bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2190: Engineering off-the-shelf T cell receptor fusion construct (TRuC) T cells
Authors: Donaghey Julie , Kieffer-Kwon Philippe , Patterson Troy , Chan Tiffany , Horton Holly , Tighe Robert , Gutierrez Dario A. , Getts Daniel , Hofmeister Robert 
Published: September 2020

Abstract
The T-Cell Receptor (TCR) can be functionally split into antigen recognition mediated by the TCRα/β heterodimer and signal transduction triggered by the CD3 complex comprising CD3ϵ/γ, CD3ϵ/δ and CD3ζ/ζ dimers. Unlike antibodies, the TCR recognizes its cognate peptide antigen only when presented on human leukocyte antigen (HLA) molecules. Recently, we reported that tethering an antibody-derived binder to one of the TCR subunits redirects T cells to specifically kill tumor cells independent of HLA. Different from CAR-T cells, the T cell receptor fusion constructs (TRuC™) are integrated into the natural TCR and require all TCR subunits for receptor translocation to the cell surface. The development of off-the-shelf TRuC-T cells is desirable to shorten the vein-to-vein production time and reduce manufacturing costs. Here, we describe the generation of TRuC-T cells expressing a fully functional TRuC TCR without alloreactivity. Inactivation of the endogenous TRAC gene employing CRISPR/Cas9 endonuclease disrupts natural TCR formation. Yet, replacing the endogenous TCRα subunit with a human TCRα constant region without variable domain to avoid alloreactivity is insufficient for TRuC TCR expression. A functional TRuC TCR, however, can be created by substituting the following constructs for the inactivated TRAC gene: (i) murine TCRα and β constant domains without variable domains, (ii) chimeric human/murine TCRα and β constant regions or (iii) TCRγ and δ constant domains. Off-the-shelf TRuC-T cells upregulate activation markers, secrete cytokines, and kill tumor cells in an antigen-specific manner. Importantly, the genome-engineered TRuC-T cells lack alloreactivity as demonstrated in mixed lymphocyte reactions and clear tumors in NSG xenograft models without signs of Graft versus host disease (GvHD). Our findings warrant further development of allogeneic TRuC-T cells for cancer therapy.
Citation Format: Julie Donaghey, Philippe Kieffer-Kwon, Troy Patterson, Tiffany Chan, Holly Horton, Robert Tighe, Dario A. Gutierrez, Daniel Getts, Robert Hofmeister. Engineering off-the-shelf T cell receptor fusion construct (TRuC) T cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2190.
Abstract 2266: SAR442085, a next generation anti-CD38 antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) against multiple myeloma
Authors: Virone-Oddos Angela , Kassem Sahar , Diallo Béré , Tang Alexandre , Fournier Alain , El-Murr Nizar , Carrie-Constantin Nadege , Nicolazzi Céline , Arnould Isabelle , Avet-Loiseau Hervé , Sidhu Sukhvinder S. , Martinet Ludovic , Chiron Marielle 
Published: September 2020

Abstract
CD38 is a cell surface glycoprotein highly expressed in multiple myeloma (MM) cells making it an attractive target for antibody–based therapy. Anti–CD38 treatment represents a major breakthrough in the treatment of relapsing and refractory multiple myeloma (RRMM) patients. However, a number of patients do not respond to anti–CD38 single agent therapy stressing the need for novel approaches. Here we describe SAR442085, a next generation anti–CD38 antibody, with higher affinity for the activating FcγRIIIa and FcγRIIa receptors expressed on effector cells as compared to the approved anti–CD38 antibody daratumumab, resulting in greater effector functions. SAR442085 targets CD38 with high affinity and is able to destroy CD38 expressing tumor cells in vitro through effector function mechanisms (ADCC and antibody dependent cellular phagocytosis, ADCP) as well as by direct apoptosis. SAR442085 exhibits better ADCC activity as compared to daratumumab with more than 8–fold EC50 improvement against RPMI–8226 MM cells. SAR442085 also inhibits CD38 enzymatic activity. Using primary bone marrow aspirates from MM patients, an increased ability of SAR442085 to engage CD16 was demonstrated, resulting in a higher level of NK cell activation and degranulation against primary plasma cells, as compared to daratumumab. In addition, SAR442085 demonstrated potent in vivo single–agent activity against murine tumor cells expressing human CD38, in a transgenic C57BL/6 mouse model humanized for all Fcγ receptors, with 90% mice survival at 10 and 1.25 mg/kg and up to 90 days median survival time. Overall, these data support the current evaluation of this next generation anti–CD38 antibody in phase I clinical trials in patients with relapsed/refractory MM.
Citation Format: Angela Virone-Oddos, Sahar Kassem, Béré Diallo, Alexandre Tang, Alain Fournier, Nizar El-Murr, Nadege Carrie-Constantin, Céline Nicolazzi, Isabelle Arnould, Hervé Avet-Loiseau, Sukhvinder S. Sidhu, Ludovic Martinet, Marielle Chiron. SAR442085, a next generation anti-CD38 antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) against multiple myeloma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2266.
Abstract 227: Maltose enhanced the growth of bladder and colon cancer cells unlike some other disaccharides: Cellobiose, isomaltose, lactose, and sucrose
Authors: Lea Michael A. , desBordes Charles 
Published: September 2020

Abstract
The addiction of most cancer cells to the metabolism of glucose is well known. The metabolism by cancer cells of other saccharides is less well characterized. We have studied the impact on growth of human bladder and colon cancer cells of mono- and disaccharides. The standard RPMI 1640 medium contains 2 mg glucose per ml. Substitution for glucose by other monosaccharides (fructose, galactose and mannose) resulted in similar growth in some cell lines but greatly diminished growth in others. For the Caco-2 and HT29 colon cancer cells, co-incubation with 2-deoxyglucose was more inhibitory for growth with fructose than with glucose as substrate. There was a similar situation with some bladder cancer cell lines (5637, HT1197 and RT4) whereas with other bladder cancer cells (HT1376, T24 and UM-UC-3) 2-deoxyglucose caused greater inhibition with glucose. In those cell lines in which alkaline phosphatase activity could be induced after incubation with butyrate (Caco-2, HT29, 5637, HT1197 and HT1376), induction by butyrate was observed with any of the monosaccharides. Similarly with the disaccharides lactose, maltose and trehalose there was induction of alkaline phosphatase by butyrate. In the course of this work it was apparent that maltose could enhance growth to an extent that was sometimes not significantly different to that seen with glucose and was not seen with cellobiose, isomaltose, lactose or sucrose. HT29 cells were the only cell line to have a substantial increased growth with trehalose. The increased growth with maltose was inhibited by 2-deoxyglucose. In conclusion, maltose increased growth of bladder and colon cancer cells without a period of adaptation.
Citation Format: Michael A. Lea, Charles desBordes. Maltose enhanced the growth of bladder and colon cancer cells unlike some other disaccharides: Cellobiose, isomaltose, lactose, and sucrose [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 227.
Abstract 23: Precision medicine approaches to Fanconi anemia oral cancer personalized prevention and treatment
Authors: Swenson Daniel K. , Wuertz Beverly R. , Ali Mustafa M. , Unger Gretchen M. , Ondrey Frank G. 
Published: September 2020

Abstract
There is an increased risk of oral cavity and other head and neck cancers as Fanconi patients live longer post transplantation. DNA repair defects in Fanconi patients contribute to “field effect” in this population, which causes frequent recurrences and often fatal, second primary oral malignancies. These developments show a need for translation of new basic science concepts for this patient population. We are examining the effects of both Metformin and Pioglitazone, and Polo kinase and Wee Kinase inhibitors in Fanconi anemia oral cancer cell lines, and leukoplakia control cells.
We employed 3 FA oral cancer cell lines for the current study. We performed clonogenic and cell proliferation (MTT) experiments in replicates and repeated those experiments to establish initial dose responses of the inhibitors at biologically relevant concentrations. We used ANOVA analysis with a P&lt;0.05 as our level of significance. Concurrently, we are examining pioglitazone-metformin signaling pathways in biopsies from precancerous oral lesion (non-FA) patients treated with pioglitazone in our multiple chemoprevention clinical trials via confocal fluorescence microscopy.
We found both the Wee Kinase inhibitor and POLO kinase inhibitor resulted in dose dependent decreases in proliferation and clonogenic potential in several experiments in all cell lines. We observed decreased proliferation at 72 hours at clinically achievable serum levels of 75%. However, we also observed cytotoxic effects as well, as judged by MTT reading at 72 hours being lower than the original Day 0 MTT readings. Pioglitazone treatment also resulted in dose dependent decreases in cell proliferation and clonogenic potential at clinically achievable serum levels. Similar effects can be achieved with metformin, however, at higher doses. Additionally, we have identified surrogate endpoints as suitable pharmacodynamic readouts by IHC analysis of the cell lines.
There are precision medicine treatments for FA-associated oral carcinoma and these are feasible, based on earlier promising results we present here. We are attempting to discover new treatment methodologies for these patients, as conventional agents and radiation therapy are often unacceptable, due to the DNA fragility of the patient population. In combination, these efforts support our future goals of chemoprevention in this underserved prevention population.
Citation Format: Daniel K. Swenson, Beverly R. Wuertz, Mustafa M. Ali, Gretchen M. Unger, Frank G. Ondrey. Precision medicine approaches to Fanconi anemia oral cancer personalized prevention and treatment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 23.
Abstract 2344: Composite score of healthy lifestyle factors and risk of hepatocellular carcinoma: Findings from a prospective cohort study
Authors: Luu Hung N. , Wang Renwei , Behari Jaideep , Adams-Haduch Jennifer , Odegaard Andrew O. , Bee George Goh , Jin Aizhen , Koh Woon-Puay , Yuan Jian-Min 
Published: September 2020

Abstract
Background. While the associations between individual lifestyle factors and risk of hepatocellular carcinoma (HCC) were examined substantially, their combined impact on HCC risk has not been evaluated.
Methods. The association of a composite score of healthy lifestyle factors, including body mass index, alcohol consumption, cigarette smoking, alternative Mediterranean Diet (aMED), and sleep duration, with the risk of developing HCC was examined in the Singapore Chinese Health Study (SCHS), an on-going prospective cohort of 63,257 Chinese men and women aged 45-74 at enrollment in 1993-1998 with up to 25 years of follow-up. Cox proportional hazard regression method was used to estimate hazard ratio (HR) and its 95% confidence interval (CI) of HCC with the composite score after adjustment for multiple potential confounders. The unconditional logistic regression method was used to confirm the association between the composite lifestyle score and HCC risk among hepatitis B surface antigen (HBsAg) negative individuals to eliminate its potential confounding effect.
Results. After a mean follow-up of 17.7 years, 561 participants of the SCHS developed HCC. Individuals with higher composite scores, which represented for healthier lifestyles, were at significantly lower risk of HCC. Compared with the lowest composite score (i.e., 0-4), the HRs (95% CIs) for 5, 6, 7 and 8 were 0.48 (0.36-0.64), 0.44 (0.34-0.67), 0.37 (0.28-0.48), and 0.26 (0.17-0.39), respectively (Ptrend&lt;0.001). A similar inverse association was observed in participants with negative HBsAg serology; HR was 0.12 (95% CI: 0.04-0.38) for the highest versus the lowest category of the composite scores (Ptrend=0.01).
Conclusion. Healthy lifestyles are protective against the development of HCC, especially for individuals without viral infection. This finding highlights the importance of a comprehensive lifestyle modification strategy for primary prevention of HCC.
Funding: The Singapore Chinese Health Study was supported by the National Institutes of Health (NIH) of the United States (grants # R01 CA144034 and UM1 CA182876).
Citation Format: Hung N. Luu, Renwei Wang, Jaideep Behari, Jennifer Adams-Haduch, Andrew O. Odegaard, George Goh Bee, Aizhen Jin, Woon-Puay Koh, Jian-Min Yuan. Composite score of healthy lifestyle factors and risk of hepatocellular carcinoma: Findings from a prospective cohort study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2344.
Abstract 2356: Novel and recurrent germline mutations in Colombian families with colorectal cancer syndromes
Authors: Rivera-Herrera Ana Lucía , Gómez-Camargo Ana Milena , Serrano-López Martha Lucía , Carvajal-Carmona Luis G. , Sanabria-Salas María Carolina 
Published: September 2020

Abstract
Hereditary colorectal cancer (CRC) syndromes accounts for approximately 5-10% of total CRC cases. Among those, Lynch syndrome (LS) is the most frequent, but the penetrance depends on the mismatch repair gene (MMR) affected. On the other hand, the Familial Adenomatous Polyposis (FAP) syndrome is less frequent, but with penetrance near to 100%. In Colombia we don't know the prevalence of these syndromes. In the National Cancer Institute from Colombia, the largest reference cancer center in the country, we aim to performed germline genetic analyses in Colombian CRC patients with a suspected hereditary cancer syndrome, as part of the Hereditary Cancer Program that seeks to identified high risk families to offer preventive measures and screening recommendations. A total of 66 patients with CRC fulfilling criteria have been so far analyzed with Next Generation Sequencing using a multigene panel. From those, the 32% have negative results, 41% have VUSs and 27% have positive results (meaning a pathogenic or potentially pathogenic genetic variant). The most prevalent CRC syndrome is Lynch (11/18, 61% with MMR mutated genes), followed by polyposis syndromes such as FAP (11% APC) and MAP (1.5% biallelic MUTYH). Most of our Lynch syndrome families fulfilled Bethesda or Amsterdam criteria. Two recurrent mutations in MLH1 were found in Lynch syndrome families (6/11, 54.5%), which are MLH1: c.1918C&gt;T (p.Pro640Ser) and MLH1: c.790+1G&gt;A. Further haplotype analysis will help us to determine if mutation carriers shared a common ancestry.
Citation Format: Ana Lucía Rivera-Herrera, Ana Milena Gómez-Camargo, Martha Lucía Serrano-López, Luis G. Carvajal-Carmona, María Carolina Sanabria-Salas. Novel and recurrent germline mutations in Colombian families with colorectal cancer syndromes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2356.
Abstract 2379: Elaborating the mechanism of PARP synthetic lethality in ATM loss
Authors: Muvaffak Asli , Coleman Kevin G. 
Published: September 2020

Abstract
PARP inhibitors have transformed the treatment for ovarian cancer, which is known to have high incidence of homologous recombination (HR) deficiency through the loss of BRCA1 or BRCA2 genes. 30-35% of ovarian cancer patients have defects in BRCA1/2 genes caused by germline, somatic or epigenetic alterations. PARP inhibitors induce cell death in HR-deficient cells through the mechanism of synthetic lethality where cancer cells cannot tolerate the loss of both SSB and DSB repair machinery. Although genetic or epigenetic alterations in other pathways such as Fanconi anemia, or in non-authentic homologous recombination repair (HRR) genes such as PTEN, IDH, and CDK12 have been reported to contribute to HR deficiency, mechanistic understanding of HR loss remains to be determined. Another DNA damage repair (DDR) protein, ATM, a kinase that phosphorylates and activates major DNA damage checkpoints, i.e. CHK2 & BRCA1, has also being increasingly recognized recently as a synthetic lethal partner with PARP inhibitors in multiple tumor indications such as prostate, lung and colorectal cancers. ATM functions in both cell cycle arrest and DNA repair in response to DSBs, however how cells respond to inhibition of PARP in the absence of ATM is not yet fully understood. In this study, we demonstrated that loss of ATM function, i.e. via generating an ATM KO by CRISPR/Cas9 in two genetic backgrounds, i.e. in DLD-1 and HeLa cell lines, induced HR-deficiency indicated by the impairment of Rad51-foci formation and increased phosphorylation of histone H2AX in ATM KO (-/-) cell lines. Furthermore DLD-1 ATM KO (-/-) cell line demonstrated increased sensitivity to niraparib (i.e. 45-fold difference in sensitivity compared to the DLD-1 parental, HR-proficient cell line) in the 14day colony formation assay. In comparison, BRCA2 (-/-) KO in DLD-1 gave a 125-fold increase compared to parental cell line. In DLD-1 ATM KO (-/-) cell line, we have also detected that loss of ATM was associated with low BRCA1 and BRCA2 protein expression suggestive of downstream effect on impairment of HR-mediated DNA checkpoint signaling in ATM loss. Thus, PARPi synthetic lethality phenotype observed in tumors with ATM loss could be regulated through the combination effect coming from the loss of both of ATM & BRCA1/2 and the subsequent effect on both HR gene functions. Our findings highlight that ATM has a critical role in DNA repair for the synergism with PARP inhibitors.
Citation Format: Asli Muvaffak, Kevin G. Coleman. Elaborating the mechanism of PARP synthetic lethality in ATM loss [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2379.
Abstract 2380: A novel role for PACS-1 in suppression of oncogenic replication stress in cancer cells
Authors: Mani Chinnadurai , Tripathi Kaushlendra , Clark David W. , Thomas Gary , Palle Komaraiah 
Published: September 2020

Abstract
PACS-1 is a protein involved in trafficking, especially transport of proteins like furin and Mannose-6-phosphate into the trans-golgi network. Intriguingly, our studies identified dynamic translocation of PACS-1 during cell division and its association with chromatin in tumor cells. Downregulation of PACS-1 in cancer cell lines attenuated cell growth, induced replication stress mediated DNA damage response (DDR), such as ATM/ATR-mediated checkpoint activation, and formation RPA, FANCD2 and pH2AX foci. Consistent with these observations, live-cell imaging revealed increased nuclear translocation of PACS-1 during S-phase and until the complete cell division. These results point to a novel role for PACS-1 during normal replication or in the suppression of oncogenic replication in tumor cells. However, a direct role for PACS-1 in cancer development or progression is not clear. Analysis of the cancer genome atlas (TCGA) data revealed occurrence of PACS-1 amplifications, mutations and deletions in cancers of different tissues. PACS-1 depletion leads to proteasome-mediated degradation of HDAC2 and HDAC3, compromised chromatin maturation, leads to replication stress and genomic instability. Intriguingly, stable overexpression of PACS-1 in MDA-MB-231 cells enhanced malignant behavior of tumor cells in their ability to form soft agar colonies and matrigel invasion compared to the cells that are expressing vector control. PACS-1 downregulation promotes replication stress in tumor cells suggesting that its upregulation in tumors may be important for replication stress recovery in cancer cells and for an efficient response to chemotherapy induced DNA damage. Furthermore, Prognoscan analysis indicated that PACS-1 expression levels correlates with poor survival in multiple studies, including breast, ovarian and lung cancers, suggesting a role for PACS-1 in tumorigenesis and a biomarker for poor prognosis.
Citation Format: Chinnadurai Mani, Kaushlendra Tripathi, David W. Clark, Gary Thomas, Komaraiah Palle. A novel role for PACS-1 in suppression of oncogenic replication stress in cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2380.
Abstract 2471: Role of FOXO transcription factor dynamics in determining cell fates following EGFR inhibition
Authors: Huynh Julie M. , Aryeh Kayenat S. , Shanks Lisa , Paek Andrew L. 
Published: September 2020

Abstract
Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a first line treatment for patients with advanced non-small cell lung cancer (NSCLC) who have specific hyperactive mutations in EGFR. Though patients have seen improvements in survival after EGFR TKI treatment, resistance commonly develops as not all NSCLC cells die following treatment. Indeed, EGFR inhibitor treatment induces both cell-cycle arrest (allowing for cell survival) and death in cancer cells. The FOXO family of transcription factors have been implicated in both death and arrest responses following EGFR inhibition. This is consistent with FOXOs function in regulating both arrest and apoptotic genes programs. However, it is unknown how the FOXO network ‘decides' between these two oppositional programs to enact following treatment with EGFR inhibitors. Protein dynamics, meaning how the levels or location of a protein changes over time, is a mechanism cells use to encode information about cellular fates. The p53 transcription system is an established example of a dynamically regulated system–it responds to multiple inputs and is capable of enacting multiple outputs (gamma radiation causes oscillations of p53 levels that result in cellular arrest while UV causes a sustained increase of p53 levels that result in cellular death). FOXO's network is similar to the p53 system (multiple input, multiple output), making it a good candidate for dynamic regulation. We have tagged Foxo3a with a fluorescent marker (Venus) at its endogenous locus in PC9 NSCLC cells using CRISPR/Cas9 to determine whether FOXO dynamics dictate cell fate following EGFR TKI treatment. Using live cell microscopy on this line, we have acquired FOXO nuclear cytoplasmic shuttling dynamics as well as cell fate (death/arrest) in single cells. Using time-series analyses we are trying to determine if there are dynamic patterns associated with each fate following EGFR inhibition. Through our studies, we hope to gain a better understanding of this non-genetic mechanism cells use to determine their fate. Our long-term goal is to identify dynamic patterns that push cancer cells to more terminal fates following treatment.
Citation Format: Julie M. Huynh, Kayenat S. Aryeh, Lisa Shanks, Andrew L. Paek. Role of FOXO transcription factor dynamics in determining cell fates following EGFR inhibition [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2471.