tbuckley/cabot-search huggingface dataset:
Abstract 5141: Optimizing peptide-drug conjugate delivery as an alternative to antibody-drug conjugates for solid tumors
Authors: Theo L. Sottero, Emily J. Girard, Carrie H. Myers, James M. Olson
Journal: Cancer Research (2017)

Abstract Antibody-drug conjugates (ADCs) have been FDA approved for targeted delivery of chemotherapy to a small subset of cancers. However, there are significant limitations in their clinical utility in the majority of cancers: despite hundreds of clinical trials, there are only two FDA approved drugs currently on the market. ADCs are further limited by their poor penetration into solid tumors and an inability to cross the blood-brain-barrier (BBB). Our lab has over a decade of experience with peptide-dye conjugates such as chlorotoxin-Cy5.5, which demonstrates tumor-specific accumulation in a wide range of cancers including solid tumors and tumors protected by the BBB. However, chlorotoxin-Cy5.5 accumulates in mouse liver – a potential liability if a chlorotoxin-drug conjugate exhibited similar biodistribution. Tumor Paint/BLZ-100 is a derivative of this molecule optimized for tumor accumulation that is currently in clinical trials to aid in cancer surgery. We sought to expand upon the utility of Tumor Paint and optimize a novel peptide that is capable of delivering both imaging agents and chemotherapeutics specifically to tumor cells in vitro and in vivo. We have identified a novel Optide (OPtimized knottin pepTIDE) able to accumulate in a range of cancers (lymphoma, sarcoma, colon cancer, and pediatric medulloblastoma). To test whether an Optide could be created with a greater tumor specificity, we looked to both natural homologs as well as specific charged residue modifications. We have identified two next-generation Optides with enhanced uptake in mouse models of sarcoma. We have used these peptides to deliver a microtubule inhibitor to sarcoma and lymphoma in vitro and in vivo. Using in vitro flow cytometry, we have also identified multiple FDA approved drugs that upregulate or downregulate uptake of our family of peptide drug-conjugates. In understanding the pathways regulating the uptake of these peptides, we hope to both be able to identify tumors best suited for treatment with peptide-drug conjugates (PDCs) based on our Optide scaffold. Citation Format: Theo L. Sottero, Emily J. Girard, Carrie H. Myers, James M. Olson. Optimizing peptide-drug conjugate delivery as an alternative to antibody-drug conjugates for solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5141. doi:10.1158/1538-7445.AM2017-5141
Abstract 19067: Lipoprotein(a) and Risk of Cardiovascular Disease in Persons With Chronic Kidney Disease: Findings From the Chronic Renal Insufficiency Cohort Study
Authors: Archna Bajaj, Scott M Damrauer, Amanda H Anderson, Alan S Go, Wendy S Post, James P Lash, Jiang He, Matthew J Budoff, Danish Saleheen, Jinbo Chen, Daniel J Rader
Journal: Circulation (2016)

Introduction:  Elevated lipoprotein(a) [Lp(a)] levels are associated with increased cardiovascular disease (CVD) risk in the general population. While Lp(a) levels are increased in patients with chronic kidney disease (CKD), its impact on CVD events in CKD remains less clear.   Hypothesis:  Higher Lp(a) level is independently associated with higher risk for atherosclerotic CVD [myocardial infarction (MI) and ischemic stroke] and death in CKD.   Methods:  The Chronic Renal Insufficiency Cohort (CRIC) is a prospective cohort study of adults with CKD. In primary analyses, we compared quartiles of Lp(a) with the risks for MI, ischemic stroke, and death using Cox proportional hazards regression. We used Fine and Gray methods to address potential effects of death as a competing risk in analyses of CVD events. In secondary analyses, we excluded participants with previous MI or stroke.   Results:  Among 3744 participants (55% men, 59% non-White) with mean age 57.7±11.0 years, 317 had an MI, 42 had an ischemic stroke, and 822 died over a median follow-up of 7.5 years. Participants were divided into quartiles of baseline Lp(a) levels (mg/dL):  61.3 (very high). The middle group was used as the reference category. After adjustment for age, sex, race and study site, the hazard ratio (HR, 95% CI) of CVD events and death for very high Lp(a) was 1.35 (1.13-1.61). After further adjustment for other potential confounders, very high Lp(a) remained significantly associated with death (HR 1.24, 1.01-1.54) as was high Lp(a) for MI (HR 1.44, 1.02-2.03). We did not find an association between Lp(a) level and ischemic stroke. In secondary analyses of 1100 participants with no prior history of CVD, very high Lp(a) was significantly associated with combined CVD events and death in the fully-adjusted model (HR 1.33, 1.02-1.73).   Conclusion:  High levels of Lp(a) in CKD are independently associated with higher risks for CVD and death.
Abstract 2296: Metformin reduces colon cancer risk in patients with type 2 diabetes: a retrospective cohort analysis
Authors: Chin-Hsiao Tseng
Journal: Cancer Research (2017)

Abstract Background: The effect of metformin on colon cancer is rarely investigated in Asian populations. Methods: This is a retrospective cohort study. Patients with newly diagnosed type 2 diabetes during 1999-2005 were recruited from Taiwan’s National Health Insurance. A 1:1 propensity score matched-pair sample of 16314 ever users and 16314 never users of metformin were followed until December 31, 2011. Cox regression incorporated with the inverse probability of treatment weighting using propensity score was used to estimate hazard ratios. Results: The incidence of colon cancer was 272.04 and 392.44 per 100,000 person-years, respectively, in ever and never users. The overall hazard ratio (0.691, 95% confidence interval: 0.578-0.826) suggested a significantly lower risk in metformin users. While compared to never users, the hazard ratio (95% confidence interval) for the first (&amp;lt;20.00 months), second (20.00-45.20 months) and third (&amp;gt;45.20 months) tertile of cumulative duration of metformin therapy was 1.455 (1.165-1.816), 0.683 (0.526-0.885) and 0.224 (0.152-0.331), respectively. The protective effect of metformin on colon cancer was not affected by the use of aspirin and statin or the infection of Helicobacter pylori in additional analyses. Conclusions: Metformin reduces colon cancer risk in patients with type 2 diabetes. The protective effect is more remarkable when the cumulative duration is more than 20 months. Citation Format: Chin-Hsiao Tseng. Metformin reduces colon cancer risk in patients with type 2 diabetes: a retrospective cohort analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2296. doi:10.1158/1538-7445.AM2017-2296
Abstract 84: CCN1/Cyr61 regulation of gemcitabine-resistant phenotype in pancreatic cancer: involvement of CTGF and dCK
Authors: Vijayalaxmi G. Gupta, Gargi Maity, Inamul Haque, Sushanta K. Banerjee, Snigdha Banerjee
Journal: Cancer Research (2017)

Abstract With an estimated half a million new cases and similar mortality rates for 2016, pancreatic ductal adenocarcinoma (PDAC) remains a life-threatening and challenging disease to diagnose and treat. As per American Cancer Society (ACS), varying efficacy in different patients has led to an increase in the mortality rate of PDAC. Gemcitabine (GEM) remains the drug of choice either alone or in combination, but is unsuccessful in reducing or curing PDAC in most patients. The limited efficacies of these drugs are due to the acquisition of chemo-resistant characteristics of PDAC. Although several molecular and physiological factors have been shown to correlate with the GEM-resistance, defined molecular mechanism(s) of GEM-resistance remains a mystery. Previous studies have shown that CCN1, which is overexpressed in PDAC and known to associate with PDAC progression, is critical for drug resistance. Here, we found that while the pancreatic cancer cell lines (i.e., Panc-1 and AsPC-1) in which CCN1 is overexpressed are typically GEM-resistant, the knocking down of CCN1 makes them sensitive to GEM. Mechanistic studies revealed that CCN1 regulates two important genes that are directly involved in regulation GEM-sensitivity in PDAC. These include cancer cell-secreted connective tissue growth factor (CTGF), a regulator of desmoplasia, and Deoxycytidine kinase (dCK), an enzyme that enhances gemcitabine sensitivity and efficacy in cancer cells. The deletion of CCN1 in PDAC cells blocks CTGF expression and under co-cultured conditions prevent the growth of alpha-smooth muscle actin (α-SMA)-positive stellate cells, which are required for desmoplastic growth in pancreatic cancers. CCN1 ablation upregulates dCK expression in PDAC cell lines as compared to CCN1 expressed PDAC cells. These two events enhance the anti-proliferative effect of GEM and can be rescued by CTGF-treatment or blocking dCK. In conclusion, CCN1 promotes GEM-resistance in PDAC cell through the regulation of CTGF and dCK and the mechanistic insights provided by these studies may help in designing future therapeutic strategies to combat PDAC. Citation Format: Vijayalaxmi G. Gupta, Gargi Maity, Inamul Haque, Sushanta K. Banerjee, Snigdha Banerjee. CCN1/Cyr61 regulation of gemcitabine-resistant phenotype in pancreatic cancer: involvement of CTGF and dCK [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 84. doi:10.1158/1538-7445.AM2017-84
Abstract LB-017: HSP110 sustains aberrant NFkB signaling in activated B-cell diffuse large B-cell lymphoma through MyD88 stabilization
Authors: Christophe Boudesco, Sebastien Causse, Arlette Hammann, Els Verhoeyen, Laurent Martin, Thierry Fest, Oliver Wolz, Alexander Weber, Carmen Garrido, Gaetan Jego
Journal: Cancer Research (2017)

Abstract Diffuse large B cell lymphoma (DLBCL) is an aggressive lymphoproliferative disorder of B lymphocytes accounting for 30 % of adult Non Hodgkin Lymphoma (NHL). Among DLBCL, Activated B Cell - DLBCL (ABC-DLBCL) is the most aggressive form and has a poor prognosis. Heat-shock proteins (HSPs) are molecular chaperons highly expressed in cancer cells and implicated in resistance to radio- and chemotherapy. Therefore, HSPs are envisioned as therapeutic targets in many cancers. Among the different HSPs, HSP110 has been recently identified as a pro-survival factor in germinal center-derived DLBCL (GC-DLBCL), through stabilization of the GC-DLBCL oncogene Bcl-6. Here, we have explored if HSP110 could also be involved in the survival of the most aggressive form of DLBCL. We observed a high HSP110 expression in all ABC-DLBCL patient samples, compared to normal reactive lymph nodes by using IHC staining of ABC-DLBCL tumor sections and transcriptional analysis of ABC-DLBCL patient tumors. Furthermore, shRNA silencing of HSP110 decreases the survival of several ABC-DLBCL cell lines, and downregulates the expression of pro-survival factors such as BcL2 and BcL-XL. SiRNA silencing of HSP110 abrogates NF-kB signaling, which is the major oncogenic pathway in ABC-DLBCL cell lines. In accord with these results, over-expression of HSP110 in DLBCL and non-DLBCL cell lines increases NF-kB signaling, indicating a tight interplay between HSP110 and the NF-kB pathway. Using immune-precipitation and DuolinkTM assays, we identified an in vitro and in cellulo interaction between HSP110 and Myd88, a critical protein of the NF-kB pathway that bears an activated mutation in many ABC-DLBC patients and that is responsible for lymphoma aggressiveness. Finally, we demonstrate that HSP110 stabilizes the wild type as well as the mutated form of Myd88, therefore facilitating the chronic NF-kB pathway activation in those cells. In conclusion, we identified HSP110 as a regulator of NF-kB signaling through MyD88 stabilization in ABC-DLBCL. This finding highlights HSP110 as a new potential therapeutic target in DLBCL. Citation Format: Christophe Boudesco, Sebastien Causse, Arlette Hammann, Els Verhoeyen, Laurent Martin, Thierry Fest, Oliver Wolz, Alexander Weber, Carmen Garrido, Gaetan Jego. HSP110 sustains aberrant NFkB signaling in activated B-cell diffuse large B-cell lymphoma through MyD88 stabilization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-017. doi:10.1158/1538-7445.AM2017-LB-017
Abstract 3: Targeting epigenetic modifiers in diffuse large B-cell lymphoma
Authors: Aarthi Goverdhan, Heng-Huan Lee, Mien-Chie Hung
Journal: Cancer Research (2017)

Abstract Diffuse Large B-Cell Lymphoma (DLBCL) is the most common type of Non-Hodgkin lymphoma, accounting for approximately 40% of all cases worldwide. In the last five years, researchers uncovered that DLBCL is characterized by widespread epigenetic deregulation. Lymphoma cells harbor loss-of-function mutations in transcriptional activators (KMT2D, EP300, CREBBP) and gain-of-function mutations in transcriptional repressors (EZH2). In our study, we aim to identify epigenetic vulnerabilities in lymphoma cells that can be targeted to deliver cytotoxic responses. We screened the therapeutic efficacy of a panel of lysine and arginine methyltransferase inhibitors in multiple lymphoma cell lines. Through these screens, we identified the Type I Protein Arginine Methyltransferase (PRMT) family as an attractive therapeutic target that induced cytotoxicity. Mechanistic dissection revealed that Type I PRMT inhibition caused apoptosis through deregulation of transcription factors and pro-survival genes. In addition, we uncovered novel crosstalk between PRMTs and other epigenetic modifiers that influenced cell fate in lymphoma. Our study demonstrates a critical role for Type I PRMTs in DLBCL, and adds a lucrative target to the growing list of promising epigenetics-based therapies. Citation Format: Aarthi Goverdhan, Heng-Huan Lee, Mien-Chie Hung. Targeting epigenetic modifiers in diffuse large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3. doi:10.1158/1538-7445.AM2017-3
Abstract 5061: TET inhibits prostate cancer tumor growth, progression and metastasis in TRAMP mice
Authors: Hari K. Koul, Prakash Srinivasan Timiri Shanmugam, Praveen K. Jaiswal, Sweaty Koul
Journal: Cancer Research (2017)

Abstract Introduction: Prostate cancer (PCa) is the 2nd most common malignancy in USA. Novel agents for treatment of advanced PCa are warranted. Transgenic adenocarcinoma of the mouse prostate (TRAMP) is an autochthonous mouse model exhibits both histological and morphological features that mimic human prostate carcinogenesis. Herein, for the first time, we evaluated the in vivo effects of TET, a derivative of Tetrandrine in TRAMP model. Methods: Beginning 12 weeks of age, male TRAMP mice were administrated with TET (30 mgm/kg body weight, orally, alternative days) in PBS or PBS alone (Control) till 30 weeks of age. Body weight (B) of animals was recorded weekly. At various time points animals were euthanized, genitourinary tract (G) were weighed. Prostate tissue was subjected to immunohistochemical analyses for SV40-TAg, epithelial-mesenchymal transition (EMT), proliferation, neuroendocrine differentiation (NED) and apoptosis. Multiple organs were examined for drug toxicity and lungs were analyzed for metastasis. Results: TRAMP mice exhibit to high-grade prostatic intraepithelial neoplasia (PIN) by 12 weeks and progresses to poorly differentiated adeno-carcinoma by 30 weeks with distant metastasis to lungs. TET feeding did not show any considerable difference body weight loss profiles during the entire treatment regimen. At the time of necropsy, there was no evidence of edema, abnormal organ size or appearance in non-target organs. TET gavage group showed (p&amp;lt;0.005) lower G/B ratio compared to the PBS treated group. These findings clearly indicate that TET dosing is non-toxic and restricts the abnormal growth of the prostate in TRAMP mice. TET repress the EMT as well as NED transition and inhibits cell proliferation (p&amp;lt;0.005) by Ki-67 staining. Oral administration of TET inhibits PCa growth and progression by increases (p&amp;lt;0.005) apoptosis in tumor tissues. Further, TET inhibited metastasis as there was significant (p&amp;lt;0.005) decrease in metastasis to lungs in TET treated animals. Conclusion: Human achievable dose of TET treatment to TRAMP mice bearing prostate tumor, exhibited no-observed-adverse-effect-level in toxicology evaluations and also significantly inhibited tumor growth, progression, local invasion and distant metastasis involving suppression of tumor, and thus could have potential against human PCa. Citation Format: Hari K. Koul, Prakash Srinivasan Timiri Shanmugam, Praveen K. Jaiswal, Sweaty Koul. TET inhibits prostate cancer tumor growth, progression and metastasis in TRAMP mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5061. doi:10.1158/1538-7445.AM2017-5061
Survival of patients with oligometastatic pancreatic ductal adenomacarcinoma treated with combined modality treatment including surgical resection: A pilot study.
Authors: Pujan Kandel, Kabir Mody, Horacio Asbun, John Stauffer, Candice W Bolan, Mellena D. Bridges, Timothy A Woodward, Massimo Raimondo, Victoria Gomez, Michael B Wallace
Journal: Journal of Clinical Oncology (2016)

e15690 Background: Limited data exists on the role of surgery in the management of oligometastatic PDAC. This study evaluated the overall survival in a highly selected group of patients with oligometastatic PDAC. Methods: This was case-control study, from 2005-2015, of patients with oligometastatic PDAC who underwent neoadjuvant chemotherapy, primary tumor resection and metastectomy and/or radiofrequency ablation of metastases (“M1 surgery” group). Cases and controls were matched for resectability status, T and N stage . Survival of cases (T3, N1, and oligo-M1) that underwent curative intent combined modality therapy was compared with two control groups: “M0 surgery” (T3, N1, M0) who underwent resection, and “M1 no surgery” group (T3, N1, M1) with oligometastatic PDAC who received palliative chemotherapy. Results: Forty two patients were included 6 (14%) “M1 surgery” cases, 18 (43%) “M0 surgery” and 18 (43%) “M1 no surgery” control patients. The median survival in the “M1 surgery”, “M0 surgery” and “M1 no surgery” groups were 2.7 yrs (95% CI 0.71- 3.69), 2.02 yrs (95% CI 0.98-3.05) and 0.98 yrs (95% CI 0.55-1.25) respectively. On univariate analysis there was no difference in overall survival comparing the “M1 surgery” and “M0 surgery” groups (log rank p = 0.6). ECOG status was associated with survival (p = 0.01). In multivariate analysis, surgically resected M1 patients had improved survival compared with non-surgical M1 and had similar survival to surgically resected M0 patients (Table 1) Conclusions: In this exploratory study, a highly selected group of oligometastatic PDAC patients treated at a high volume tertiary-care referral center benefitted from multimodal therapy. Further studies are warranted with larger sample sizes to confirm these preliminary findings. “M1 surgery” vs “M1 no surgery” group. HR (95% CI) P-value ECOG (ref = 0) 5.6 (1.4-21.8) 0.01 M1 no surgery ( ref = M1 surgery) 5.1 (1.4-32.9) 0.01 “M1 surgery” vs “M0 surgery” group. ECOG (ref = 0) 8.3 ( 1.9-34.3) 0.005 M1 surgery (ref = M0 surgery) 1.7 (0.5-5.8) 0.3 “M0 surgery
Abstract 4358: The immunomodulatory anticancer agent RRx-001 induces a vaccine-like interferon response through epigenetic induction of viral mimicry
Authors: Hongjuan Zhao, Shoucheng Ning, Rosalie Nolley, Jan Scicinski, Bryan Oronsky, Susan J. Knox, Donna M. Peehl
Journal: Cancer Research (2017)

Abstract RRx-001, sourced from the aerospace industry and currently in phase II clinical trials, is a novel anti-cancer agent that mediates immunomodulatory effects, either directly through polarization of tumor associated macrophages or indirectly through vascular normalization and increased T-lymphocyte infiltration. With multiple additional mechanisms of action including upregulation of oxidative stress, depletion of GSH and NADPH, anti-angiogenesis and epigenetic modulation, RRx-001 is being studied as a single chemotherapeutic agent to resensitize tumors to prior therapy and to prime tumors to respond to radiation, chemotherapy and immunotherapy in combination therapy studies. In this study, we identified another mechanism, viral mimicry, which refers to the ‘unsilencing’ of epigenetically repressed viral genes present in the tumor that provokes an immune response and may contribute to the anti-cancer activity of RRx-001. Specifically, RRx-001 inhibited the growth of human colon cancer cells (HCT 116) and decreased levels of the DNA methyltransferases Dnmt1 and Dnmt3a in a time and dose-dependent manner. Treatment of HCT 116 cells with 0.5 μM RRx-001 for 24 hours significantly increased transcripts of interferon (IFN)-responsive genes and this induction was sustained for up to 4 weeks after transient exposure to RRx-001. ELISA assays showed that RRx-001 increased secretion of type I and III IFNs by HCT 116 cells, and these IFNs were confirmed to be bioactive. Transcription of endogenous retroviruses was induced by RRx-001 through demethylation of the promoter of endogenous retrovirus genes as determined by methylation-specific polymerase chain reaction and combined bisulfite restriction analysis. Immunofluorescence staining with J2 antibody confirmed induction of double-stranded RNA. In conclusion, transient exposure of HCT 116 cells to low-dose RRx-001 induced transcription of silenced retroviral genes present in the cancer cell DNA with subsequent synthesis of IFN in response to this “pseudo-pathogenic” stimulus, mimicking an antiviral defense. RRx-001-mediated IFN induction may have the potential to improve the efficacy of immunotherapies as well as radiotherapy, standard chemotherapies and molecularly targeted agents when used in combination. Citation Format: Hongjuan Zhao, Shoucheng Ning, Rosalie Nolley, Jan Scicinski, Bryan Oronsky, Susan J. Knox, Donna M. Peehl. The immunomodulatory anticancer agent RRx-001 induces a vaccine-like interferon response through epigenetic induction of viral mimicry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4358. doi:10.1158/1538-7445.AM2017-4358