bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 575: Prediction of genomic instability in triple-negative breast cancer patients utilizing a CTC phenotype classifier
Authors: Jendrisak Adam , Ebrahim Nadia , Rodriguez Angel , Lee Jerry , Sutton Ramsay , Wang Yipeng , Landers Mark , Dittamore Ryan
Published: August 2018

Background: Genomic scars and HRD gene mutations are biomarkers for PARP inhibitor (PARPi) and platinum agent therapy response in breast cancer. Tests for these markers are usually performed by next-generation sequencing (NGS) of tumor tissue or circulating tumor DNA (ctDNA) and have limitations such as sample accessibility/availability and under-sampling due to inter/intratumor heterogeneity. Previously we predicted genomic instability (GI) using CTC phenotypic features without the use of NGS in metastatic castration-resistant prostate cancer (mCRPC) pts with high accuracy (>76%) (ASCO 2016). In addition, patients with phenotypically predicted GI (pGI) CTCs had significantly better PSA responses on abiraterone + veliparib (92%) vs. abiraterone alone (23%) (ESMO 2016), and also responded better to platinum agents vs. taxane agents (ESMO 2017). Here, we sought to develop and analytically validate an algorithm for predicting CTC pGI in TNBC.

Methods: Training set: 521 CTCs from 26 mCRPC pts were detected with the Epic Sciences CTC platform and analyzed for 19 phenotypic digital pathology features, including protein expression and cell morphology. The same CTCs were single-cell sequenced for the number of large-scale transitions (LSTs) as an indicator of GI. A linear regression algorithm to predict GI by CTC phenotype was developed, cross validated, and utilized to generate a CTC pGI score. Test set: 114 CTCs from 8 TNBC blood samples, median of 8 CTCs/pt, were sequenced for GI and phenotypically predicted for pGI.

Results: Analytical cutoff for GI (8.74) was determined in the mCRPC training set by separation of a binomial distribution low vs. high GI scores. pGI cutoff (8.74) was set the same as GI. The training set performance was: sensitivity = 69%, specificity = 83%, accuracy = 77%. In the TNBC test set, pGI vs. GI demonstrated: sensitivity = 86%, specificity = 92%, accuracy = 88%.

Conclusions: Previous studies showed that pGI was an analytically validated biomarker with clinical utility to predict PARPi or platinum therapy response in mCRPC pts. Here we show the same test concept can be applied to TNBC. Further analytical validation in a larger cohort is ongoing. The ability to identify PARPi/platinum sensitivity using an IF CTC staining method for CTC phenotype without the use of NGS will help to stratify patients more rapidly, at reduced cost, and aid in the acceleration of drug development.

Citation Format: Adam Jendrisak, Nadia Ebrahim, Angel Rodriguez, Jerry Lee, Ramsay Sutton, Yipeng Wang, Mark Landers, Ryan Dittamore. Prediction of genomic instability in triple-negative breast cancer patients utilizing a CTC phenotype classifier [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 575.
Abstract 5753: Cancer stem cell markers allow for immune evasion in triple-negative breast cancer
Authors: Hoffmann Andrew D.
Published: August 2018

Triple-negative breast cancer tumor-initiating cells, or cancer stem cells (CSCs) are identified as a population that is CD44+ and CD24low. These cells are important drivers of distant metastasis and recurrence. An important component of both the recurrence and metastasis functions of CSCs is the capacity to evade immune detection. Our work has identified key members of the antigen presentation machinery required for proper immunosurveillance as being differentially expressed in tumor cells expressing CD44 compared to cells lacking CD44, including a differential response to important immune system cytokines. We are currently working to identify functional differences related to the altered protein levels in these cells.

Citation Format: Andrew D. Hoffmann. Cancer stem cell markers allow for immune evasion in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5753.
Abstract 5759: Discovery of a novel claudin 6 (CLDN6) specific monoclonal antibody
Authors: Stafford Lewis J. , Screnci Brad , Sulli Chidananda , Rosenberg Erin , Molino Nicholas , Tucker David , Sullivan Jonathan , Barnes Trevor , Pfaff Jennifer , Hazarika Tanmayee , Charpentier Thomas , Gilman Samantha , Rimkunas Rebecca , Wilf Rona , Willis Sharon , Doranz Benjamin , Rucker Joseph , Chambers Ross
Published: August 2018

Claudin 6 (CLDN6) is a tight junction molecule that is involved in cell to cell adhesion of epithelial and endothelial cell sheets. CLDN6 is considered an oncofetal protein which is not expressed in normal human tissue but is expressed in some cancers such as endometrial, ovarian and testis cancer. Expression of CLDN6 in endometrial and urothelial cancer leads to a poor prognosis. The problem of developing antibodies against CLDN6 is that the family member claudin 9 (CLDN9) is highly homologous, only varying by 2 amino acids in the extracellular domain. To address this need, Integral Molecular has developed the MPS Discovery Engine® to enable the isolation, characterization, and engineering of monoclonal antibodies for tight junction proteins, GPCRs, ion channels, and transporters. MPS utilizes a collection of technologies to address each of the barriers to monoclonal antibody development against the native extracellular epitopes of multispan membrane proteins. These include, antigen engineering to attain high levels of surface expression, DNA and Lipoparticle immunization to present native epitopes to the immune system, diverse immunization host species to deal with highly conserved proteins, Lipoparticles (high concentration native membrane proteins) to enable phage display, microfludic B-cell isolation to isolate rare MAbs, and shotgun mutagenesis (comprehensive alanine scanning) for epitope mapping. Using the MPS Discovery Engine® we were able to successfully screen a large panel of clones for claudin 6 specificity. From these clones there were 72 potential antibodies that reacted with either claudin 6 or 6/9. A subset of these antibodies reacted only to claudin 6 and not to claudin 9 which has led to our lead drug candidate. With our MPS Discovery Engine® platform, we have the ability to target intact, conformationally specific, and functional antibodies to multipass membrane proteins.

Citation Format: Lewis J. Stafford, Brad Screnci, Chidananda Sulli, Erin Rosenberg, Nicholas Molino, David Tucker, Jonathan Sullivan, Trevor Barnes, Jennifer Pfaff, Tanmayee Hazarika, Thomas Charpentier, Samantha Gilman, Rebecca Rimkunas, Rona Wilf, Sharon Willis, Benjamin Doranz, Joseph Rucker, Ross Chambers. Discovery of a novel claudin 6 (CLDN6) specific monoclonal antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5759.
Abstract 576: A cancer drug atlas enables prediction of parallel drug vulnerabilities
Authors: Narayan Ravi , Molenaar Piet , Teng Jian , Tannous Bakhos , Wurdinger Tom , Koster Jan , Westerman Bart
Published: August 2018

Personalized cancer treatments using synergistic combinations of drugs is attractive but proves to be highly challenging. The combinatorial nature of such problems results in an enormous parameter space that cannot be resolved by empirical research, i.e. testing all combinations for all molecularly defined tumors. In addition, effective drug synergy is hard to predict. Here we present an approach to map data of drug-response encyclopedias and represent these as a drug atlas. This atlas consists of a framework of chemotherapeutic responses that represents a drug vulnerability landscape of cancer. Based on data from the literature we found that many synergistic drug combinations show distinct inter therapy responses and drug sensitivities. We confirmed this by performing a drug combination screen against glioblastoma where we used 270 combination experiments. From the identified dual therapies we were able to predict and validate a triple drug synergy which was validated in vivo. This new and generalizable strategy opens the door to unforeseen personalized multidrug combination approaches.

Citation Format: Ravi Narayan, Piet Molenaar, Jian Teng, Bakhos Tannous, Tom Wurdinger, Jan Koster, Bart Westerman. A cancer drug atlas enables prediction of parallel drug vulnerabilities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 576.
Abstract 5818: Globally optimizing therapeutic combinations against bortezomib-resistant multiple myeloma using a quantitative parabolic optimization platform
Authors: Rashid Masturah , Toh Tan Boon , Hooi Lissa , Silva Aleidy , Zhang Yanzhou , Karnani Neerja , Jha Sudhakar , Ho Chih-Ming , Chng Wee Joo , Ho Dean , Chow Edward Kai-Hua
Published: August 2018

Multiple myeloma is an incurable hematological malignancy that relies on drug combinations as first and secondary lines of treatment. The inclusion of proteasome inhibitors, such as bortezomib, into these drug combination regimens has improved median survival. Resistance to bortezomib, however, is a common occurrence that ultimately contributes to treatment failure. Thus, there remains a need to identify improved drug combinations that may serve as later lines of treatment for improved treatment against bortezomib-resistant multiple myeloma. We have developed the quantitative parabolic optimization platform (QPOP) to optimize drug combinations against bortezomib-resistant multiple myeloma. By mapping phenotypic output data to parabolic response surfaces, QPOP is able to deterministically optimize drug combinations as well as drug dosages. By continuously optimizing in multiple systems of interest, from in vitro to in vivo, drug combinations can be globally optimized for greater efficacy in increasingly complex biological systems. While QPOP does not rely on molecular mechanism modeling or prediction, identified optimal drug combinations can reverse DNA hypermethylation and silencing of tumor suppressors that occurs following acquired bortezomib-resistance in multiple myeloma. Furthermore, this drug combination is broadly effective across a range of primary multiple myeloma patient samples. Beyond bortezomib-resistant multiple myeloma, global optimization of drug combinations by QPOP can serve to improve drug combination design across a range of other cancers and diseases through a continuous optimization process across the entire drug development pipeline.

Citation Format: Masturah Rashid, Tan Boon Toh, Lissa Hooi, Aleidy Silva, Yanzhou Zhang, Neerja Karnani, Sudhakar Jha, Chih-Ming Ho, Wee Joo Chng, Dean Ho, Edward Kai-Hua Chow. Globally optimizing therapeutic combinations against bortezomib-resistant multiple myeloma using a quantitative parabolic optimization platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5818.
Abstract 5836: Activation Induced Cytosine Deamination, AICDA, is induced after EGFR TKI exposure leading to secondary resistant mutations in lung adenocarcinoma
Authors: Kadi Najwa El , Davis April , Cooke Alexander , Wang Luo , Korkaya Hasan , Kalemkerian Gregory , Hassan Khaled
Published: August 2018

Background: Epidermal growth factor receptor (EGFR) activation mutations occur in 10-50% of lung adenocarcinomas. This leads to constitutive activation of EGFR, which triggers multiple downstream survival and proliferation pathways. EGFR tyrosine kinase inhibitors (TKIs) are the mainstay of treatment for stage IV non-small cell lung cancer (NSCLC) patients with EGFR mutations. Acquired EGFR mutations are the main mechanism of on-target resistance to TKIs. T790M mutation that occurs after first line TKI treatment, is a cytosine to thymine (C>T) single nucleotide transition leading to a threonine to methionine amino acid change at position 790 (i.e. T790M). Interestingly, treatment with Osimertinib, that overcomes the T790M mutation, leads to other acquired resistant mutations, C797S, G796S/R and L792F/H. Our data suggest that resistant mutations are acquired events secondary to cytosine deamination through Activation Induced Cytosine Deamination enzyme (AICDA).

Results: Sub clones of the lung adenocarcinoma cell line PC9 with no evidence of T790M mutation by droplet digital PCR (ddPCR) at baseline, were treated with EGFR TKI. After serially increasing the treatment dose, T790M mutation was detected by ddPCR associated with a significant increase in AICDA expression. Knocking down AICDA by shRNA, decreases the development of T790M in PC9 cell lines after TKI exposure. Similarly, when the resistant T790M PC9 clones were treated with Osimertinib, the expression of AICDA was also induced. Using mass spectrometry, we established that cytosine at codon 790 is methylated; thus, deamination of 5-methylcytosine leads to thymine directly, explaining the T790M C>T mutation. In addition, using ChIP assay and pharmacological inhibition we confirm that upon TKI exposure, NFĸB binds AICDA promoter and induces its expression. In a mouse xenograft model, the induction of NFĸB and AICDA after EGFR TKI exposure is abrogated by concurrent use of an NFĸB inhibitor. Finally, patients treated with EFR TKI had an increased expression of AICDA upon progression.

Conclusion: In EGFR driven lung adenocarcinoma, NFĸB pathway is activated upon exposure to EGFR TKIs which induces AICDA expression. AICDA deaminates cytosine into other nucleotides leading to treatment resistance.

Citation Format: Najwa El Kadi, April Davis, Alexander Cooke, Luo Wang, Hasan Korkaya, Gregory Kalemkerian, Khaled Hassan. Activation Induced Cytosine Deamination, AICDA, is induced after EGFR TKI exposure leading to secondary resistant mutations in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5836.
Abstract 585: Exosomal EphA2 transmits chemoresistance and predicts pancreatic cancer patient responses to therapy
Authors: Fan Jia , Wei Qian , Koay Eugene J. , Liu Yang , Zhao Zhen , Hu Ye
Published: August 2018

Exosomes are small extracellular vesicles secreted by most cells that are found in blood and other bodily fluids, and which contain cytoplasmic material and membrane factors corresponding to their cell type of origin. Exosome membrane factors and contents have been reported to alter adjacent and distant cell behavior in multiple studies, but the impact of cancer-derived exosomes on chemoresistance is less clear. We therefore analyzed exosomes from the human pancreatic cancer (PC) cell lines PANC-1, MIA PaCa-2 and BxPC-3 for their ability to transmit chemoresistance, finding that PANC-1 exosomes increased the gembicitabine (GEM) resistance of MIA PaCa-2 and BxPC-3 cell cultures. Comparative proteomics determined that PANC-1 exosomes overexpressed Ephrin type-A receptor 2 (EphA2) versus exosomes of less chemoresistant PC cell lines MIA PaCa-2 and BxPC-3. EphA2-knockdown in PANC-1 cells inhibited their ability to transmit exosome-mediated chemoresistance to MIA PaCa-2 and BxPC-3, while treatment of MIA PaCa-2 and BxPC-3 cells with soluble EphA2 did not promote chemoresistance, indicating that membrane carried EphA2 was important for the EphA2 chemoresistance effect. EphA2 levels on circulating exosomes were markedly increased in mice bearing PANC-1 tumors and PC patients who subsequently revealed poor responses to treatment. We thus concluded that exosomal EphA2 expression could transmit chemoresistance and may serve as a minimally-invasive predictive biomarker for PC treatment response. Further work should address whether additional exosomal factors regulate resistance to other cancer therapeutic agents for PC or other cancer types.

Citation Format: Jia Fan, Qian Wei, Eugene J. Koay, Yang Liu, Zhen Zhao, Ye Hu. Exosomal EphA2 transmits chemoresistance and predicts pancreatic cancer patient responses to therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 585.
Abstract 5853: Targeting NAD+/PARP DNA repair pathway as a novel therapeutic approach to SDHB-mutated cluster I pheochromocytoma and paraganglioma
Authors: Pang Ying , Lu Yanxin , Caisova Veronika , Liu Yang , Bullova Petra , Huynh Thanh-Truc , Frysak Zdenek , Hartmann Igor , Taïeb David , Pacak Karel , Yang Chunzhang
Published: August 2018

Background: Cluster I pheochromocytomas and paragangliomas (PCPGs) tend to develop malignant transformation, tumor recurrence, and multiplicity. Transcriptomic profiling suggests that cluster I PCPGs and other related tumors exhibit distinctive changes in the tricarboxylic acid (TCA) cycle, the hypoxia signaling pathway, mitochondrial electron transport chain, and methylation status, suggesting that therapeutic regimen might be optimized by targeting these signature molecular pathways.

Experimental design: We investigated molecular signatures in clinical specimens from cluster I and II PCPGs, with a focus on the therapeutic resistance mechanisms. Further, we tested the applicability of a combination therapy including an FDA approved PARP inhibitor olaparib (Ola) and temozolomide (TMZ) in both in vitro cellular model and an in vivo allograft animal model.

Results: Our findings showed that cluster I PCPGs develop a distinctive dependency on mitochondrial complex I, evidenced by the upregulation of complex I components and enhanced NADH dehydrogenation. Mechanistically, alteration in mitochondrial function resulted in strengthened NAD+ metabolism, which provides essential cofactor for PARP catalytic activity, prompting base excision repair and chemo resistance. Combining PARP inhibitor Ola with TMZ not only improved cytotoxicity but also reduced metastatic lesions, with prolonged overall survival in a mouse model with PCPG allograft.

Conclusions: Our results suggest that the NAD+/PARP pathway is a crucial targetable therapeutic resistance mechanism in SDHB-mutated PCPG. Combination therapy using TMZ and Ola could become an effective strategy against these and other advanced cluster I tumors.

Disclosure Statement: The authors have nothing to disclose.

Citation Format: Ying Pang, Yanxin Lu, Veronika Caisova, Yang Liu, Petra Bullova, Thanh-Truc Huynh, Zdenek Frysak, Igor Hartmann, David Taïeb, Karel Pacak, Chunzhang Yang. Targeting NAD+/PARP DNA repair pathway as a novel therapeutic approach to SDHB-mutated cluster I pheochromocytoma and paraganglioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5853.
Abstract 5892: miR-217 sensitizes chronic myelogenous leukemia cells to tyrosine kinase inhibitors by targeting pro-oncogenic anterior gradient 2
Authors: Pan Bin , Wang Xiangmin , Xu Kailin , Ikezoe Takayuki
Published: August 2018

BCR-ABL1 independent mechanisms had been indicated to mediate drug resistance to tyrosine kinase inhibitors (TKIs) in patients with chronic myelogenous leukemia (CML). In this study, we observed increased level of pro-oncogenic anterior gradient 2 (AGR2) in TKIs-resistant CML cells. Silencing of AGR2 in dasatinib-resistant K562 (K562DR) cells led to restored sensitivity to dasatinib both in vitro and in vivo. Exposure to dasatinib induced up-regulation of AGR2 in K562 cells, which indicated a probable treatment related drug resistance. We further investigated the potential interaction between microRNA (miRNA) and AGR2 in K562DR cells, and found that down-regulation of miR-217 was associated with over-expression of AGR2 in K562DR cells. Luciferase reporter assay identified that miR-217 negatively regulated expression of AGR2 through binding 3'-untranslated region (3'-UTR) of AGR2. Forced expression of miR-217 led to decreased expression of AGR2 as well as compromised TKIs-resistant potential of K562DR cells. Similarly, over-expression of miR-217 re-sensitized K562DR cells to dasatinib-treatment in a murine xenograft transplantation model. Taken together, TKIs-treatment induced drug-resistance is correlated with decrease of miR-217 and up-regulation of AGR2. miR-217/AGR2 interaction might be a potential therapeutic target in treating CML patients with TKIs-resistant.

Citation Format: Bin Pan, Xiangmin Wang, Kailin Xu, Takayuki Ikezoe. miR-217 sensitizes chronic myelogenous leukemia cells to tyrosine kinase inhibitors by targeting pro-oncogenic anterior gradient 2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5892.
Abstract 5894: Snail reduces the antitumor efficacy of mTOR kinase inhibitors by transcriptional repression of 4E-BP1
Authors: Ye Qing , Wang Jun , Cao Yanan , Guo Yubin , Huang Xiuping , Mi Wenting , Liu Side , Wang Chi , Yang Hsin-Sheng , Zhou Binhua , Evers Bernard M. , She Qing-Bai
Published: August 2018

The mTOR inhibitors, including the second generation of mTOR kinase inhibitors, for cancer treatment have been evaluated in clinical trials, but their overall activity as monotherapy is limited. The cap-dependent translation repressor, 4E-BP1, is an important downstream effector of the mTOR kinase in controlling cell proliferation and tumor growth. Loss of 4E-BP1 expression has been linked to cancer progression and resistance to mTOR inhibitors. However, the molecular mechanism underlying 4E-BP1 downregulation in tumors remains unclear. Here, we identify Snail as a strong transcriptional repressor of 4E-BP1. We find that 4E-BP1 expression inversely correlates with Snail level in cancer cell lines and clinical specimens. Snail binds to three E-boxes present in the human 4E-BP1 promoter to block the transcription of the 4E-BP1 gene. Ectopic expression of Snail in cancer cell lines lacking Snail profoundly represses 4E-BP1 expression, promotes the formation of the eIF4F translation initiation complex for active translation in polysomes, and reduces the antiproliferative effect of mTOR kinase inhibitors. Conversely, genetic disruption of Snail or pharmacologic inhibition of Snail activity using the Snail co-repressor HDAC inhibitors restores 4E-BP1 expression and sensitizes cancer cells to mTOR kinase inhibitors by enhancing 4E-BP1-mediated translation-repressive effect on cell proliferation and tumor growth. Together, our findings reveal a novel oncogenic function of Snail in mTOR/4E-BP1-mediated translational control of tumorigenesis, and provide a rationale for targeting Snail to improve mTOR-targeted therapies.

Citation Format: Qing Ye, Jun Wang, Yanan Cao, Yubin Guo, Xiuping Huang, Wenting Mi, Side Liu, Chi Wang, Hsin-Sheng Yang, Binhua Zhou, Bernard M. Evers, Qing-Bai She. Snail reduces the antitumor efficacy of mTOR kinase inhibitors by transcriptional repression of 4E-BP1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5894.
Abstract 596: Impact of histologic type on survival in primary thyroid lymphomas
Authors: Al-Juhaishi Taha , Yazbeck Victor
Published: August 2018

Background:

Primary Thyroid Lymphoma (PTL) is a rare disease constituting less than 2% of all extranodal lymphomas; and approximately 2-8% of all thyroid malignancies. In this study, we sought to describe the impact of histologic types on survival.

Methods:

The Surveillance, Epidemiology and End Results (SEER) database was used to identify patients (≥18 years) diagnosed with PTL between 1973 and 2014. B-cell and T-cell lymphomas of all stages were included. Overall survival (OS) was estimated using the Kaplan-Meier method, and compared using Log-Rank test. Cox proportional hazards models were used for adjusted survival analyses.

Results:

Total of 2397 patients were included. Median age was 65 years (56-77); majority were female (n=1734, 72%) and caucasian (n=2178, 91%). Diffuse large B cell lymphoma was the most common histology (DLBCL, N=1351, 56%), followed by marginal zone (MZL, N=334, 14%), follicular (FL, N= 214, 8.9%), Burkitt (BL, N=43, 1.8%), chronic/small lymphocytic leukemia/lymphoma (CLL/SLL, N=41, 1.7%), Hodgkin lymphoma (HL, N=33, 1.4%), T cell lymphomas (TCL, N=14, 0.6%), Lymphoplasmocytic lymphoma (LPL, N=11, 0.4%), and Mantle cell (MCL, N=8, 0.3%). 349 patients (14.6 %) were reported with unclear histology. Total of 1502 (63%) had surgery, 1417 (59%) had chemotherapy and 1153 (48%) had radiation. At a median follow-up of 10.5 years, 1187 (50%) patients died. Median overall survival was 11.4 [10.6-12.3; 95% CI] years. Survival was different by histology type (table, P<0.001). Compared with DLBCL, follicular lymphoma (HR 0.72 [0.57-0.92], P=0.008) and MZL (HR 0.62 [0.48-0.78], P<0.001) were associated with lower mortality, independently of age, sex, race, surgery, chemotherapy, radiation and year of diagnosis. Adjusted mortality decreased by a relative 1% annually (HR 0.99 [0.98-0.99], P<0.001).

Conclusion:

PTL is a rare disease mostly affecting elderly caucasian women. Outcomes vary depending on histologic type. Follicular, MZL and Hodgkin's lymphoma seem to have a favorable prognosis.

Overall Survival by HistologyHistologyNumber (%)Mean Survival in Years (95% CI)1-year survival5-year survivalDLBCL1351 (66%)12.6 [11.7-13.4]80%66%Burkitt43 (2.1%)15.9 [13.5-18.3]79%79%CLL/SLL41 (2%)13 [9.5-16.5]78%67%Follicular214 (10.4%)17.8 [15.1-20.6]97%83%Hodgkin33 (1.6%)25 [20-30]94%84%LPL10 (0.5%)14.2 [7.4-21]100%76%MZL334 (16.3%)13 [11.9-14.1]95%83%Mantel-Cell8 (0.4%)8.7 [3.9-13.5]87%56%T-cell14 (0.7%)10.7 [3.9-17.5]70%53%

Citation Format: Taha Al-Juhaishi, Victor Yazbeck. Impact of histologic type on survival in primary thyroid lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 596.
Abstract 607: Inhibition of CDK4/6 and Pi3Kγ modulates mammary tumor immune microenvironment to enhance response to immunotherapy
Authors: Mont Stacey , Black Kevin , Chen Sheau-Chiann , Ayers Gregory D. , Richmond Ann , Vilgelm Anna E.
Published: August 2018

An antitumor immune response is critical in achieving immunotherapy-driven tumor regression. Despite remarkable clinical advances in immunotherapies, patients with breast cancer have been only moderately responsive. In this study, we tested whether CDK4/6 inhibition in combination with Pi3Kγ inhibition can augment the immunotherapy response. Tumor growth was inhibited in the MMTV-PyMT breast cancer model when treated with palbociclib (CDK4/6i) in combination with anti-CD137, an antibody agonist of T cell co-stimulatory receptor 4-1BB. We also assessed the effect of palbociclib alone in a postsurgical model, where treatment began 5 days after injecting 37,000 MMTV-PyMT cells into the mammary fat pad, and show a significant inhibition of both average tumor weight and volume. In addition, we demonstrate that palbociclib can be effective in reducing total tumor burden in the PyMT-FVB spontaneous breast cancer model. Furthermore, mice treated with palbociclib in this model had an increase in CD3+ cell infiltrate in tumor lung metastasis. We used the Pi3Kγ-null mice treated with palbociclib or vehicle control to assess the effect of dual inhibition of CDK4/6 and Pi3Kγ on MMTV-PyMT tumors. We found an increase in CD45+ cells within the tumor microenvironment and an increase in MHC class II+, antigen-presenting macrophages upon palbociclib treatment. Additionally, gene expression analysis of chemokines in palbociclib-treated MCF-7 cells showed an increased expression of CCL4, CCL5, CXCL9, CXCL10, and CXCL11, each of which is implicated in T-cell tumor-homing. Overall, our results suggest that dual inhibition of CDK4/6 and Pi3Kγ may enhance tumor immunogenicity. Drugs targeting CDK4/6 and Pi3Kγ are of high clinical relevance and our findings indicate that they may be used in combination with immunotherapies for the treatment for breast cancer.

Citation Format: Stacey Mont, Kevin Black, Sheau-Chiann Chen, Gregory D. Ayers, Ann Richmond, Anna E. Vilgelm. Inhibition of CDK4/6 and Pi3Kγ modulates mammary tumor immune microenvironment to enhance response to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 607.
Abstract 622: Differential impact of pembrolizumab and ipilimumab on IFNgamma and IL-10 production from in-vitro monocyte-derived DC and T cell co-cultures
Authors: Tang Tina , Stewart Fay , Roberts Alexander , Gordon John , Curnow John , Barnes Nicholas , Qureshi Omar
Published: August 2018

Despite the success with checkpoint inhibitors in-vivo, demonstrating efficacy in-vitro using human primary immune cells remains a challenge. Our aim was to determine the impact of pembrolizumab and ipilimumab on proliferation, as well as IFNγ and IL-10 production, from monocyte-derived dendritic cell and T cell co-cultures.

CD14+ monocytes from the peripheral blood of healthy donors were isolated before differentiating into immature dendritic cells (iDC) with IL-4 and GM-CSF. Immature dendritic cells were subsequently matured (mDC) by exposure to IL-1β, IL-6, TNFα and PGE2. Allogeneic purified CD4+ T cells (from healthy donors) were co-cultured with either iDC or mDC in the absence (media alone or isotype control) or presence of either pembrolizumab or ipilimumab. T cell proliferation and IFNγ and IL-10 secretion were subsequently assessed.

Whilst there was no consistent impact of either pembrolizumab or ipilimumab on the proliferation of CD4+ T cells in co-culture with iDC or mDC, IFNγ secretion by CD4+ T cells was increased in iDC- and mDC-co-cultures by pembrolizumab (percentage increase at 1μg/ml compare to isotype control: 524.5±196.1, P=0.037; 200.7±80.6, P=0.047, respectively, n=7) and reduced in iDC cultures with ipilimumab (percentage increase at 1μg/ml compared to isotype control: -63.4±11.7, P=0.012, n=4). IL-10 secretion was also impacted upon by pembrolizumab, whereby it increased in both iDC and mDC cultures with CD4+ T cells (percentage increase at 1μg/ml compare to isotype control: 175.3±27.0, P=0.003; 183.2±16.7, P<0.001, respectively, n=4). Ipilimumab however, whilst having no evident effect in iDC-T cell co-cultures, reduced IL-10 production of mDC co-cultures (percentage decrease at 1μg/ml compare to isotype control: -27.7±6.3, P=0.022, n=4).

These data support the positive in-vivo results with pembrolizumab and ipilimumab, and demonstrates a reliable method for investigating the impact of checkpoint inhibitors in immune cells.

Citation Format: Tina Tang, Fay Stewart, Alexander Roberts, John Gordon, John Curnow, Nicholas Barnes, Omar Qureshi. Differential impact of pembrolizumab and ipilimumab on IFNgamma and IL-10 production from in-vitro monocyte-derived DC and T cell co-cultures [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 622.
Abstract 632A: Microbiome diversity in sputum and circulating exosomes of women with breast cancer and nontuberculous mycobacterial lung disease
Authors: Philley Julie V. , Griffith David E. , Dasgupta Santanu
Published: August 2018

The nontuberculous Mycobacterial lung disease, primarily caused by Mycobacterium avium complex is an alarming health problem in the United States and worldwide. Being prevalent among Caucasian women with a history or current diagnosis of breast cancer, Nontuberculous Mycobacterial lung disease poses a significant challenge towards treatment. A large community of resident microbes, including bacteria, virus, Archeas and Fungi living in the human body are being increasingly recognized as the key components of controlling human health and disease. In this study, we examined microbiome diversity in sputa and circulating exosomes derived from women with both breast cancer and nontuberculous Mycobacterial lung disease, women with nontuberculous Mycobacterial lung infection only and healthy women by 16S rDNA sequencing. Our study identified a diverse microbiome community in the sputa and the exosomes dominated by Streptococcus, Haemophillus, Veillonella, Neisseria, Prevotella, Fusobacterium, Bacteroides, Allistipes, Faecalibacterium and Staphylococcus in women with both breast cancer and nontuberculous Mycobacterial lung disease and nontuberculous Mycobacterial lung disease only. Some of these genera, including Fusobacterium, Bacteroides, Allistipes have estrobolome activity and are associated with the development of breast and other neoplasm. This work confirms the presence of a distinct microbiome other than the Mycobacteriome in the sputa and the circulating exosomes of these patients. Further studies investigating the role of the sputa and exosome microbiome linking nontuberculous Mycobacterial pathogenesis and breast cancer are warranted.

Citation Format: Julie V. Philley, David E. Griffith, Santanu Dasgupta. Microbiome diversity in sputum and circulating exosomes of women with breast cancer and nontuberculous mycobacterial lung disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 632A.
Abstract 650: Effect of antigen retrieval on immuno-based microdissection methods
Authors: Tangrea Michael , Liu Meeiyueh , Roberge Adam , Noyes Kristen , Sanders Kennedy , Emmert-Buck Michael , Johann Donald J.
Published: August 2018

Introduction - Immunohistochemical staining (IHC) of histological sections is a well-established and useful technique for a large number of research studies and clinical applications, and is increasingly used as a targeting strategy for procurement of labeled cells via tissue microdissection, including immuno-LCM, immuno/computer-LCM, expression microdissection, and other techniques. The antigen retrieval (AR) process employed at the beginning of most IHC protocols increases epitope availability and improves staining characteristics; however, the procedure can damage DNA to an unknown extent.

Experimental Procedures - To better understand the effects of AR on DNA quality and quantity, model system samples (lung cancer PDX tissue) and clinical specimens (KRAS gene mutation positive cases) were subjected to commonly employed AR methods [heat induced epitope retrieval (HIER), protease digestion] and the effects on DNA were assessed by Qubit, Fragment Analyzer, agarose gels, kappa qPCR, digital droplet PCR, NGS library preparation, and targeted sequencing.

Data Summary - The results showed that HIER resulted in optimal staining characteristics, but induced significant damage to DNA, producing extensive fragmentation and decreased yields. Variation in the HIER protocol mitigated but did not eliminate the negative effects. In contrast, the consequences of protease treatment on DNA were relatively minor and immunostaining quality was acceptable, although diminished in intensity compared to HIER treated sections. Apart from the AR procedure, the IHC process itself also resulted in a decreased yield of DNA. However, in spite of the observed deleterious effects on DNA, none of the AR methods combined with IHC negatively affected PCR amplification of small amplicons, and KRAS gene mutations were successfully identified in the clinical cases under all conditions.

Conclusions - The data indicate that DNA recovered from histology slides after standard AR and IHC processing can be successfully employed for the majority genomic applications, but studies that require larger DNA fragments such as long-read sequencing should avoid the use of HIER.

Citation Format: Michael Tangrea, Meeiyueh Liu, Adam Roberge, Kristen Noyes, Kennedy Sanders, Michael Emmert-Buck, Donald J. Johann. Effect of antigen retrieval on immuno-based microdissection methods [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 650.
Abstract 659: A novel manganese MRI contrast agent (PyC3A) for the evaluation of hepatic neoplasms
Authors: Erstad Derek J. , Ramsay Ian , Sojoodi Mozhdeh , Farrar Christian , Rotile NIcholas J. , Li Shen , Ghoshal Sarani , Michael Lanuti , Caravan Peter , Tanabe Kenneth K. , Fuchs Bryan C. , Gale Eric
Published: August 2018

Introduction:

Magnetic resonance imaging (MRI) is routinely used to diagnosis hepatic neoplasms. However, Gadolinium (Gd) is contraindicated in patients with severe renal impairment, and recent evidence also suggests Gd accumulates in brain tissue after repeated contrast injections. Manganese (Mn2+) is a paramagnetic ion that is cleared via biliary excretion, and provides an ideal alternative to Gd-based MR contrast agents. We present a novel Mn-based contrast agent, [Mn(PyC3A)(H2O)]- (referred to as PyC3A), and compare its efficacy to gadoxetic acid (Eovist) by imaging orthotopically implanted colorectal cancer hepatic metastases in mice.

Methods:

Male BALB/c mice (n = 8) were injected in the left lobe of the liver with 5x104 MC26/MCA-26 murine colon carcinoma cells, and were imaged on postoperative day 10 using a 4.7T MR scanner with PyC3A and gadoxetic acid (Eovist) 24 hrs apart. Signal contrast-to-noise ratio (CNR) was calculated for normal liver relative to tumor for each probe and compared.

Results:

Relaxivity of PyC3A in blood plasma was shown to be comparable to commercial Gd contrast agents. Biodistribution analysis confirmed that PyC3A clears via a mixed renal/hepatobiliary pathway with greater than 99% clearance within 24 hours. For imaging hepatic metastases, all mice survived to the study endpoint and developed radiographically discernible tumors (5 ± 2 mm diameter) without evidence of carcinomatosis. Calculated CNRs for liver relative to tumor for all recorded times are shown in Table 1. There was no difference in CNR between gadoxetic acid and PyC3A for all time points, suggesting near-equivalent enhancement of normal liver and tumor by both probes.

Conclusions:

PyC3A provides resolution of metastatic liver metastases that is comparable to gadoxetic acid. PyC3A may provide a safe and effective alternative to Gd constrast agents for imaging hepatic neoplasms in patients with renal impairment.

Table 1. Contrast-to-Noise Ratio (CNR) of Normal Liver Relative to TumorTime (minutes post injection)Gadoxetic AcidPyC3Ap-value02.61 ± 1.082.60 ± 1.640.9237.72 ± 4.677.53 ± 3.020.9387.85 ± 3.898.85 ± 4.430.66138.02 ± 3.987.62 ± 5.490.88189.79 ± 4.175.60 ± 3.080.06238.72 ± 4.167.03 ± 2.060.36

Citation Format: Derek J. Erstad, Ian Ramsay, Mozhdeh Sojoodi, Christian Farrar, NIcholas J. Rotile, Shen Li, Sarani Ghoshal, Lanuti Michael, Peter Caravan, Kenneth K. Tanabe, Bryan C. Fuchs, Eric Gale. A novel manganese MRI contrast agent (PyC3A) for the evaluation of hepatic neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 659.
Abstract 683: SOS1 allosterically linked conformational changes modulate KRas4B activation
Authors: Liao Tsung-Jen , Jang Hyunbum , Fushman David , Nussinov Ruth
Published: August 2018

Son of sevenless homology 1 (SOS1) is a robust guanine nucleotide exchange factor (GEF) that exchanges GDP by GTP and activates Ras. SOS1 is a large multidomain protein with molecular weight of ~153 kDa. The C-terminal catalytic region, composed of RAS exchanger motif (REM) and CDC25 domains, is responsible for Ras activation. SOS1 offers two Ras binding sites; one at the allosteric site in REM and the other at the catalytic site in CDC25. Experimental studies provided a Ras-SOS1-Ras ternary complex and suggested that Ras binding to REM allosteric site is essential to activate GDP-bound Ras at the CDC25 catalytic site. However, details of SOS1 conformational changes due to different binding modes of Ras at the allosteric and catalytic sites in Ras activation are not well understood. Here, using molecular dynamics (MD) simulations, we examine Ras activation mechanism for SOS1 systems containing GDP- and GTP-bound, and nucleotide-free KRas4B. Among the three Ras isoforms, including HRas, NRas, and KRas (with two splice variants of KRas4A and KRas4B), KRas4B is highly oncogenic, the most frequently mutated in RAS-driven cancers. We observed that the REM domain inherently and sterically obstructs the Ras binding site of CDC25 domain. Upon binding to the REM allosteric site, KRas4B-GTP relieves the steric occlusion, making the CDC25 catalytic site capable of associating with KRas4B-GDP, leading to the nucleotide exchange. Allosteric effects lead to the dislocation of the helix-hairpin motif at the CDC25 catalytic site. This large movement of the helix-hairpin motif causes the Ras catalytic site to open and liberates GDP. Allosteric signals propagating through the REM-CDC25 tandem domains of SOS1 can explain the communication between two Ras proteins modulating the large conformational changes. Our simulations provide insight into the structural correlation of KRas4B-SOS1 as well as the allosteric effect. The conformational changes of SOS1 correspond to the allosteric signaling between two KRas4B at REM and CDC25 domains, promoting Ras activation.

Citation Format: Tsung-Jen Liao, Hyunbum Jang, David Fushman, Ruth Nussinov. SOS1 allosterically linked conformational changes modulate KRas4B activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 683.
Abstract 701: An inflammation paradox: Obesity vs. neutrophil-lymphocyte ratio in immunotherapy
Authors: Park Wungki , Florou Vaia , Torres Alfredo , Saravia Diana , Algaze Sandra , Lopes Gilberto ,   University of Miami
Published: August 2018

Background: The dual roles of inflammation in malignancy has been well-described. Neutrophils play a key role in inflammation and carcinogenesis. We previously showed that high NLR may confer resistance to PD1/PDL1 inhibitors in lung cancer patients. In addition, obesity has been shown to produce chronic inflammation and neutrophil dysfunction have been described. The interplay between obesity and neutrophil in solid tumor patients treated with immunotherapy is unknown. Methods: We retrospectively evaluated 408 patients with solid tumors who treated with immunotherapies at the University of Miami. Cox regression was performed to evaluate correlation of obesity (BMI >30) and NLR <5 with Progression Free Survival (PFS) and Overall Survival (OS). Pearson Correlation was used for correlation between BMI and NLR. Results: Median follow-up was 8.6 months. There were head, neck and thoracic (n=257), gastrointestinal (n=32), genitourinary (n=58), skin and musculoskeletal (n=61). There were 230 males, mean age was 65.8. Treatments include nivolumab (n=204), pembrolizumab (n=128), atezolizumab (n=35), and combination with ipilimumab (n=41). There were underweight (BMI<18.5, n=27), normal weight (18.5≤BMI<25, n=186), overweight (25≤BMI<30, n=117), and obese patients (BMI≥30, n=78). Obesity (BMI≥30) and NLR <5 were strongly correlated with better OS with HR: 3.031 and HR: 2.424, respectively. (Table 1) There was trend of better PFS in obese patients, however it was not statistically significant. BMI and NLR showed inverse correlation. (r= -0.172, p=0.001) Conclusions: Surrogates of inflammation, such as obesity and NLR in patients with solid cancer may predict immunotherapy responses. High NLR was associated with adverse clinical outcomes and failure to checkpoint inhibitors, perhaps due to unfavorable tumor-associated neutrophil phenotypes. There was also a strong correlation between obesity and overall survival in these solid tumor patients.

Table 1. Multivariate analysisPFSOSFactorHR95% C.I.p-valueHR95% C.I.p-valueECOG>12.188(1.561-3.068)0.00013.031(1.937-4.742)0.0001BMI<301.136(0.806-1.601)0.4682.934(1.484-5.801)0.002NLR≥51.704(1.301-2.230)0.00012.424(1.661-3.538)0.0001

Citation Format: Wungki Park, Vaia Florou, Alfredo Torres, Diana Saravia, Sandra Algaze, Gilberto Lopes, University of Miami. An inflammation paradox: Obesity vs. neutrophil-lymphocyte ratio in immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 701.
Abstract 709: Anti-PD-1 therapy reduces bone lesion growth in a novel syngeneic bladder cancer bone metastasis model
Authors: Kähkönen Tiina E. , Suominen Mari I. , Halleen Jussi M. , Bernoulli Jenni , Scholz Arne
Published: August 2018

Bladder cancer is a common and aggressive type of cancer occurring both in women and in men. At diagnosis, lymph node involvement is frequently observed and in some cases metastatic spread can already be seen at early stage. With advanced stages, the metastatic incidence increases and the most common metastatic sites are bones, lung, liver and peritoneum. Bone metastases count about 50% of all metastases and the 5-year survival rate in metastatic disease is only 15%. Bone metastases are incurable but can be treated to reduce tumor burden in bone, and new therapies such as immunotherapies hold the potential to treat patients with bone metastatic bladder cancer. The aim of the study was to establish a novel syngeneic model for bladder cancer bone metastasis that could be used to study efficacy of new immunotherapies, and to test efficacy of anti-PD-1 therapy in the model.

In the model establishment study, an intratibial injection of varying number of murine MBT-2 bladder cancer cells was given to 5-6 weeks old female C3H/HeN mice. Tumor-induced bone changes were followed by X-ray imaging once a week. At sacrifice, tumor-bearing tibias were collected and evaluated by histology. In the efficacy study, 5x105 MBT-2 cells were used. The mice were stratified to treatment groups based on similar bone lesion areas at 10 days after cancer cell inoculations and treated with anti-PD-1 therapy (RMP1-14) or isotype control (rat IgG2a, 200 µg per dose) at Q3D schedule. Bone lesion growth was followed by X-ray imaging one week after start of treatment and at sacrifice after three weeks on treatment.

In the model establishment study, tumor take rate of 50% was observed. MBT-2 cells induced an osteolytic bone reaction resulting in substantial bone loss in the mice. The osteolytic bone lesions started to be visible between 7-14 days and the maximum duration of the study was 4 weeks from the cancer cell inoculations. Histology confirmed a large tumor and decreased bone mass in the inoculated tibia. In the efficacy study, treatment with anti-PD-1 reduced bone lesion growth. A trend towards decreased bone lesion area was seen already at one week on treatment and a significant reduction of bone lesion area was seen at sacrifice.

A novel syngeneic bladder cancer bone metastasis model was established. According to the observed significant effects on bone lesion growth by anti-PD-1 treatment this model can be used in preclinical efficacy assessment of new immunotherapies as monotherapy or in combination with other therapies.

Citation Format: Tiina E. Kähkönen, Mari I. Suominen, Jussi M. Halleen, Jenni Bernoulli, Arne Scholz. Anti-PD-1 therapy reduces bone lesion growth in a novel syngeneic bladder cancer bone metastasis model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 709.