastry , Pathuri Gopal , Terzyan Simon , Zhang Yuting , Singh Anil , Scotti Marcus T. , Madka Venkateshwar , Rao Chinthalapally V.
Published: July 2021

Lung cancer patients are more vulnerable to COVID-19 infection. Treatment of patients with lung cancer during the current COVID-19 pandemic is challenging and development of drugs for COVID-19 and lung cancer is urgently needed. Cathepsin L plays key role in lung cancer progression, invasion and more so, endocytosis of SARS-Cov-2 virus into the lung epithelial cells. Importantly, patients with KrasG12V mutation show agreessive disease and high-resistance to chemotherapy due to over-expression of Cathepsin L. Thus, Cathepsin L is a common target for lung cancer and COVID-19 infection. Chymostatin is a known cathepsin L inhibitor, here we screened it for dual inhibition of COVID-19 Mpro and lung cancer patients with COVID-19. In vitro COVID-19 Mpro fluorometric assay was performed to evaluate its inhibitory efficacy by chymostatin. Chymostatin showed dose-dependent inhibition of COVID-19 Mpro activity with IC50 of 15.81 µM (P<0.0001). Isothermal titration calorimetry based binding studies determined that chymostatin strongly bound to COVID-19 Mpro (KD=22.45 µM). CD spectrum analysis demonstrated that chymostatin (10 µM)-induced changes in the secondary structure of COVID-19 Mpro. A unit cell crystal parameter COVID-19 Mpro co-crystalized with chymostatin (a = 49.926 Å, b = 108.71 Å, c = 56.49 Å, α = 90.0°, β = 102.7553°, γ = 90.0°; unit cell volume: 299.03 Ao) was determined using X-ray diffractometer. Molecular docking studies demonstrated that chymostatin interacts with active site amino acids (Cys145). Pro-apoptotic effect of chymostatin was evaluated on human H441 lung cancer cells and mouse lung normal epithelial cells using Annexin V/propidium iodide staining. Chymostatin did not show any cytotoxicity on normal mouse lung epithelial cells up to 100 µM, where as it inhibited proliferation of human H441 lung cancer cells (KrasG12V mutant) with IC50 of 1.2 µM. In conclusion, preliminary in vitro studies demonstrated that naturally occurring cathepsin L inhibitor chymostatin is a SARS-CoV-2 Mpro inhibitor and exhibited anticancer activity against lung cancer cells. The results of the study warranted detailed studies to develop as drugs for lung cancer patients during COVID-19 pandemic (supported by VPR-PHF, the University of Oklahoma Health Sciences Centre for financial support through COVID-19 seed grant program).

Citation Format: Nagendra Sastry Yarla, Gopal Pathuri, Simon Terzyan, Yuting Zhang, Anil Singh, Marcus T. Scotti, Venkateshwar Madka, Chinthalapally V. Rao. Chymostatin, a cathepsin L inhibitor, inhibits lung cancer cell proliferation and COVID-19 Mpro in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB074.
Abstract LB097: MET inhibitor enhances efficacies of gemcitabine and olaparib in pancreatic cancer cells
Authors: Chen Meikuang , Gao Yuan , Yu Dihua , Hung Mien-Chie
Published: July 2021

Gemcitabine is one of the current first-line chemotherapy agents in pancreatic cancer treatment. However, the response rate of pancreatic cancer patients to gemcitabine treatment is lower than 20%. Among the potential targeted therapies for pancreatic cancer patients, PARP inhibitor (Olaparib) has been approved by the U.S. Food and Drug Administration for maintenance treatment of metastatic pancreatic adenocarcinoma patients with germline BRCA-mutation. Taking advantages of the high oxidative stress in most pancreatic cancer cells, therapeutic agents that enhance the burden of oxidative DNA damages in these cancer cells can be introduced in novel treatment strategies. Because c-MET overexpression positively correlates with poor prognosis in pancreatic cancer, and our previous studies show that oxidative stress induced-nuclear c-MET phosphorylates PARP1 to reduce oxidative DNA damages, we focused on developing novel treatment strategies by combining c-MET inhibitors (crizotinib and tivantinib) with either gemcitabine or olaparib. In this study, we found that gemcitabine induced nuclear accumulation of c-MET, and that tivantinib reduced c-MET mediated PARP1 phosphorylation in both BxPC-3 and L3.6pl pancreatic cancer cell lines. We also found that combination of tivantinib with either gemcitabine or Olaparib induced more DNA damages than the single agent treatments. Further, we demonstrated the synergistic effects of c-MET inhibitors combined with gemcitabine or Olaparib in pancreatic cancer cell lines, suggesting that combining c-MET inhibitor with PARP inhibitor or gemcitabine is a novel and rational therapeutic strategy for pancreatic cancer treatment.

Citation Format: Meikuang Chen, Yuan Gao, Dihua Yu, Mien-Chie Hung. MET inhibitor enhances efficacies of gemcitabine and olaparib in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB097.