tbuckley/cabot-search huggingface dataset:
Abstract 130: Discovery and characterization of small molecules targeting the DNA-binding ETS domain of ERG in prostate cancer
Authors: Miriam S. Butler, Mani Roshan-Moniri, Michael Hsing, Desmond Lau, Ari Kim, Paul Yen, Marta Mroczek, Mannan Nouri, Scott Lien, Peter Axerio-Cilies, Kush Dalal, Clement Yau, Fariba Ghaidi, Yubin Guo, Takeshi Yamazaki, Sam Lawn, Martin Gleave, Cheryl Y. Gregory-Evans, Lawrence P. McIntosh, Paul S. Rennie, Artem Cherkasov, Michael E. Cox
Journal: Cancer Research (2017)

Abstract Genomic alterations involving translocations of the ETS-related gene ERG occur in approximately half of prostate cancer cases. These alterations result in aberrant, androgen-regulated production of ERG protein variants that directly contribute to disease development and progression. This study describes the discovery and characterization of a new class of small molecule ERG antagonists identified through rational in silico methods. These antagonists are designed to sterically block DNA binding by the ETS domain of ERG and thereby disrupt transcriptional activity. We confirmed the direct binding of a lead compound, VPC-18005, with the ERG-ETS domain using biophysical approaches. We then demonstrated VPC-18005 reduced migration and invasion rates of ERG expressing prostate cancer cells, and reduced metastasis in a zebrafish xenograft model. These results demonstrate proof-of-principal that small molecule targeting of the ERG ETS domain can suppress transcriptional activity and reverse transformed characteristics of prostate cancers aberrantly expressing ERG. Clinical advancement of the developed small molecule inhibitors may provide new therapeutic agents for use as alternatives to, or in combination with, current therapies for men with ERG-expressing metastatic castration-resistant prostate cancer. Citation Format: Miriam S. Butler, Mani Roshan-Moniri, Michael Hsing, Desmond Lau, Ari Kim, Paul Yen, Marta Mroczek, Mannan Nouri, Scott Lien, Peter Axerio-Cilies, Kush Dalal, Clement Yau, Fariba Ghaidi, Yubin Guo, Takeshi Yamazaki, Sam Lawn, Martin Gleave, Cheryl Y. Gregory-Evans, Lawrence P. McIntosh, Paul S. Rennie, Artem Cherkasov, Michael E. Cox. Discovery and characterization of small molecules targeting the DNA-binding ETS domain of ERG in prostate cancer [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 130. doi:10.1158/1538-7445.AM2017-130
Abstract 1820: Synergistic lethality of mAbs with an EMT reversal agent, Nintedanib, in epithelial ovarian cancer
Authors: Jocelyn Teo, Heng Liang Tan, Ruby Yun-Ju Huang, Andre Choo
Journal: Cancer Research (2017)

Abstract Epithelial-mesenchymal transition (EMT) has long been associated with cancer progression and metastasis. As a reversible process, it has the potential to be a target for cancer therapy. However, this concept of reversing EMT has not yet been widely explored in current treatment strategies. With the identification of Nintedanib as an EMT reversal agent, we aim to broaden the utility of this triple angiokinase inhibitor by identifying agents that show synergistic lethality with it, using monoclonal antibodies (mAbs) as a combinatory therapeutic. Nintedanib alone is not significantly cytotoxic to cells, but it causes cell cycle arrest and reverses EMT. By selecting for this sub-population of cells that are sensitive to Nintedanib, their subsequent eradication can then be more intricately directed. Since the anti-cancer application of EMT reversal agents are not fully developed, it is vital to investigate mechanisms that sensitize cancer cells to cytotoxic agents following EMT reversal.Our group has generated panels of mAbs that are able to bind differentially to various breast and ovarian cancer cell lines along the EMT spectrum. Some mAbs preferentially bind to Epithelial lines, while some have stronger affinity to Mesenchymal lines. This implies that mAbs have the ability to differentiate between epithelial and mesenchymal phenotypes, uncovering a new dimension to the capability of mAbs which have yet to be explored.Using a mesenchymal ovarian cancer cell line as a starting model, Nintedanib-treated cells were screened with the mAbs and those showing a &amp;gt;2-fold increase in binding were shortlisted for further validation. Based on this criteria, 26 mAbs were identified and further characterized in functional Antibody Drug Conjugate (ADC) assays with mAbs conjugated to a toxic drug, Saporin (or Zap). Mabs successfully internalizing and killing the cancer cells will then be further chosen for antigen characterization and in vivo functional studies. Ultimately, there is huge potential for mAbs to be discovered that shows synergy with Nintedanib to enhance lethality to various types of cancer cells. A novel clinical strategy, the application of EMT reversal in terms of utilising a synthetic lethality-like approach allows better design of combinatory therapeutics, increasing treatment efficacy that might revolutionalise cancer treatment. Citation Format: Jocelyn Teo, Heng Liang Tan, Ruby Yun-Ju Huang, Andre Choo. Synergistic lethality of mAbs with an EMT reversal agent, Nintedanib, in epithelial ovarian cancer [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 1820. doi:10.1158/1538-7445.AM2017-1820
Abstract 246: Assessing microbial dysbiosis of electronic cigarettes and cigarette smokers using oral and lung microbiome
Authors: Kevin Ying, Min-Ae Song, Daniel Y. Weng, Quentin Nickerson, David Frankhouser, Pearlly S. Yan, Ralf Bundschuh, Mark D. Wewers, Ewy Mathé, Jo L. Freudenheim, Peter G. Shields
Journal: Cancer Research (2017)

Abstract The link between smoking tobacco and changes in the oral microbiome in response to tobacco smoking are well established. It is not known if there are changes in response to electronic cigarettes (e-cig). These changes in the microbiome are associated with increased numbers of disease causing pathogens. Currently there are no published studies that have investigated the relationship of smoking tobacco on both the oral and lung microbiome. There is insufficient evidence showing whether changes in oral cavity and lung microbiome are also seen in e-cig users. We will study the oral cavity and lung of non-smokers, smokers and e-cig users to examine concordance between oral cavity and the lungs as well as comparing the three groups, examining the microbiomes and expression of inflammatory markers. We hypothesize that microbial dysbiosis and expression of inflammatory cytokines will differ for smokers and non-smokers; and that e-cig users will have microbial dysbiosis similar to cigarette smokers. A cross-sectional study is being conducted on three groups, 1) never-smokers, 2) cigarette smokers, and 3) e-cig users. For each study participant, saliva and bronchoalveolar lavage (BAL) are being collected to measure microbiome. RNA is extracted from saliva and BAL samples for total transcriptome analysis using RNA-seq. This analysis will detect human and bacterial reads thereby allowing observations of bacterial communities as well as human inflammatory cytokine response to bacterial presence. 85% to 98% of BAL sample reads aligned to the human genome compared to less than 50% from saliva samples. The alignment results allow us to deduce that the majority of reads from BAL samples are human and that the majority of the reads in saliva samples are bacterial. Preliminary results show detection of human RNA expression and of bacterial reads are present in both saliva and BAL samples. More samples are being processed and the comparison of BAL and saliva samples between the three groups will be discussed. Citation Format: Kevin Ying, Min-Ae Song, Daniel Y. Weng, Quentin Nickerson, David Frankhouser, Pearlly S. Yan, Ralf Bundschuh, Mark D. Wewers, Ewy Mathé, Jo L. Freudenheim, Peter G. Shields. Assessing microbial dysbiosis of electronic cigarettes and cigarette smokers using oral and lung microbiome [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 246. doi:10.1158/1538-7445.AM2017-246
Abstract 2350: In vivo E2F reporting on efficacious dosing schedules of MEK plus CDK4/6 inhibition in melanoma
Authors: Jessica Teh, Neda Nikbakht, Timothy Purwin, Inna Chervoneva, Prem Patel, Michael Davies, Andrew Aplin
Journal: Cancer Research (2017)

Abstract Pharmacological targeting of cyclin dependent kinases 4 and 6 (CDK4/6) could represent a viable therapeutic option in combination with BRAF and/or MEK inhibitors in different genetic subsets of melanoma. Indeed, continuous and concurrent dosing of MEK inhibitor (MEKi) plus a CDK4/6 inhibitor (CDK4/6i) leads to melanoma regressions in in vivo models and delays the onset of MEKi resistance. Current scheduling in breast cancer patients for the CDK4/6i, palbociclib, is intermittent due to adverse effects resulting in neutropenia. It is unclear what the most efficacious schedules are of palbociclib plus a MEKi. Utilizing an E2F reporter system, we sought to analyze the efficacy of different CDK4/6i plus MEKi schedules in a quantitative and temporal manner. Intermittent dosing (3 weeks on/1 week off) of both CDK4/6i and MEKi combination therapy resulted in tolerant tumors and rapid reactivation of E2F activity during drug holiday. Continuous MEKi with intermittent CDK4/6i led to more complete responses as compared to continuous CDK4/6i with intermittent MEKi. Weight loss of mice was also evident in the continuous CDK4/6i plus intermittent MEKi arm suggesting adverse events related to continuous CDK inhibition. Importantly, functional proteomic analysis revealed distinct mechanisms of acquired resistance/drug tolerance that arose from the three scheduling arms. Here, we report that upregulation of S6 phosphorylation is associated with acquired resistance to MEK plus CDK4/6 inhibition and can be overcome with an mTOR inhibitor. Taken together, in vivo reporting allows for quantitative measurement of pathway activity associated with inhibitor resistance and can be utilized to optimize combination schedules to improve the therapeutic index in patients. Citation Format: Jessica Teh, Neda Nikbakht, Timothy Purwin, Inna Chervoneva, Prem Patel, Michael Davies, Andrew Aplin. In vivo E2F reporting on efficacious dosing schedules of MEK plus CDK4/6 inhibition in melanoma [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 2350. doi:10.1158/1538-7445.AM2017-2350
Abstract 1210: Hederagenin overcomes the cisplatin resistance of head and neck cancer by targeting the antioxidant defense mechanisms
Authors: Daiha Shin, Eun Hye Kim, Hyejin Jang, Jaewang Lee, Ji Won Kim, Jae Ryung Lee, Minsu Kwon, Seungho Baek, Jong-Lyel Roh
Journal: Cancer Research (2017)

Abstract Background: Cisplatin is a first-line chemotherapeutic agent for head and neck cancer (HNC). Acquired resistance to cisplatin is the most common reason for the failure of cisplatin chemotherapy. Hederagenin is extracted from the leaves of Cyclocarya paliurus, also known as sweet tea, which is one of the most popular teas utilized in traditional Chinese medicine. There is accumulating evidence it exhibited significant cytotoxicity against several types of cancers, however, which has been rarely tested in HNC cells. Herein, we examined the potential utility of hederagenin for overcoming cisplatin resistance in HNC cells and further clarified its molecular mechanisms of action. Methods: Parental and cisplatin-resistant HNC cells, and Nrf2 or SLC7A11 gene overexpressed HNC cell lines and other human HNC cells were used. The cells were used to examine the effects of hederagenin treatment in HNC cell lines by measuring cell viability, cell cycle, cell death, reactive oxygen species (ROS) production, glutathione level, mitochondrial membrane potential (ΔΨm), and protein expression. The anti-tumor effect of hederagenin in mouse tumor xenograft models was also tested. Results: Hederagenin induced cell death in both cisplatin-sensitive and -resistant HNC cells. Hederagenin treatment resulted in effective death of cisplatin-resistant HNC cells in a form of apoptotic cell death with the ΔΨm change. Hederagenin inhibited Nrf2 and SLC7A11 resulting in an increased ROS accumulation in HNC cells, of which effects were reversed by the pretreatment of antioxidant trolox. In addition, hederagenin caused the apoptosis effectively induced by targeting the antioxidant defense mechanisms in HNC cells. Subsequently, hederagenin activated signaling pathways of cell death involving caspase-3, PUMA, and PARP in the cells. The growth inhibitory effects of hedragenin were also confirmed in the tumor xenograft model implanted with cisplatin-resistant HNC cells. Conclusions: Our data suggests that hederagenin can overcome the resistance of cisplatin in resistant HNC cells via targeting antioxidant systems. Citation Format: Daiha Shin, Eun Hye Kim, Hyejin Jang, Jaewang Lee, Ji Won Kim, Jae Ryung Lee, Minsu Kwon, Seungho Baek, Jong-Lyel Roh. Hederagenin overcomes the cisplatin resistance of head and neck cancer by targeting the antioxidant defense mechanisms [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 1210. doi:10.1158/1538-7445.AM2017-1210
Abstract 5562: Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer: a pilot multidisciplinary study
Authors: Jingsong Zhang, Jessica J. Cunningham, Joel S. Brown, Robert A. Gatenby
Journal: Cancer Research (2017)

Abstract Background: Prior studies have investigated “intermittent therapy” to delay hormone resistance in prostate cancer but did not explicitly include quantitative analysis of the evolutionary dynamics. We hypothesize that evolution-informed strategies may prolong time to progression but require a multidisciplinary effort to simulate intratumoral Darwinian dynamics and design a clinically feasible treatment protocol. Methods: We investigate intratumoral evolutionary dynamics during treatment of metastatic castrate resistant prostate cancer (mCRPC) with abiraterone, which blocks CYP17A1 autosynthesis of testosterone from endocrine precursors. We build a mathematical model assuming three competing phenotypes: (i) TP cells express CYP17A1 and produce testosterone; (ii) T+ cells require exogenous androgen; and (iii) T- cells are androgen-independent and resistant to abiraterone. Model predictions were tested in a pilot clinical trial. Results: Mathematical Model: Computer simulations demonstrate continuous maximum dose abiraterone treatment produces competitive release of resistant T- cells. However, limited treatment designed to maintain residual TP and T+ populations and suppress proliferation of T- cells was predicted to prolong response while lowering the required drug dose. Clinical Trial: In a pilot clinical trial, 11 men with asymptomatic mCRPC were treated with abirateone according to an evolution-informed, patient-specific algorithm based on the modeling results. Pre-treatment biopsies (available for 3 patients) demonstrated the predicted tumor subpopulations. Cycles of response and regrowth similar to model simulations were observed with cycle lengths varying from 3 months to &amp;gt; 1 year. Over a median follow up period of 18 months, 10 subjects remain responsive to Abiraterone without PSA or radiographic progression. Median time to PSA progression significantly (P&amp;lt;0.001) exceeds the 11.1 months historical control. As predicted by the simulations, tumor control required significantly less abiraterone with average cumulative dose less than 40% of standard of care (P&amp;lt;0.001). Conclusion: Integration of mathematical models and Darwinian first principles into trial design, may allow patient-specific modifications to prolong response while lowering drug doses in mCRPC. Citation Format: Jingsong Zhang, Jessica J. Cunningham, Joel S. Brown, Robert A. Gatenby. Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer: a pilot multidisciplinary study [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 5562. doi:10.1158/1538-7445.AM2017-5562
Abstract 5230: Targeting two unique end-insertion G-quadruplexes formed in the 3′-end of the PDGFR-β core promoter nuclease hypersensitive element with ellipticine analog
Authors: Buket Onel, Prashansa Agrawal, Megan Carver, Laurence H. Hurley, Danzhou Yang
Journal: Cancer Research (2017)

Abstract Aberrant expression of PDGFR-β promotes multiple hallmarks of cancer, and its transcriptional regulation provides an attractive means to inhibit the PDGFR-β signaling pathway. The nuclease hypersensitive element (NHE) region of the human PDGFR-β core promoter has been shown to be responsible in regulating approximately 60% of the PDGFR-β basal promoter activity. Multiple overlapping G-quadruplexes (G4s) have been shown to form in this NHE region. We previously determined the most stable G4 structure formed in the 5’-mid of PDGFR-β NHE region. Significantly, an ellipticine analog, GSA1129, has been shown to selectively bind to the G4 formed in the 3’-end NHE region, thereby shifting the dynamic equilibrium toward the 3’-end G4. This selective interaction was shown to result in suppression of PDGFR-β activity in both cancer cell lines and a preclinical animal model. Thus, characterization of 3’-end G4 provides an important basis for understanding the molecular recognition of this G4 and for rational drug design. In this study, we used NMR spectroscopy to show that the PDGFR-β NHE 3′-end sequence forms two novel end-insertion intramolecular G4s which exist in a dynamic equilibrium under physiological salt condition. One is the 3′-insertion-G4 with a 3′ non-adjacent flanking guanine inserted into the 3′-external tetrad. The other is a 5′-insertion-G4 with a 5′ non-adjacent flanking guanine inserted into the 5′-external tetrad. We further confirmed that these novel end-insertion G4s can readily form in the 3’-end NHE sequence under physiologically relevant ionic conditions using dimethyl sulfate (DMS) footprinting experiments. To elucidate the molecular interactions of ellipticine analog with the 3’-end G4s, we studied the binding of GSA1129 to both of the end-insertion G4s. Significantly, our CD melting studies showed that GSA1129 markedly increased the stability of both end-insertion G4s by about 25°C. Furthermore, 1H NMR titration experiments have shown that GSA1129 selectively binds to the G4 formed in the 3’-end NHE region. The novel end-insertion structures and the dynamic nature of the PDGFR-β NHE 3′-end G4 may make it an effective target for GSA1129 binding and regulation. Our result highlights the dynamic nature of the PDGFR-β NHE 3′-end sequence and the importance of identifying the exact sequence for the formation of the naturally occurring G4 structure. Citation Format: Buket Onel, Prashansa Agrawal, Megan Carver, Laurence H. Hurley, Danzhou Yang. Targeting two unique end-insertion G-quadruplexes formed in the 3′-end of the PDGFR-β core promoter nuclease hypersensitive element with ellipticine analog [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 5230. doi:10.1158/1538-7445.AM2017-5230
Abstract 3213: Antagonism of D2-like dopamine receptors plays a role in Onc201’s anticancer effects
Authors: Christina Leah B. Kline, Amriti Lulla, Jessica Wagner, David Dicker, Marie Baumeister, Sophie Oster, Wafik El-Deiry
Journal: Cancer Research (2017)

Abstract ONC201/TIC10 is a first-in-class small molecule inducer of TRAIL that causes early activation of the integrated stress response and inactivates both Akt and ERK. Its promising safety profile and broad spectrum efficacy in vitro has been confirmed in Phase I/II trials in several advanced malignancies. Biochemical and reporter assays have shown that ONC201 is a selective and competitive antagonist of the D2-like receptors, specifically, dopamine receptor D2 (DRD2) and dopamine receptor D3 (DRD3) with a KD value of ~3 µM. The theme that dopamine and dopamine receptors are important in cancer has emerged in the literature. We hypothesize that ONC201’s interaction with DRD2 is critical for ONC201’s anticancer effects. Co-treating HCT116 and RKO colorectal cancer cells with ONC201 and dopamine or the selective D2-like receptor agonist sumanirole partially abrogated ONC201-induced ATF4/CHOP expression and apoptosis. Knocking down DRD2 expression using siRNA negated ONC201’s effects on viable cell count. Overexpressing DRD2 in a cancer cell line that has very low levels of DRD2, increased ONC201-induced PARP cleavage. Quantitative RT-PCR analyses showed that cells that have acquired resistance to ONC201 did not express detectable mRNA levels of the D2-like receptors. To further determine the anti-tumor potential of targeting the D2-like receptor, we treated different cancer cell lines with other D2-like receptor antagonists. Similar to ONC201, the D2-selective antagonist L-741,626 decreased cell viability and induced apoptosis in a number of cancer cell lines. In contrast to ONC201, however, L-741,626 has a poor therapeutic index. Our findings show that the ability of ONC201 to inhibit D2-like receptors contributes to ONC201’s antiproliferative and pro-apoptotic activity. Ongoing work is aimed at elucidating the mechanisms by which antagonism of D2-like receptors can promote apoptotic cell death, especially with regard to ATF4/CHOP/DR5 and Akt/ERK/Foxo3a/TRAIL, which have been shown to be stimulated in ONC201-treated and -sensitive tumor cells. Citation Format: Christina Leah B. Kline, Amriti Lulla, Jessica Wagner, David Dicker, Marie Baumeister, Sophie Oster, Wafik El-Deiry. Antagonism of D2-like dopamine receptors plays a role in Onc201’s anticancer effects [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 3213. doi:10.1158/1538-7445.AM2017-3213
Thyroid Metastasis as First Manifestation of a Colon Adenocarcinoma With KRAS Mutation
Authors: Beatriz Lecumberri, Elena López, Mónica Coronado, Sonia Rodado, Beatriz Castelo
Journal: Clinical Nuclear Medicine (2017)

The synchronous diagnosis of a thyroid metastasis and of the primary colon adenocarcinoma that produces it is very rare, with only 5 cases reported to date, all of them treated with thyroid surgery showing a mean survival of 7 months. An ¹⁸F-FDG PET/CT in an asymptomatic 74-year-old woman with a thyroid cytology suggestive of malignancy but uncertain about the origin of the tumor revealed an stage IV colon adenocarcinoma with KRAS mutation and multiple metastasis (thyroid, lung, and liver). A prompt therapeutic planning with chemotherapy allowed 21 months of survival.