tbuckley/cabot-search huggingface dataset:
The cost-effectiveness of post-operative radiotherapy after breast conservation surgery in stage I-II breast cancer in Sweden
Authors: T. A. Alvegard, S. Borg, J. Ferras-Nunez, S. Franzen, A. Genell, P.-O. Malmström, U. Persson, A. Wallgren, A. Östlund
Journal: Journal of Clinical Oncology (2005)

805 Background: Adjuvant medical therapy as well as postoperative radiotherapy (RT) after breast conservation surgery is widely accepted as two measures to reduce the risk of local recurrences. However, when weighted against the incremental use of resources it is not obvious that the benefit of radiotherapy is cost-effective in Stages I-II breast cancer in Sweden. Methods: A stochastic decision analytic model follow patients from primary breast conservation therapy during adjuvant therapy and include five possible events of local or regional events, metastases and death. Clinical data were taken from a randomised clinical trial (SweBCG 91-RT) including 1,187 women aged 75 or younger who had received breast conservation surgery and axillary dissection in Sweden between 1991 and 1997 and with a median follow-up of five years. Data on health care costs were taken from a breast cancer register, a health care database including all hospital and primary care contacts in the West Healthcare Region. Costs for pharmaceuticals, hospice, homecare and values of utilities were taken from the literature. Results: Model results show a ten years risk of local and regional event of 24.1 and 8.4 percent for the no RT and RT groups, respectively. There was a significant increase in average Quality Adjusted Life Years (QALYs) of 0.13 (from 7.60 to 7.73) but no significant difference in average life expectancy. Treatment costs increased from SEK97,467 (€10,800) to SEK101,453 (€11,300) per patient. RT shows an incremental cost per QALY of SEK 32,000 (€3,600), which is well accepted in Sweden. Model applications for 15 and 20 years results in cost savings due to a larger amount of prevented relapses. Considering RT as an add-on to novel adjuvant medical treatments regimens will however, reduce the incremental benefit of radiotherapy and the subsequent cost offsets. Conclusions: Postoperative RT is cost-effective for pre- and postmenopausal breast cancer women with Stage I-II undergoing breast conservation therapy in Sweden only as an adjunction to no medical adjuvant treatment. As an adjunct to novel adjuvant medical therapies, RT is cost-effective in high-risk groups. 1,980 characters excluding authors names No significant financial relationships to disclose.
Bortezomib, Lenalidomide and Dexamethasone Vs. Lenalidomide and Dexamethasone in Patients (Pts) with Previously Untreated Multiple Myeloma without an Intent for Immediate Autologous Stem Cell Transplant (ASCT): Results of the Randomized Phase III Trial SWOG S0777
Authors: Brian Durie, Antje Hoering, S. Vincent Rajkumar, Muneer H. Abidi, Joshua Epstein, Stephen P. Kahanic, Mohan C. Thakuri, Frederic J Reu, Christopher M. Reynolds, Rachael Sexton, Robert Z. Orlowski, Bart Barlogie, Angela Dispenzieri
Journal: Blood (2015)
Abstract 763: Exosomal miR-6126 as a novel tumor suppressor in ovarian cancer
Authors: Pinar Kanlikilicer, Mohammed Mohammed H. S. Rashed, Recep Bayraktar, Rahul Mitra, Cristina Ivan, Burcu Aslan, Xinna Zhang, Rodriguez-Aguayo Cristian, Emine Bayraktar, Martin Picher, Bulent Ozpolat, George A. Calin, Anil K. Sood, Gabriel Lopez-Berestein
Journal: Cancer Research (2016)

Abstract Tumor microenvironment has been known to play a key role in cancer by the development of drug resistance, epithelial-mesenchymal transition, metastasis and angiogenesis. There is emerging evidence that cancer originated exosomes may contribute to the tumor microenvironment to promote tumorigenesis. Exosomes are nano-sized vesicles that contain non-coding RNAs such as miRNAs or siRNAs. Non-coding RNAs are involved in the pathogenesis of the majority of cancer and reveals a new layer of complexity in the molecular architecture of tumorigenicity. The purpose of this study is to identify miRNA content of both sensitive and resistant ovarian cancer-cell derived exosomes for the identification of exosomal RNA-mediated tumorigenesis in ovarian cancer. Using miRNA microarray profiling, we identified differentially expressed exosomal miRNAs in three sensitive (Heya8, Skov3, A2780) and resistant (Heya8-MDR, Skov3-TR, A2780-CP20) isogenic ovarian cancer cell lines. miR-6126 was found to be only miRNA significantly up-regulated in all cancer cell exosomes released to tumor microenvironment. In vitro functional assays showed that miR-6126 act as a tumor suppressor by inhibiting proliferation, migration, invasion and tube formation. miR-6126 acts as a novel potential tumor suppressor through targeting integrin beta-1, leading to inhibition of PI3K/AKT and Ras/Raf signaling. In vivo experiments also demonstrated that administration of miR-6126 into the nude mice with established tumors inhibited tumor weight. Immunohistochemistry results showed that miR-6126 treatment inhibits many oncogenic functions such as proliferation and angiogenesis of ovarian cancer. We believe that these findings help the identification of exosomal RNA-mediated tumorigenesis in ovarian cancer. Citation Format: Pinar Kanlikilicer, Mohammed Mohammed H. S. Rashed, Recep Bayraktar, Rahul Mitra, Cristina Ivan, Burcu Aslan, Xinna Zhang, Rodriguez-Aguayo Cristian, Emine Bayraktar, Martin Picher, Bulent Ozpolat, George A. Calin, Anil K. Sood, Gabriel Lopez-Berestein. Exosomal miR-6126 as a novel tumor suppressor in ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 763.
Abstract 346: Potential role for R191, potent and selective IRAK4 kinase inhibitor, in treatment of hematologic malignancies
Authors: Vadim V. Markovtsov, Chrystelle Lamagna, Meagan Chan, Sothy Yi, Chi Young, Roy Frances, Stacey Siu, Sylvia Braselmann, Hui Li, Rajinder Singh, Gary Park, Esteban Masuda, Vanessa Taylor, Donald G. Payan
Journal: Cancer Research (2016)

Abstract Recent advances in genome sequencing and tumor proteome and transcriptome analysis uncovered a key role for MyD88-dependent Toll-Like Receptor (TLR) and Interleukin-1 Receptor (IL-1R)-mediated signaling pathways in multiple hematologic malignancies. A third of activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL) and nearly 100% of Waldenstrom macroglobulinemia (WD) patients carry an activating Myd88 L265P mutation. Overexpression of multiple TLR pathway components, associated with deregulation of innate immune system and subsequent induction of proinflammatory bone marrow environment, are prominent features of myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). IRAK4 kinase is a crucial enzyme in all MyD88-dependent signaling pathways, potentially making it an ideal target for disease modification with small molecule inhibitors. Through cell-based screening, we identified a potent small molecule IRAK1/4 kinase inhibitor, R191. R191 blocks TLR- and IL-1R-induced cytokine production in primary cells with potencies below 50nM while sparing unrelated pathways with at least 20-fold window. R191 is extremely potent in vitro against IRAK4 kinase (3 nM), yet exhibits good selectivity against a broad panel of kinases. In vivo, it decreases serum IL-6 in an acute mouse model of IL-1β-induced cytokine release and blocks joint inflammation in the collagen-induce arthritis model. R191 exhibited strong synergy with Bcl2 and BCR pathway inhibitors against a number of DLBCL lines in vitro. In multiple AML lines, R191 potently inhibited expression of PD-L1, potentially promoting recognition of AML blasts by the immune system. Based on the potential critical role of IRAK kinases in MDS, AML and Myd88 L265P lymphomas, R191 could provide a novel therapeutic modality in the management of multiple inflammation-driven hematologic malignancies. Citation Format: Vadim V. Markovtsov, Chrystelle Lamagna, Meagan Chan, Sothy Yi, Chi Young, Roy Frances, Stacey Siu, Sylvia Braselmann, Hui Li, Rajinder Singh, Gary Park, Esteban Masuda, Vanessa Taylor, Donald G. Payan. Potential role for R191, potent and selective IRAK4 kinase inhibitor, in treatment of hematologic malignancies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 346.
Abstract 1353: Validation and implementation of screens for partial agonists and antagonists of the ErbB4/HER4 receptor tyrosine kinase: Targeted melanona drug discovery
Authors: Richard Cullum, Allan David, David J. Riese
Journal: Cancer Research (2016)

Abstract Introduction: Gain-of-function mutations in the gene encoding the ErbB4 (HER4) receptor tyrosine kinase have been detected in melanoma cell lines and these cell lines are dependent on ErbB4 expression for proliferation. Consequently, ErbB4 antagonists hold promise as targeted melanoma therapeutics and we have sought to identify small molecule ErbB4 antagonists. Our approach is based on the observation that the Q43L mutant of the ErbB4 peptide growth factor agonist Neuregulin 2beta (NRG2b) functions as a partial agonist at ErbB4; NRG2b/Q43L stimulates ErbB4 tyrosine phosphorylation, fails to stimulate ErbB4 coupling to cell proliferation, antagonizes stimulation of cell proliferation by ErbB4 full agonists, and causes ErbB4 down-regulation. Experimental procedures: We have developed a high-throughput screening (HTS) strategy that can be used to identify ErbB4 antagonists. The primary screen identifies molecules that stimulate ErbB4 tyrosine phosphorylation. The secondary screen distinguishes between molecules that stimulate and fail to stimulate ErbB4-dependent proliferation. The tertiary screen identifies molecules that antagonize agonist stimulation of ErbB4-dependent proliferation. Results: An phospho-ErbB4 sandwich ELISA assay identifies molecules that stimulate ErbB4 tyrosine phosphorylation with high sensitivity and fidelity (Z’ &amp;gt;0.5). MTT assays using a cell line that displays ErbB4-dependent proliferation distinguish between molecules that stimulate and fail to stimulate ErbB4-dependent proliferation (Z’&amp;gt;0.5) and identify molecules that antagonize agonist stimulation of ErbB4 dependent proliferation (Z’&amp;gt;0.5). These assays have been used to identify small molecules that stimulate ErbB4 tyrosine phosphorylation. Efforts to determine whether these hits function as ErbB4 full agonists or partial agonists (antagonists) are underway and will be reported. Structures of these small molecule ErbB4 full and partial agonists may be reported, pending submission of a provisional patent application. Conclusions: We have validated an HTS strategy for identifying ErbB4 partial agonists that function as ErbB4 antagonists and deployment of that strategy has led to the identification of several hits. Such molecules may hold promise as targeted therapeutics for melanoma and other ErbB4-dependent tumors. Citation Format: Richard Cullum, Allan David, David J. Riese. Validation and implementation of screens for partial agonists and antagonists of the ErbB4/HER4 receptor tyrosine kinase: Targeted melanona drug discovery. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1353.
Abstract 382: Concomitant administration of acid reducing agents can impact the pharmacokinetics of the balanced pan-PI3K and mTOR inhibitor PQR309
Authors: Karin Jorga, Eva Huehn, Grace Fraczkiewicz, Debora Schmitz, Doriano Fabbro, Sasa Dimitrijevic
Journal: Cancer Research (2016)

Abstract Introduction Acid reducing agents (ARAs) - such as proton pump inhibitors, H2-antagonists or antacids - are commonly prescribed medications to reduce stomach acidity in cancer patients. Increased gastric pH can significantly impair the dissolution of agents that exhibit pH-dependent solubility, thus possibly reducing their absorption and influence their pharmacokinetics (PK). PQR309 is a novel oral balanced dual pan-PI3K and mTOR inhibitor currently in clinical development for treatment of solid tumors and hematological malignancies. PQR309 is a weak base and exhibits pH-dependent solubility. Therefore, the assessment of the potential for drug-drug interactions with ARAs is essential to avoid treatment failure in cancer patients. Methods GastroPlusTM v.9.0 (Simulations Plus, Inc.) was used to build a physiologically-based absorption and pharmacokinetic (PBPK) model of PQR309. A baseline model was built with the physicochemical properties of the compound and pre-clinical PK data after iv and po administration. The model was then extended using PK data from cancer patients. Volume of distribution and renal clearance were calculated using the Lukacova and fup*GFR methods, respectively. Hepatic clearance was estimated from in vitro clearance obtained in hepatocytes and the intestinal absorption was calculated by the Advanced Compartmental Absorption and Transit (ACATTM) Model. Results The parameter sensitivity analysis showed that at fasted stomach pH of ∼1.5, PQR309 is fully dissolved and rapidly absorbed in the upper part of gastrointestinal tract leading to a distinct maximum plasma concentration (Cmax) and a predicted bioavailability of almost 100%. At a stomach pH of 4.0 dissolution is delayed and the absorption shifted towards distal parts of the gastrointestinal tract. The predicted bioavailability is still estimated to be good (&amp;gt; 75%), but the observed plasma concentration time profile is much shallower and the expected Cmax considerably reduced. Conclusions Our model predicts that concomitant administration of ARAs can impact PQR309 absorption and change its pharmacokinetic profile. The clinical relevance of this potential drug-drug interaction is unknown. In currently ongoing clinical studies co-medication of PQR309 with ARAs should be avoided until further clinical investigations confirm the model predictions and mitigation strategies are explored. Citation Format: Karin Jorga, Eva Huehn, Grace Fraczkiewicz, Debora Schmitz, Doriano Fabbro, Sasa Dimitrijevic. Concomitant administration of acid reducing agents can impact the pharmacokinetics of the balanced pan-PI3K and mTOR inhibitor PQR309. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 382.
Abstract 4598: Androgen receptor acetylation at K618 by ARD1 is essential for dissociation from HSP90 in prostate tumorigenesis
Authors: John S. DePaolo, Zehua Wang, Jianhui Guo, Guanyi Zhang, Haitao Zhang, Jovanny Zabaleta, Wanguo Liu
Journal: Cancer Research (2016)

Abstract Prostate cancer is an androgen receptor (AR)-driven disease and post-translational modification of AR is critical for its activation in both hormone-sensitive and castration-resistant disease. We previously reported that ARD1 is an oncoprotein in prostate cancer. It acetylates and activates AR to promote prostate tumorigenesis. However, the target residue within AR and the roles and mechanisms of the acetylation event in prostate tumorigenesis remained unknown. Here we show that ARD1 interacts with the AR DNA-binding domain and acetylates AR at lysine 618 (K618) in vivo and in vitro. Inhibition of K618 acetylation by replacing lysine with arginine significantly reduces AR transcriptional activity, prostate cancer cell growth, and xenograft tumor formation due to attenuation of AR nuclear translocation. Constitutive acetylation at K618 by replacing lysine with glutamine reverses these effects. Mechanistically, ARD1 forms a complex with both AR and HSP90. Expression of ARD1 increases levels of AR acetylation and AR-HSP90 dissociation in a dose dependent manner. Moreover, the AR acetylation-defective K618R mutant is unable to dissociate from HSP90 following ligand exposure, and HSP90-dissociated AR is acetylated. This work identifies a new mechanism for ligand-induced AR-HSP90 dissociation and AR activation. Targeting ARD1-mediated AR acetylation may be a potent intervention for AR-dependent prostate cancer therapy. Given that K618 is also present in AR variants, the significance of ARD1-dependent acetylation of AR variants for castration-resistant PCa will be discussed. Citation Format: John S. DePaolo, Zehua Wang, Jianhui Guo, Guanyi Zhang, Haitao Zhang, Jovanny Zabaleta, Wanguo Liu. Androgen receptor acetylation at K618 by ARD1 is essential for dissociation from HSP90 in prostate tumorigenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4598.
Abstract 516: The mechanism associated with radio-resistant renal cell carcinoma and its targeting strategy
Authors: Eun-Jin Yun, Chun-Jung Lin, Debabrata Saha, Jer-Tsong Hsieh
Journal: Cancer Research (2016)

Abstract Introduction and Purpose: Although ionizing radiation (IR) represents an effective regimen for most solid tumors, renal cell carcinoma (RCC) is known to be highly radio-resistant and the underlying mechanisms associated with IR-resistance remained elusive. In this study, we unveiled the factors associated with IR-resistance and the potential targeting strategy. Experimental procedures: Several RCC sublines were generated with different genetic manipulation and cells were irradiated with different doses and the surviving fractions were evaluated in 7 days. To investigate the underlying mechanism, various biochemical and molecular biologic methods, such as quantitative real-time PCR, mass-spectroscopy (MS), immunoprecipitation (IP), western blot, and ELISA were performed. Results: DAB2IP (DOC-2/DAB2 interactive protein) known as a tumor suppressor that functions as a scaffold protein modulating many signal pathways associated cell growth/survival, apoptosis/autophage, and cell migration/invasiveness. In RCC, the status of DAB2IP has not been characterized. We found DAB2IP was frequently lost in RCC; more than 50% in every subtype of RCC. We observed that DAB2IP-deficient RCC cells exhibited IR-resistance whereas re-introduction of DAB2IP could sensitize RCC cells to IR. From MS and IP, it appeared that DAB2IP could directly interact with poly (ADP-ribose) polymerase-1 (PARP-1). In the presence of DAB2IP, PARP-1 activities were suppressed because DAB2IP was able to induce PARP-1 protein degradation via unique proteasome pathway. Since PARP-1 is commonly involved in many cellular functions such as DNA damage repair or transcription modulation, which is also considered as a therapeutic target particularly IR therapy. In this study, elevated PARP-1 led to rapid DNA repairing and IR resistance in DAB2IP-expressing RCC cells. In contrast, by knocking-down PARP-1 in DAB2IP-deficient RCC cells can sensitize cells to IR, suggesting that PARP-1 inhibitors can be a potential radio-sensitizer. Conclusion: In summary, this study demonstrates a new functional role of DAB2IP in IR-resistant RCC cells via modulating PARP-1 expression and activities. Therefore, targeting PARP-1 by small molecular inhibitor or gene therapy becomes a potential therapeutic strategy to overcome IR resistant RCC. Citation Format: Eun-Jin Yun, Chun-Jung Lin, Debabrata Saha, Jer-Tsong Hsieh. The mechanism associated with radio-resistant renal cell carcinoma and its targeting strategy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 516.
Abstract 5059: Cancer cell invasion dynamics in microchannels during stromal cell coculture
Authors: Andrew W. Holle, Verena Kast, Ralf Kemkemer, Joachim Spatz
Journal: Cancer Research (2016)

Abstract Metastasizing cancer cells must escape their tumor microenvironment and invade into surrounding healthy stromal tissue. During this process, they must balance intercellular crosstalk with ECM degradation, physical force generation, and cytoskeletal rearrangement. To mimic this process in vitro, PDMS microchannels fabricated with photolithography and replica molding were used to examine the interaction of cancer cells with healthy stromal cells during physical confinement in three dimensional environments. A focus was placed on understanding the variations in invasion behavior between healthy cells and cancer cells, then attempting to explain these differences by cell mechanical properties and gene expression. Distinct differences in cancer cell invasion characteristics were observed between wide 10 μm channels and narrow 3 μm channels, with the latter exhibiting smooth velocity profiles and increased channel permeation. Live cell actin staining, ECM protein alteration, and chemical inhibition of both Rac1 and RhoA mechanical pathways were all used to better understand these differences, leading to the conclusion that the actin cytoskeleton is greatly altered during invasion into very confined channels. To better understand the role of stromal cells in this process, both indirect and direct coculture of MDA MB-231 basal breast cancer cells and stromal cells were performed in microchannel chips with the aid of live cell permeable tracking dyes. To reflect a diverse range of stromal cell types, cocultures were performed with MCF 10A non-tumorigenic breast epithelial cells, macrophage-differentiated THP-1 monocytes, and HN-CAFs (head and neck carcinoma-associated fibroblasts). Both the cancer cells and the stromal cells exhibited increases in invasion speed upon direct co-culture of the two cancer cell lines, both in wide and narrow channels. The use of stromal cell-conditioned media as well as observed differences in migration speed and persistence when unconfined provided further understanding of the complex processes underlying cancer cell and stromal cell invasion. Citation Format: Andrew W. Holle, Verena Kast, Ralf Kemkemer, Joachim Spatz. Cancer cell invasion dynamics in microchannels during stromal cell coculture. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5059.