bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4128: Identification and characterization of LHC165, a TLR7 agonist designed for localized intratumoral therapies
Authors: Deane Jonathan A. , Cortez German A. , Li Chun , Eifler Nora , Kasibhatla Shailaja , Parikh Nehal , Pan Shifeng , Bender Steven 
Published: August 2019

Abstract
Checkpoint inhibition has transformed immunotherapy by alleviating T cell exhaustion in a subset of patients. However, an important component of effective immune targeting to expand the benefit of immune response requires engagement of both innate and adaptive responses. Our understanding of safe and effective engagement of the innate immune system is evolving, with multiple preclinical and clinical agents targeting pathways such the Toll-like Receptors. Here we disclose the structure and preclinical activity of LHC165, a benzonapthyridine TLR7 agonist that is adsorbed to aluminum hydroxide. The interaction between LHC165 and aluminum hydroxide allows for a slow release from the injection site resulting in improved efficacy in mouse models compared with free LHC165. This localization allows for immune activation at the site of the tumor and also results in lower systemic exposure and cytokine induction. Intratumoral studies in syngeneic preclinical studies show single agent activity and a benefit when dosed in combination with checkpoint blockade. LHC165 as a single agent and in combination with PDR001 is currently enrolling patients with advanced malignancies in CLHC165X2101.
Citation Format: Jonathan A. Deane, German A. Cortez, Chun Li, Nora Eifler, Shailaja Kasibhatla, Nehal Parikh, Shifeng Pan, Steven Bender. Identification and characterization of LHC165, a TLR7 agonist designed for localized intratumoral therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4128.
Abstract 4129: Novel small molecule TLR7/8 agonists for enhancing NK cell-mediated ADCC
Authors: Khanna Vidhi , Kim Hyunjoon , Zhang Wenqui , Larson Peter , Ferguson David , Panyam Jayanth 
Published: August 2019

Abstract
Antibody-dependent cell-mediated cytotoxicity (ADCC) is a key mechanism of action for some therapeutic antibodies. ADCC involves killing of an antibody-coated target cell by an effector cell through the release of cytotoxic or cell death-inducing molecules. ADCC is triggered through interaction of Fcγ receptors present on the effector cell surface with the Fc region of the target-bound antibody. Natural killer (NK) cells are one of the primary effector cells that mediate ADCC. There is significant interest in designing therapeutic agents that can enhance ADCC because this can result in improved clinical responses with approved antibodies. We have developed a suite of highly substituted imidazoquinolines, which activate TLR 7 and/or 8 and induce significantly higher levels of cytokines compared to the FDA-approved TLR7 agonist imiquimod. In the current study, we evaluated our series of TLR7-specific, 8-specific and 7/8 dual selective agonists for their ability to improve ADCC with Cetuximab. We investigated NK cell activation in the presence of these compounds, as well as NK cell mediated ADCC against an EGFR expressing lung cancer cell line, A549. In addition, we also measured cytokine induction in human peripheral blood mononuclear cells in response to these compounds. Our studies show dual TLR 7/8 and 8-specific agonists induce robust pro-inflammatory cytokine secretion and activate NK cells. however, mixed agonists also induce greater immunosuppressive cytokines compared to TLR8-specific agonists. Further, these agonists also significantly enhanced Cetuximab mediated ADCC in vitro. In vivo studies examining the anticancer efficacy of the combination of selected TLR7/8 agonists and Cetuximab are ongoing.
Citation Format: Vidhi Khanna, Hyunjoon Kim, Wenqui Zhang, Peter Larson, David Ferguson, Jayanth Panyam. Novel small molecule TLR7/8 agonists for enhancing NK cell-mediated ADCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4129.
Abstract 4137: Circulating TGFâ and TNFá in metastatic breast cancer patients treated with eribulin. The TRANSERI project
Authors: Garrone Ornella , Nigro Cristiana Lo , Michelotti Andrea , Montemurro Fillippo , Vandone Anna Maria , Abbona Andrea , Paccagnella Matteo , Falletta Antonella , Genua Elena , Angelis Claudia De , Tonissi Federica , Vanella Paola 
Published: August 2019

Abstract
Background: Eribulin (E) is approved for the treatment of metastatic breast cancer (mBC) patients (pts) after failure of antracyclines and taxanes. E interferes with microtubule leading to apoptosis and G2/M cell cycle arrest. In human cancer cell lines and in mice, it reverses epithelial mesenchimal transition (EMT) and reduces metastases in mice. TGFβ, an immunosuppressive cytokine, acts as growth factor for cancer-associated fibroblasts (CAFs) and promotes EMT. TNFα synergizes with TGFβ to promote EMT. The TRANSERI study investigates the modifications of TGFβ and TNFα levels in 40 mBC pts treated with E.
Methods: Plasma levels of TGFβ and TNFα were determined by ELISA assay at baseline, before cycle (C) 3, 5 and at disease progression in mBC pts treated with E at 1.23 mg/m2, d 1-8 every 21 d. Statistical analysis of the changes in the longitudinal samples was performed by GraphPad 5. Clinical outcome was monitored according to standard internal follow up procedure.
Results: We report analyses in pts who completed 5 C or progressed before C 5. So far, we have evaluated TGFβ level in 34 pts and TNFα in 26 pts. The median (M) basal TGFβ value was higher in pts than in 9 healthy volunteers (201.9 pg/ml vs 115.1 respectively). At C 5, 14 pts had a decrease in TGFβ with a M value approaching the one of healthy controls (161.9 pg/ml vs 115.1 pg/ml respectively). 19 pts progressed before C 5. Overall 26/33 pts experienced progression. The M value of TGFβ in pts at progression was 293.4 pg/ml. A significant difference of TGFβ was observed between non progressed vs progressed pts (p=0.021). The M TNFα value at baseline was higher in pts than in healthy volunteers, even if in both groups it was close to the lower sensitivity cut-off of the assay. Altogether 20/26 pts experienced progression, that occurred before C 5 in 14 out of them.Intriguingly, at C 5, the TNFα / TGFβ ratio was significantly lower in pts who did not progressed compared to the value at progression (p=0.048).
Conclusions: TGFβ levels changed during treatment with E and correlate with outcome. We are evaluating the role of tumor burden in modulating the TNFα / TGFβ ratio. Definitive data will be presented.
Citation Format: Ornella Garrone, Cristiana Lo Nigro, Andrea Michelotti, Fillippo Montemurro, Anna Maria Vandone, Andrea Abbona, Matteo Paccagnella, Antonella Falletta, Elena Genua, Claudia De Angelis, Federica Tonissi, Paola Vanella. Circulating TGFâ and TNFá in metastatic breast cancer patients treated with eribulin. The TRANSERI project [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4137.
Abstract 4138: Understanding the effects of NF-kappaB signaling on macrophage phenotype to inform therapeutic approaches
Authors: Glass Evan B. , Hoover Alyssa , Harris Whitney , Mirafzali Zahra , Giorgio Todd D. , Wilson Andrew , Yull Fiona 
Published: August 2019

Abstract
It is recognized that modulation of macrophage phenotypes within the tumor microenvironment has the potential to achieve anti-tumor outcomes. However, formulating a strategy to achieve the benefits of such an approach in a cell-specific manner while minimizing off-target or uncontrolled deleterious side effects remains a challenge. We hypothesize that modulation of Nuclear Factor Kappa-B (NF-kappaB) signaling within macrophages in the proximal tumor microenvironment represents an effective approach. However, there remains controversy whether NF-kappaB signaling in macrophages induces pro- or anti-tumor outcomes. Understanding the mechanisms by which this signaling pathway defines predominant macrophage characteristics is therefore critical in order to use strategic interventions to obtain therapeutic benefits. Our goal is to gain insight into how to modulate NF-kappaB signaling in macrophages to generate anti-tumor phenotypes and to use this information to develop new treatments. We use immortalized bone marrow-derived macrophages or ex vivo macrophages in cell culture approaches to investigate impacts of modulation of NF-kappaB signaling on macrophage phenotypes. We have three methods to modulate signaling: doxycycline inducible transgenic mice, liposomal delivery of the bacterial cell mimic MTP-PE, and optimized polymeric nanoparticle-mediated delivery of siRNA targeting the NF-kappaB inhibitor. In addition to our in vitro assays, we also employ in vivo murine models of ovarian and breast tumor progression. This multi-faceted approach is providing insights into how altering NF-kappaB signaling in macrophages impacts their interactions with tumor cells and other cells in the tumor microenvironment. Our data suggests that high levels of NF-kappaB signaling in macrophages induce both direct tumor cell-killing and immune-stimulating responses. These studies are designed to better understand the mechanisms by which NF-kappaB regulates macrophage functions to inform development of a novel macrophage-based immunotherapy that will be effective across a wide spectrum of solid tumors and metastatic disease.
Citation Format: Evan B. Glass, Alyssa Hoover, Whitney Harris, Zahra Mirafzali, Todd D. Giorgio, Andrew Wilson, Fiona Yull. Understanding the effects of NF-kappaB signaling on macrophage phenotype to inform therapeutic approaches [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4138.
Abstract 4157: Idenitificaiton of pathogenic germline variants of patients with double primary cancer of stomach and colon
Authors: Choi Yoon Young , Park Ji Soo , Lee Seung-Tae , Shin Su-Jin , Lee Jae Eun , Jo Jeong-Hyeon , Nam Eun Ji , Son Taeil , Kim Hyoung-Il , Hyung Woo Jin , Noh Sung Hoon , Cheong Jae-Ho 
Published: August 2019

Abstract
Purpose: The incidence of multiple primary cancers has increased as survival of cancer patients has improved. The most common type of multiple primary cancers is the combination of stomach and colon cancer in Korea. Patients affected by two primary cancers at early age would be mainly related to their own genetic risk, however, germline variant of patients with double primary cancer have not been well evaluated.
Methods: Patient who is with pathologically confirmed cancers in both stomach and colon in Severance hospital between January, 2000 and December, 2016 were enrolled in this study. The patients were classified into two groups: early-age group was defined as both cancers were diagnosed before 55-years, and others were considered as late-age group. The overall early-age group (n=19) and randomly selected a fourth of late-age group (n=36) were enrolled in this study. The DNA was extracted from an archived formalin fixed paraffin embedded normal mucosa that was retrospectively reviewed. Target sequencing analysis focused on 65 genes that are known to be related to hereditary cancer was conducted. The characteristics of both cancers and family history were also evaluated.
Results: Overall 11 pathogenic/likely pathogenic germline variants (PGVs) were detected in nine patients (16.4%, 9/55, MLH1 [n=7], BLM [n=1], BRCA1 [n=1], MSH6 [n=1], and MSH2 [n=1]). The incidence of PGVs was 36.8% (7/19) and 5.6% (2/36) in early and late-age group, respectively (p&lt;0.001). The early-age (Odds ratio[OR]: 9.92, 95% confidence interval [CI]: 1.81-54.49, p=0.008), Amsterdam_II criteria (OR: 24.29, 95% CI: 2.45-241.36, p=0.006), multiple lesions either gastric and colon cancer (OR: 13.13, 95% CI: 2.48-69.55, p=0.002) and mucinous/poorly differentiated histology of colon cancer (OR: 10.75, 95% CI: 1.48-78.06, p=0.019) were significant risk factors of PGVs in patients with double primary cancer at stomach and colon.
Conclusions: The Lynch syndrome related PGVs were identified in patients with double primary cancer at stomach and colon. Patients with double primary cancers at stomach and colon related to early age, multiple lesions, family history especially Amsterdam_II criteria, and poorly differentiated histology of colon cancer would be good candidate for genetic evaluation.
Citation Format: Yoon Young Choi, Ji Soo Park, Seung-Tae Lee, Su-Jin Shin, Jae Eun Lee, Jeong-Hyeon Jo, Eun Ji Nam, Taeil Son, Hyoung-Il Kim, Woo Jin Hyung, Sung Hoon Noh, Jae-Ho Cheong. Idenitificaiton of pathogenic germline variants of patients with double primary cancer of stomach and colon [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4157.
Abstract 4168: Identify the predisposition genes to endometrial cancer
Authors: Chiang Yu-Cheh , Lee Ting-Fang , Lin Yung-Feng , Weng Hui-Ying , Tsai Shih-Feng , Wu Cheng-Wen 
Published: August 2019

Abstract
Endometrial carcinoma is the most dominant gynecological tumor worldwide. Familial risk of endometrial cancer has been reported but little is known about the predisposition genes. Here we focused on a family with high incidence of cancer, aiming to identify potential markers with low allele frequency and high disease-causing probability. Whole-genome sequencing was performed with available DNA from 4 family members: one healthy control and 3 endometrial cancer patients. We analyzed the non-synonymous variations in the coding region expressed in 3 of the patients but not in the healthy control. The variations with high allele frequencies in Taiwanese population were excluded. Five potential candidates, KMT2D, PCDHA8, COG5, RAPGEF3 and PFDN1, were identified as heterozygous mutations predisposed to endometrial cancer. In addition, we demonstrated that PCDHA8 and COG5 genes play crucial roles in cell proliferation in endometrial cancer cells. Notably, KMT2D (lysine methyltransferase 2D) is highly mutated in the tumors of endometrial cancer. An interaction between mutated KMT2D and other candidate genes may explain the high risk of cancer formation in this family. These results validate the potential markers of endometrial cancer and create opportunities for therapeutic applications and personalized prevention.
Citation Format: Yu-Cheh Chiang, Ting-Fang Lee, Yung-Feng Lin, Hui-Ying Weng, Shih-Feng Tsai, Cheng-Wen Wu. Identify the predisposition genes to endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4168.
Abstract 4171: Identification of individuals with colonic polyposis in a highly inbred region
Authors: Lajus Tirzah Braz Petta , Timoteo Ana Rafaela 
Published: August 2019

Abstract
Familial adenomatous polyposis (FAP), also known as colonic polyposis, is a hereditary autosomal dominant disease, responsible for only 1% of colorectal cancer (CRC) in the population. FAP patients with a germline mutation in the APC gene have a 100% risk of developing CRC. MAP (Mutyh associated polyposis) is the polyposis associated with biallelic mutations in the MUTYH gene, and carriers are at risk of developing CRC. Few studies propose heterozygous Mutyh mutation is associated with high risk for breast cancer, but the results are conflicting. In the city Caicó, Brazil, we identified 8 non-related breast cancer patients with the same mutation c.536A&gt;G, p.Tyr179Cys. In this region we find high frequencies of consanguineous marriages, which varied from about 9% to 32%, suggesting a direct association to genetic diseases. We hypothesize the founding mutation MUTYH_c.536A&gt;G was established during Dutch colonization in Brazil between 1620 and 1650. For this, we are developing a population-based, case-control study of all newly diagnosed breast cancer in this city. In our group we have one oncologist, one psychologist and one geneticist. We recruited the patients (index-cases) from the archives in the Laboratory of Pathology at the Hospital Liga contra o Cancer and we invited the individuals to participate in the research.
Citation Format: Tirzah Braz Petta Lajus, Ana Rafaela Timoteo. Identification of individuals with colonic polyposis in a highly inbred region [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4171.
Abstract 4179: Identification of BRCA1 and BRCA2 mutation spectrum and their founder effect in epithelial ovarian cancer from Middle East
Authors: Siraj Abdul K. , Bu Rong , Iqbal Kaleem , Siraj Nabil , Alrasheed Maha , Ghazwani Laila , Masoodi Tariq , Parvathareddy Sandeep Kumar , Al-Kuraya Khawla S. 
Published: August 2019

Abstract
Epithelial ovarian cancer (EOC) remains the most fatal gynecological malignancies. Germline mutations in Breast Cancer susceptibility gene 1 and 2 (BRCA1 and BRCA2) have previously been estimated to contribute to 13-18% of all EOC. The prevalence and influence of BRCA1 and BRCA2 mutations in EOC in Middle Eastern population is not fully explored. Ethnic differences of ovarian cancer genomics have prompted us to investigate the spectrum of BRCA1 and BRCA2 mutations among our Middle Eastern EOC patients. To characterize the prevalence of BRCA mutations in our patients, BRCA mutation screening was performed in over 400 unselected ovarian cancer patients using Capture and/or Sanger sequencing. Seventeen short tandem repeat (STR) markers were used for founder mutation analysis. A total of 19 different types of pathogenic mutations were identified in 50 cases (40 mutant cases in BRCA1 and 10 in BRCA2). Nine mutations were recurrent accounting for 80% (40/50) of all mutant cases (9.8% (40/407) of the entire cohort). Haplotype analysis carried out on all unrelated cases with these mutations revealed only two (c.4136_4137 delCT and c.1140 dupG) sharing the same haplotypes thus representing founder Saudi mutations. Remarkably, lifetime risk estimation for these founder mutations appears to approach 100% given their complete absence in healthy controls. BRCA1 mutant cases were significantly associated with positive family history (p &lt;0.0001), grade 3 tumors (p = 0.0003) and loss of BRCA1 protein expression (p &lt;0.0001). 85.0% (34/40) of all BRCA1 mutant cases were of serous histology. BRCA2mutant cases were associated with loss of BRCA2 protein expression (p=0.0102) and a trend towards younger age (p=0.0505). Identification of the mutation spectrum, prevalence and founder effect in Middle Eastern population facilitates genetic counseling, risk assessment and development of cost-effective screening strategy.
Citation Format: Abdul K. Siraj, Rong Bu, Kaleem Iqbal, Nabil Siraj, Maha Alrasheed, Laila Ghazwani, Tariq Masoodi, Sandeep Kumar Parvathareddy, Khawla S. Al-Kuraya. Identification of BRCA1 and BRCA2 mutation spectrum and their founder effect in epithelial ovarian cancer from Middle East [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4179.
Abstract 4186: Aggressive prostate cancer among men in Pennsylvania: Differences between Appalachian and non-Appalachian counties
Authors: McDonald Alicia C. , Wasserman Emily , Lengerich Eugene J. , Raman Jay D. , Geyer Nathaniel , Hohl Raymond , Wang Ming 
Published: August 2019

Abstract
Introduction: The incidence of prostate cancer (PC) is known to vary within Appalachia, with Northern Appalachia and Southern Appalachia having higher and lower rates, respectively. However, the geographical disparity for aggressive PC has not been investigated. The objective of this study was to determine whether having more aggressive PC was associated with residing in an Appalachian/non-Appalachian county and rural/urban community.
Methods: A cross-sectional study was conducted among men, aged &gt = 40 years, who had a primary, clinical PC diagnosis identified in the Pennsylvania Cancer Registry between 2004 and 2014. PC aggressiveness was defined as less aggressive (Gleason score 6 or 7 [3+4] and clinical/pathologic tumor stage T1-T2) and more aggressive (Gleason score &gt = 7 [4+3], clinical/pathologic tumor stage T3-T4, or distant metastasis) PC. Logistic regression analysis was used to examine the association between having aggressive PC (less vs more aggressive PC - dependent variable) and residing in a geographical region (Appalachian versus non-Appalachian county - independent variable), stratified by rural/urban, after adjusting for age, race, ethnicity, insurance status, marital status, serum PSA, positive lymph node status, and cancer treatment.
Results: There were 94,264 PC cases, aged 40 to 105 years, included in the study. The majority of the PC cases were white (83.9%) followed by black race (10.7%). PC cases from urban Appalachian counties (35.42%) had the highest frequency of aggressive PC followed by rural non-Appalachian (34.18%), rural Appalachian (32.12%), and urban non-Appalachian counties (32.08%). In urban areas, Appalachian PC cases were more likely to be aggressive compared to non-Appalachian PC cases, after adjusting for confounders (odds ratio [O.R.] =1.16; 95% confidence interval [C.I.], 1.13-1.21). Conversely, in rural areas, Appalachian PC cases were less likely to be aggressive compared to non-Appalachian PC cases, after adjusting for confounders (O.R. =0.91; 95% C.I., 0.85-0.98).
Conclusion: Differences in having more aggressive PC was observed for Appalachian populations by rural/urban status, with urban Appalachian PC cases more likely and rural Appalachian PC cases less likely to have more aggressive disease, compared to their non-Appalachian counterparts. Further investigation on the underlying mechanisms of aggressive PC in urban Appalachia in PA is warranted.
Citation Format: Alicia C. McDonald, Emily Wasserman, Eugene J. Lengerich, Jay D. Raman, Nathaniel Geyer, Raymond Hohl, Ming Wang. Aggressive prostate cancer among men in Pennsylvania: Differences between Appalachian and non-Appalachian counties [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4186.